Outpatient Management of COVID-19
As we enter the third year of the COVID-19 pandemic, there still is controversy over the most effective clinical management as primary care physicians (PCPs) have had to navigate often confusing and contradictory expert advice as well as investigate politically engendered theories as we try “to follow the science.”
- The multiple and still-evolving mutations of the COVID-19 virus have resulted in variable disease severity and responsiveness to vaccines and therapeutics.
- Early in the pandemic, there was arguably more compliance with public health measures, such as masking, personal hygiene, and social distancing. Now, with less virulent variants and the concomitant fatigue with masking and vaccine hesitancy (and outright refusal), we still are confronted with continuing symptomatic cases.
- The clinical manifestations are legion and often nonspecific. Symptomatic therapies and antiviral agents have been developed but have not always been widely available, and their use has been restricted to specific sub-populations.
- This issue summarizes the current recommendations for therapy, although new variants most likely will require revised vaccines and therapies.
- PCPs need to be available to their patients for questions and be current in the appropriateness of emerging therapies and interventions.
The COVID-19 pandemic continues to be a major public health concern because of the amount of healthcare resources allotted and expended on addressing patients’ needs for guidance, testing, and treatment. To prevent further strain on our healthcare system, many targeted research efforts to address the gap in the management of outpatient COVID-19 patients are beginning to pay off by the recent approval of outpatient therapies. However, the availability of these new therapies, as well as their use, continues to be shrouded in confusion. This discussion provides a brief clinical overview of COVID-19, followed by a focus on outpatient management and therapy based on our current understanding and available therapies.
Review of COVID-19
Origin of SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2, referred to as SARS-CoV-2, is the causative virus of COVID-19 and was first clinically identified toward the end of 2019 after the Chinese Center for Disease Control and Prevention reported an outbreak of human viral pneumonia in Wuhan, China. The infectious disease was named COVID-19 as a shorthand of coronavirus disease 2019.1,2 The causative virus of the outbreak was rapidly identified as a coronavirus, which is a positive-stranded ribonucleic acid (RNA) virus.
Prior to this outbreak, coronaviruses commonly were identified as the group that causes minor disease processes in humans, such as the common cold, and more life-threatening illnesses, such as severe acute respiratory syndrome (SARS) coronavirus and Middle East respiratory syndrome (MERS) coronavirus.
On March 11, 2020, the World Health Organization (WHO) declared COVID-19 a pandemic. By then, more than 118,000 cases and more than 4,200 deaths from COVID-19 had been reported in more than 114 countries.3 Since then, nearly all efforts from the medical and scientific community have been concerted to understanding more about the virus, developing immunizations for the virus, and adapting common practices, such as physical distancing, isolation, and adoption of surgical and cloth masks for public use, to better mitigate the risk of infection.4 In the clinical setting, resources have been concentrated toward ensuring hospitals are equipped to care for patients with COVID-19. Initially, there was a great strain placed on the healthcare system, since resources to care for patients with COVID-19 were exceedingly limited and treatment was not yet established.
In the meantime, clinical understanding of COVID-19 pathogenesis and management has evolved, with significant positive milestones toward control or adaptation to the viral infection. For example, clinical staff have become increasingly adept at managing patients, beginning with triage of patients for admission to hospitals or intensive care setting, use of invasive vs. noninvasive respiratory devices, and managing medications used for therapy. As the pandemic evolves, much remains to be learned about COVID-19. Misinformation, exacerbated by social media outlets, continues to be a major obstacle toward accepting vaccines or following Centers for Disease Control and Prevention (CDC) recommendations in general.5
Each successive COVID-19 wave presented challenges to the healthcare system. For example, in the initial wave there were no therapies or vaccines, and clinicians were inexperienced in managing this new disease. With the second (Delta) wave, the U.S. healthcare system was inundated with cases that overwhelmed some geographic regions of the country.6 As the third wave, the Omicron variant, unfolded, the virus had become more infectious and less deadly.7 Now, on the verge of a new wave with the BA.2 subvariants (April 2022), we should not be surprised by the evolutionary capabilities of this virus or the comorbidities that can result from it.8 Since the emergency approval of the first parenteral agent for the management of COVID-19, remdesivir, there have been several other agents, as well as preventive vaccines, approved.
