COMMENTARY

Outpatient Strategies for COVID-19 Therapy: Clinical Equipoise in Defense of Pascal

Jan E. Patterson, MD, MS; Ruth E. Berggren, MD

Disclosures

December 23, 2020

A few weeks ago, Medscape published an opinion piece regarding supplements for COVID-19, which we read with great interest. In it, the choice to concede to a patient's request to take a supplement that has some biological plausibility or preliminary evidence and a good safety profile is portrayed as akin to Pascal's Wager. This is the 17th century philosopher's view that it is not harmful to believe in God and may be beneficial, so why not do it?

The author argues that this philosophy breaks down if the wrong god is chosen, and that this is similar to taking multiple agents for COVID-19 because they could be the wrong one(s) and/or could be antagonistic to another agent. The conclusion was that waiting for evidence from a randomized controlled trial (RCT) is best.

We believe in the RCT, and our center participates in COVID-19 RCTs that are generating evidence for hospitalized patients. However, to date, RCT evidence for outpatient therapy lags behind that for inpatient therapy, and the public is concerned about the lack of direction for early therapy of COVID-19.

Currently, there are no oral therapies for COVID-19 approved by the US Food and Drug Administration (FDA). The National Institutes of Health (NIH) and Infectious Diseases Society of America (IDSA) guidelines recommend against therapies not FDA-approved for COVID-19 outside of a clinical trial. Recently, two monoclonal antibody intravenous preparations for COVID-19 outpatients at high risk for disease progression received emergency use authorization from the FDA. They are, however, currently scarce and challenging to administer.

Meanwhile, COVID-19 outpatients and their providers are seeking guidance for symptom mitigation and disease management with increasing urgency as the pandemic surges. Some potentially harmful agents for which there is now negative evidence continue to be used.

In the setting of uncertainty, clinical equipoise requires balancing the avoidance of harm with the obligation to provide comfort and relieve suffering. In the interest of patient-centered care, we discuss some outpatient options that have good safety profiles, biological plausibility, and/or preliminary evidence, with various mechanisms of action that are unlikely to be antagonistic. We also address at-home supplies and warning signs, which have not been emphasized sufficiently in outpatient management recommendations.

Starting With the Basics

Patients should remain in isolation for 10 days after onset of symptoms and 24 hours after resolution of fever. A thermometer, pulse oximeter, and blood pressure cuff are valuable to have at home. Acetaminophen and NSAIDs can be used for fever. Inhaled tobacco products or vaping should be discontinued.

Advise patients about warning signals to come to a healthcare facility for evaluation, including an oxygen saturation < 94% at rest, a significant decrease in oxygen saturation upon walking, persistent shortness of breath, decreased mental status, or significant decrease in blood pressure.

Supplements and Other Strategies 

Zinc may prevent viral entry into cells and decrease virulence. Zinc lozenges, which potentially provide direct protection in the upper respiratory tract, have been shown to reduce the severity and duration of common cold symptoms when initiated within 24-48 hours of symptom onset. NIH guidelines recommend not exceeding the recommended daily allowance in daily dosage because long-term use of high doses can cause gastrointestinal side effects and copper deficiency.

Vitamin D is known to enhance the immune system. It can also be an immune modulator and may help reduce the inflammatory response to SARS-CoV-2. In addition, vitamin D deficiency has been associated with worse outcomes in COVID-19. Supplementation may be helpful for patients at risk for both vitamin D deficiency and poor outcomes from COVID-19 (ie, older patients, persons with melanin-rich skin). A safe dose is 2000-4000 IU daily.

Melatonin is an antioxidant and anti-inflammatory agent known to inhibit NLRP3 inflammasome activation and NFkB activation. Although commonly used as a supplement for insomnia, it can also reduce recruitment of inflammatory cells in viral infections and reduce oxidative lung injury. Pineal melatonin production is decreased in older adults, who are already at higher risk for severe COVID-19 illness.

A 3-mg dose at night is usually well tolerated. If morning grogginess occurs, a lower dose of 0.5 mg in liquid form can be used.

Prone positioning has been shown to improve oxygenation and has been used in patients who are hospitalized or in the emergency department. Any patient with significant oxygen desaturation should come to a healthcare facility for evaluation, but a cooperative patient with mild oxygen desaturation could benefit from this strategy at home.

Over-the-Counter Medications

Acetylsalicylic acid. Thrombotic complications of COVID-19 in patients with moderate to severe disease are well known. Hospitalized adults receive venous thromboembolism prophylaxis, and those with a thromboembolic event should receive therapeutic anticoagulation. However, venous thromboembolism prophylaxis is not recommended in nonhospitalized patients unless there are other indications.