Undoubtedly, approved vaccines and therapies have attenuated the severity of the COVID-19 pandemic. Recent publications have suggested that the development and administration of vaccines have averted more than 1 million deaths in the United States alone.9 Without the rapid and efficient funding support for COVID-19 research by the U.S. government and the work of many dedicated scientists and clinicians, effective therapies against COVID-19 would not have been available to save American lives.
The primary means of transmission of SARS-CoV-2 is via person-to-person respiratory transmission and occurs primarily during close contact when an infected person coughs, sneezes, or talks within the range of another person who subsequently inhales the respiratory particles, or the respiratory particles make contact with their mucous membranes.10 There also is a possibility of infection if a person’s hands come into direct contract with contaminated surfaces and subsequently touch their mucous membranes; however, this no longer is thought to be as major a source of transmission as the respiratory route. Currently, no evidence suggests that contact transmission can occur with non-mucous membrane sites.11
Variants of Interest
Viruses have the ability to mutate, leading to new variations in their genome and subsequently altered aspects of pathogenicity. For COVID-19, the WHO used Greek alphabet nomenclature for the naming of SARS-CoV-2 variants.
- The Alpha variant, or B.1.1.7 lineage, was first identified the United Kingdom in late 2020 and was the predominant variant prior to the Delta variant. B.1.1.7 was noted to be more transmissible than prior strains, with some studies suggesting an association with more severe disease.12
- The Beta variant, or B.1.351 lineage, first was identified in South Africa, also in late 2020, but did not become a dominant variant. A feature of concern for the B.1.351 variant was its ability for immune evasion.13
- The Gamma variant, or P.1 lineage, first was identified in Japan in December 2020, with noted prevalence in Brazil. Although this variant did not achieve dominance, mutations in its genome suggested increased transmissibility.14
- The Delta variant, or B.1.617.2 lineage, first was identified in India in December 2020 and quickly became the most prevalent variant worldwide. B.1.617.2 was more transmissible than the already highly transmissible Alpha variant and was associated with higher risk of severe disease and hospitalization.15
- The Omicron variant, or B.1.1.529 lineage, first was reported in South Africa in November 2021. It was associated with an increase in infections and virulence and accounted for the majority of COVID-19 infections in the United States as early as December 2021. The Omicron variant possesses more than 30 mutations to its spike protein, ultimately associated with increased transmissibility and decreased susceptibility to neutralizing antibodies produced as a result of SARS-CoV-2 infection or vaccination. 16,17
The Omicron variant also has one of the fastest replication rates among the variants. In fact, Omicron’s high replication rate led to its cases outpacing cases of Delta, which led to Omicron quickly becoming the most prevalent variant of COVID-19.17 Rather than having an intrinsic increase in transmissability, Omicron's increased replication is believed to be secondary to its ability to escape immunity, but this is not fully known. Some studies suggest that the Omicron variant carries a lower risk of severe disease when compared with other variants.7 This also may have been, in part, the result of immune protection either from vaccination or prior infection.
At the time of this publication, the newly emerging variant is a sublineage of Omicron referred to as Omicron sublineage BA.2. This differs from the original Omicron sublineage BA.1 by approximately 40 mutations, which confer an increased replication advantage. Vaccine efficacy largely is unchanged for BA.2. Reinfections with the prior BA.1 variant are noted to be rare and primarily occur in unvaccinated persons.18
Individuals infected with SARS-CoV-2 may present with a broad spectrum of clinical symptoms. For example, in the first SARS-CoV-2 wave of infections in early 2020, COVID-19 cases were categorized into either mild, severe, or critical disease.19 Mild disease was found to be the most prevalent, with clinical findings of either no or mild pneumonia. Patients with mild infection typically presented with cold symptoms, alterations in taste and smell, or gastrointestinal symptoms.20 Severe disease involved the presence of dyspnea, hypoxia, and > 50% lung involvement of disease burden on imaging. Critical disease included patients with respiratory failure, shock, or multi-organ dysfunction.21
The risk factors associated with severe disease include increasing age or the presence of multiple comorbidities, such as immunocompromising medical conditions (cancer, chronic steroid use, use of immunosuppressive agents, human immunodeficiency virus [HIV]), type 1 and 2 diabetes mellitus, coronary artery disease, cardiomyopathies, chronic liver disease, chronic kidney disease, and various similar medical conditions.22,23 Not surprisingly, these risk factors are similar to risk factors for other common respiratory infections, such as influenza and pneumococcus.
Asymptomatic persons testing positive for SARS-CoV-2 are included among the patients counted with mild disease; however, the distinction between colonized and infected is not clinically well-defined. For symptomatic patients, the Alpha and Delta SARS-CoV-2 strains were reported most commonly to cause cough, fever, myalgia, headache, and even diarrhea.24 The most serious and recurring manifestation was viral pneumonia presenting with bilateral infiltrates on chest imaging. On the other hand, the Omicron variant included similar presentations to the Alpha and Delta strains; however, milder symptoms, such as nasal congestion, sneezing, and cough were much more common. 25 This is largely believed to be secondary to the Omicron variant’s site of replication being the oropharynx/upper respiratory tract rather than the lower respiratory tract.26
With more than one-third of the U.S. population already infected and almost 1 million deaths, counts for new cases of COVID-19 have become much less accurate since home testing kits were distributed to broad segments of the population. Hence, mild or asymptomatic infection is considerably underreported. From this large population cohort in this data gathering-intensive era, rapid research reports provided a picture of an infectious disease that has varied presentations ranging from asymptomatic to critically ill. Furthermore, although the severity of the disease is associated with the presence of risk factors described earlier, otherwise healthy individuals also have been affected, to a lesser degree. (See Figure 1.)
Figure 1. COVID-19 Death Risk Ratio for Select Age Groups and Comorbid Conditions
Source: Centers for Disease Control and Prevention. Underlying medical conditions associated with higher risk for severe COVID-19: Information for healthcare professionals. Updated Feb. 15, 2022. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html
Adapted from: Kompaniyets L, Pennington AF, Goodman AB, et al. Underlying medical conditions and severe illness among 540,667 adults hospitalized with COVID-19, March 2020-March 2021. Prev Chronic Dis 2021;18:E66.
Pennington AF, Kompaniyets L, Summers AD, et al. Risk of clinical severity by age and race/ethnicity among adults hospitalized for COVID-19 — United States, March-September 2020. Open Forum Infect Dis 2020;8:ofaa638.
Complications of Severe Disease
With nearly two years’ worth of data regarding the clinical implications of COVID-19, it is well established that the mortality rate from COVID-19 increases significantly among unvaccinated and hospitalized individuals. Additionally, patients with mild disease are at risk of progression to severe disease, often documented within five to seven days of illness.27
The most worrisome and common complication of COVID-19 infection is the development of acute respiratory distress syndrome (ARDS), which can present shortly after patients begin experiencing dyspnea. ARDS is a critical illness that often requires mechanical ventilation to prevent further worsening.28
Another marker of severe disease in COVID-19 infection is encephalopathy, which sometimes can present without any signs of respiratory involvement. However, it is commonly seen in critically ill patients, often without the accompaniment of stroke, movement disorders, ataxia, or other neurologic deficits/disorders.29
Other potentially severe complications, such as thromboembolic disease, are the result of the hypercoagulable state associated with COVID-19 infection. Thromboembolic disorders manifested as deep venous thrombosis or pulmonary embolism are commonly reported in critically ill patients.