Acetylsalicylic acid therapy has been considered in this patient population because of its oral form and anti-inflammatory and antithrombotic properties. In a retrospective study, acetylsalicylic acid given within 24 hours of admission or 7 days before admission was associated with a decreased risk for mechanical ventilation support, ICU admission, and in-hospital mortality. There were no differences in bleeding episodes or thrombosis.

Aspirin must be avoided in children because of the risk for Reye's syndrome.

Famotidine is a histamine-2 receptor antagonist available in 20-mg tablets for the prevention and relief of acid indigestion. Early studies suggested that COVID-19 patients taking famotidine had improved clinical outcomes. Although the mechanism is unknown, preventing histamine release may modulate the cytokine storm in the hyperinflammatory phase of COVID-19. A retrospective study documented lower mortality and combined rates of death or intubation. These findings warrant further study. The drug is well tolerated and has a good safety profile.

Prescription Medications

Corticosteroids. Although dexamethasone was shown by the RECOVERY trial to reduce mortality in patients with COVID-19 requiring oxygen, patients who did not require oxygen did not benefit. Given the potential deleterious effects of steroids, such as glucose intolerance and superimposed infections, outpatient steroid therapy is not recommended, and this includes inhaled steroids. For patients already taking oral or inhaled steroids for underlying conditions, these medications should not be discontinued.

Hydroxychloroquine and azithromycin. Initially promising results from hydroxychloroquine pilot studies led to many well-conducted trials in mild to moderate and severe illness, as well as in prophylaxis — but they have shown lack of efficacy, with or without azithromycin.

In general, side effects were more common with hydroxychloroquine than with placebo. The most common side effects were gastrointestinal (nausea, diarrhea) and neurologic (dizziness, headache) symptoms. Prolongation of the QT interval was particularly noted in studies combining azithromycin with hydroxychloroquine because both drugs have this effect. Problematic cardiac arrhythmias were not noted, but it is unclear how outpatients would receive the recommended cardiac monitoring.

Azithromycin, commonly used for bacterial respiratory infections, is also an immunomodulator. Most azithromycin studies done with hydroxychloroquine lacked benefit. Injudicious use of this agent contributes to antimicrobial resistance and may cause Clostridium difficile colitis. The NIH, IDSA, and American College of Physicians guidelines recommend against the use of hydroxychloroquine and azithromycin outside of a clinical trial.

Ivermectin is used widely to treat parasitic diseases and has an excellent safety profile in that setting. It has been shown to have in vitro activity against some viruses, including SARS-CoV-2. However, the concentration needed to treat SARS-CoV-2 is not attainable with the approved clinical dose of ivermectin, and it is not approved for treatment of any viral infection.

A clinical retrospective analysis evaluated hospitalized patients with COVID-19 who received ivermectin vs those who did not. A single dose of 200 µg/kg was given with repeat dosing 7 days later if the patient was still in the hospital. Mortality was lower in the ivermectin group, warranting further study.

Although ivermectin may have some promise as an anti-inflammatory agent, there is concern about potential neurotoxicity in a hyperinflammatory state. Thus, it could be harmful in later COVID-19 disease. The NIH recommends against the use of ivermectin for COVID-19 except in the setting of a clinical trial.

Fluvoxamine. A small RCT was done using this selective serotonin reuptake inhibitor that is also a sigma-1 receptor agonist. The sigma-1 receptor mediates immune modulation for the hyperinflammatory response in COVID-19. No patients in the fluvoxamine group showed clinical deterioration, compared with 8.3% of patients in the control group.

Conclusion

Clinical trials are ongoing for many of these and other oral therapies. Several of these strategies have excellent safety profiles and are promising enough for potential use. These alternatives can steer patients and prescribers away from options that have negative evidence and are potentially deleterious. Recommendations for these therapies should be combined with transparent disclosures about the quality of existing evidence.

We believe that Pascal, a brilliant mathematician, would endorse the RCT. We also suspect that — while waiting for RCT results — he would favor a patient-centered approach using what evidence is available for relief of suffering without causing harm.

Jan E. Patterson, MD, MS, MACP, is a professor of medicine/infectious diseases and Associate Dean of Quality & Lifelong Learning at the Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio. She has had many publications and presentations on infectious diseases and healthcare epidemiology over a period of three decades. Her areas of expertise include clinical infectious diseases, infection prevention, antimicrobial resistance and stewardship, and integrative medicine. She has served in leadership positions regionally and nationally, including the boards of national professional organizations.

Ruth E. Berggren, MD, MACP, is a professor of medicine and infectious diseases at the Joe R. and Teresa Lozano Long School of Medicine, where she directs the Center for Medical Humanities & Ethics. Her areas of clinical expertise include HIV/AIDS, HIV and hepatitis C co-infection, and medical error disclosure. She has spoken nationally at more than 100 programs and serves on many committees of several professional organizations. She is currently President of the Texas Chapter of the American College of Physicians.

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