Furthermore, arterial thrombotic events, such as stroke and limb ischemia, also have been identified in patients irrespective of risk factors.30
The pathophysiology of COVID-19 is known to cause a pro-inflammatory cytokine storm leading to continued inflammatory response with elevated cytokines, such as interleukin (IL)-2, granulocyte-colony stimulating factor, and tumor necrosis factor-α.29 The elevated cytokines also can lead to auto-antibody production resulting in other less common complications, such as Guillain-Barré syndrome in adults and multisystem inflammatory syndrome in children.31,32 Several of the approved therapies, which are to be discussed in greater detail, in both the hospital and outpatient setting target certain cytokines and were formulated to assist in attenuating the hyperinflammatory response without completely preventing the immune system from mounting a response.
Recovery from COVID-19 depends on the extent of disease, but patients with mild disease are expected to make a near-full recovery within two weeks. Patients with more severe disease may experience a longer course to recovery, often two to three months.33
Regardless of the extent of infection or disease presentation, the termed “long-haul” post-COVID-19 syndromes are known to affect any patient who was infected with COVID-19, with symptoms noted to persist for at least two months, although often up to 12 months. These symptoms most often include chronic fatigue, dyspnea, chest pain, cough, and subtle cognitive impairments. Ongoing research also suggests that patients are at increased risk for future respiratory and cardiac impairment and should be monitored closely after recovery for development or progression of these findings.34,35
Prevention of Severe COVID-19
Vaccination for Adults
Clinicians should continue recommending that all adults receive a COVID-19 vaccine, as well as boosters when indicated. The messenger RNA (mRNA) vaccines, manufactured by Pfizer-BioNTech and Moderna and first approved for emergency use by the Food and Drug Administration (FDA) in the latter part of 2020, remain the most efficacious for preventing infection and progression to severe disease with prevention of hospitalization and death.36,37 In the United States, a vector vaccine also was approved in February 2021, manufactured by Johnson & Johnson/Janssen.38
Administration of subsequent COVID-19 boosters is based on a recent study published by the CDC demonstrating that receiving a third vaccine dose (booster) during the Delta- and Omicron-predominant surges prevented emergency department and urgent care visits as well as hospitalization.39 In April 2022, the FDA and CDC announced new recommendations for an additional fourth vaccine dose (booster) for all adults 50 years of age or older regardless of risk factors.40
Other strategies for individuals to prevent infection include physical distancing and the use of surgical masks. These have been proven to slow the spread of COVID-19. The availability of approved N-95 masks for public use can further reduce the burden of infection; however, their widespread use is limited because of the relative cost and reported discomfort with wearing them compared with standard surgical or cloth masks.41
Vaccines for Teens and Children
The majority of guidance on vaccines generally applies to individuals 18 years of age or older, along with the recommendation for a booster dose. For individuals 12 to 17 years of age, the CDC recommends vaccination with the Pfizer-BioNTech two-dose series and subsequent booster dose after six months. For individuals 5 to 11 years of age, the CDC also recommends vaccination with the Pfizer-BioNTech two-dose series, although formal recommendations are pending regarding a booster dose.42 Formal recommendations from the CDC do not currently exist for children ages 6 months to 4 years.43 While the FDA previously delayed authorizing vaccines for pediatric-aged patients, on June 15, 2022, the FDA approved both the Pfizer-BioNTech and Moderna vaccine series for children 6 months of age and older.44 Given the new approval from the FDA, the decision will be taken up by the CDC, with formal recommendations expected in the coming weeks.
Timing of Vaccination
For those eligible to receive vaccines, there generally are no timing restrictions to get vaccinated if individuals are not infected with COVID-19 currently. For individuals who are either quarantining because of exposure or isolating as the result of a positive test, vaccination should be delayed until isolation or quarantine periods are over.45
What to Expect After Vaccination and Booster
Patients should be counseled on expected side effects from vaccination, for which the majority of symptoms include pain and swelling at the site of injection as well as fatigue, headache, and myalgia. Some side effects also may include fever, chills, rigors, and lymphadenopathy.45 Patients should be advised that these are not true adverse reactions to vaccination and that any form of anaphylaxis or severe allergic reaction would occur shortly after receiving their COVID-19 vaccine. These symptoms are self-limited, often lasting 12 to 48 hours, and can be treated supportively with acetaminophen, ibuprofen, or aspirin if older than 18 years of age. The CDC recommends that mRNA (Pfizer-BioNTech, Moderna) vaccines are the preferable first choice; however, individuals who do not tolerate mRNA vaccines or who have developed a serious side effect should consider receiving a vector vaccine.
Isolated cases of myocarditis and pericarditis also have been reported, primarily in male adolescents and young adults, following administration of mRNA vaccines. However, these cases occur infrequently, and the benefits of receiving the vaccine greatly outweigh the mild nature of reported myocarditis and pericarditis cases. Nonetheless, patients who develop myocarditis and pericarditis after the first dose of mRNA vaccine should defer the second dose until further discussion with their physician.46
What to Do if Your Patient Tests Positive for COVID-19
Clinicians should advise their patients to get tested if they suspect they may have COVID-19 or if they were knowingly exposed to someone with COVID-19 and to contact their healthcare provider in the event they test positive. If a patient tests positive, it is important to first assess the presence of symptoms. Published reports suggest this can be done with a nurse call, telehealth visit, or use of a dedicated clinic for respiratory infections to minimize transmission.47
This initial assessment should evaluate for the presence of dyspnea, the severity and duration, and oxygenation status if available, as well as identify risk factors for developing severe disease. As discussed previously, these risk factors include chronic lung disease, chronic kidney disease, diabetes mellitus, smoking, or immunocompromise (HIV, cancer, solid organ or blood stem cell transplants, or use of corticosteroids or other immunosuppressive medications). Clinical assessment of these factors should be able to determine quickly which patients may require an in-person visit at either the clinic or emergency department.
All COVID-19-infected patients with mild disease may be treated symptomatically for fever, headaches, and myalgia with over-the-counter antipyretics and analgesics, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs).48
For cough or mild dyspnea, patients can attempt self-proning, which is the practice of lying in a prone position rather than supine position, if tolerated.49 Additionally, breathing exercises, such as pursed-lip breathing or slow exhalation, may assist in easing dyspnea and cough. If cough is interfering with sleep or comfort, the use of agents to suppress cough, such as dextromethorphan or benzonatate, may be considered.50 See Table 1 for currently available therapies for outpatient treatment of mild to moderate COVID-19 infection.
Table 1. Currently Available Therapies Used for Treatment of Mild to Moderate COVID-19 Infection in the Outpatient Setting
Recommended for Use
Any patient with mild to moderate COVID-19 infection with fever, headache, and/or myalgia
Advise acetaminophen treatment before the use of nonsteroidal
Any patient with mild to moderate COVID-19 infection with cough unrelieved by conservative measures
Dextromethorphan is known to cause dizziness, drowsiness, restlessness, nausea, and vomiting.
Patients with mild to moderate COVID-19 infection and risk factors for progression to severe illness only if other therapies are unavailable
Intravenous; one-time 175-mg infusion
May cause hypersensitivity reactions, such as anaphylaxis or transfusion-related reactions.
Patients with COVID-19 infection; should be started as soon as diagnosed and within five days of diagnosis
Oral; nirmatrelvir 300 mg (two 150-mg capsules) and ritonavir 100 mg twice daily for five days
Renal adjustment is based on glomerular filtration rate 30 mL/min to 59 mL/min; nirmatrelvir is reduced to 150 mg, and the remainder of dosage is unchanged. CYP3A inhibitors may affect concentrations of other medications using CYP3A.
Patients with COVID-19 infection who may not be eligible for nirmatrelvir-ritonavir; should be started as soon as diagnosed and within five days of diagnosis
Oral; 800 mg (four 200-mg capsules) twice daily for five days
Molnupiravir should not be given to patients who are pregnant, lactating, or with childbearing potential because of the risk of fetal abnormalities.
Patients without COVID-19 infection with risk factors and who are at a high risk of contracting illness
Intramuscular; consecutive administration of tixagevimab 150 mg followed by cilagavimab 150 mg
This medication may cause hypersensitivity reactions, such as anaphylaxis, or transfusion-related reactions.
Patients with mild to moderate COVID-19 infection with risk factors for progression
Intravenous; 200-mg infusion on day 1 followed by 100-mg infusions days 2 and 3
Bradycardia, hypotension, and elevated transaminases have been reported; remdesivir may cause hypersensitivity reactions.
The treatment of COVID-19 infection in non-hospitalized patients is based on identification of patient risk factors that increase the likelihood of progression to severe disease. Patients with risk factors that meet the criteria for therapy have available therapy options to consider that have shown benefit in halting the progression to severe disease.50
One popular treatment intervention is monoclonal antibodies. Among the monoclonal antibodies, tixagevimab/cilgavimab (Evusheld) is available for pre-exposure prophylaxis. Pre-exposure prophylaxis is recommended for individuals who have moderate to severe immune compromise because of their underlying medical conditions, are receiving immunosuppressive medications, or have a contraindication to current available vaccines.51,52 This infusion can be considered for use in qualifying patients who are at risk for contracting COVID-19 (for example, patients on dialysis receiving frequent infusions).
Bebtelovimab, an investigational monoclonal antibody, currently is approved under an emergency use authorization (EUA) for treatment of high-risk, non-hospitalized patients 12 years of age or older with mild to moderate COVID-19. Treatment parameters include administration within seven days of illness onset. The administration involves a 30-second infusion followed by close monitoring for one hour in the event of any immediate adverse reaction. It is approved for treatment of all current COVID-19 variants in the event that other therapies are not available.53
Sotrovimab (Xevudy) was available previously under an EUA by the FDA and was shown to be effective against the Omicron variant if administered within five days of illness onset.50 However, the FDA recently rescinded the EUA, since sotrovimab is shown to be less effective in treatment of the currently (as of April 2022) more prevalent BA.2 subvariant. Currently, the FDA also has recommended against the use of casirivimab/imdevimab (REGEN-COV) and bamlanivimab/etesevimab for treatment. Although authorized previously under an EUA by the FDA for treatment, recent data suggest they are less effective against the Omicron variant.51,53
Remdesivir (Veklury), the first EUA-approved therapy for hospitalized COVID-19 patients, is a nucleotide analogue that inhibits the SARS-CoV-2 RNA polymerase. In the outpatient setting, remdesivir is EUA-approved for a 30- to 120-minute intravenous infusion once per day for three days. Outpatient remdesivir may be used within seven days of symptom onset. Treatment with remdesivir gradually has become more controversial, since the WHO and the British Medical Journal recommend against the use of this medication for COVID-19.53 A randomized controlled trial studying the benefits of remdesivir among 562 unvaccinated outpatients with risk factors for progression to severe disease ultimately found there was no significant effect on mortality but reported a reduction of hospitalization as a secondary outcome.54 As such, treatment with this medication should be considered in eligible patients for whom a three-day infusion is feasible.
Two oral antiviral agents also are available under EUA by the FDA. The first, nirmatrelvir-ritonavir (Paxlovid), is a combination of oral protease inhibitors recommended for use within five days of COVID-19 symptom onset. Nirmatrelvir-ritonavir is authorized for use in mild-moderate COVID-19 infection in individuals 12 years of age and older who are at risk of COVID-19 progression. Tablets administered over five days reduced the risk of hospitalization or death at 28 days by 89% compared to placebo in a preliminary study.55 Doses should be adjusted based on the presence of impaired kidney function (estimated glomerular filtration rate 30 mL/min to 59 mL/min). Nirmatrelvir-ritonavir has significant potential drug-drug interactions because it is a CYP3A inhibitor. Hence, the drug label insert should be reviewed for potential interactions with co-administered medications. When feasible, co-administered medications with a known interaction may be held during nirmatrelvir-ritonavir use.
Recent reports from the CDC following nirmatrelvir-ritonavir use in patients with COVID-19 have noted a “rebound” of symptoms that were thought to be a part of the natural history of SARS-CoV-2 infection regardless of treatment or vaccination status. This effect also has manifested as patients who test positive at least once after being treated with nirmatrelvir-ritonavir after testing negative, occurring in about 1% to 2% of participants in the clinical trial for nirmatrelvir-ritonavir. Symptoms from rebound are noted to be overwhelmingly mild, including fatigue and upper respiratory symptoms lasting approximately three days without treatment. The full nature of rebound positivity following COVID-19 and treatment with nirmatrelvir-ritonavir is currently being studied, with more findings to come.56
Molnupiravir (Lagevrio), the second oral antiviral for COVID-19, is a nucleoside analogue that inhibits replication of the virus. The drug may be considered as an alternative therapy for mild-moderate COVID-19 infection in adults older than 18 years of age if other drugs are not available. Patients diagnosed with COVID-19 should receive molnupiravir within five days of symptom onset.57 Although molnupriravir was not found to interact with other co-administered medications and does not require renal dose adjustments, it is contraindicated in patients younger than 18 years of age because of bone and cartilage toxicity. It also is not recommended for pregnant and/or lactating adults as well as adults with childbearing potential because of the risk of fetal abnormalities. Otherwise, the drug is well tolerated, and common side effects include nausea, diarrhea, or dizziness.
As the COVID-19 pandemic raged globally, healthcare providers around the world administered a variety of drugs based on small trials, with some reporting promising results. One of the earliest trials was from France and identified hydroxychloroquine and azithromycin as potential therapeutic drugs to fight COVID-19. These agents were heavily used globally at the beginning of the pandemic, and some agents continue to be used because of their wide availability and low cost, despite the fact that subsequent trials showed no benefit. A multitude of other therapies have been tried with mixed evidence of benefit. Hence, these therapies remain under investigation or have fallen out of use, lacking the high-quality data required as evidence of efficacy.
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) approved by the FDA for use in obsessive-compulsive disorder. Although several trials have been published with preliminary data showing a trend to reduction in progression to severe disease, neither the FDA nor the CDC has given a recommendation for or against its use. Further definitive data to guide therapeutic recommendations have yet to be published or assessed.58
High-titer convalescent plasma from COVID-19-infected patients is investigational and available through clinical trials, although data thus far have not demonstrated efficacy for mild disease. However, there is some reported benefit in reducing progression to severe disease.59,60 In August 2020, the FDA issued an EUA for use of convalescent plasma in hospitalized patients with COVID-19 infection. Subsequently, a revised EUA was issued on Feb. 4, 2021, with the recommendation for use of “high-titer” COVID-19 convalescent plasma. Hence, convalescent plasma products that do not have the label “high-titer” should not be used. Convalescent plasma administration for mild-moderate COVID-19 infection is not recommended in outpatient settings.
Inhaled glucocorticoids, FDA-approved for respiratory conditions such as asthma or chronic obstructive pulmonary disease, have mixed data, with smaller trials suggesting benefits and larger trials showing no effect.61,62 These agents may impair SARS-CoV-2 viral replication by downregulating receptors used for cell entry. Further studies are needed to assess inhaled steroid benefits for outpatient COVID-19 management. Although systemic glucocorticoids are used nearly routinely in hospitalized patients with COVID-19, they should not be used in non-hospitalized patients, since they have not shown any additional benefit and may be associated with harm.62
Throughout the pandemic, several oral nutritional supplements have been touted as potential remedies to prevent contracting disease and/or progression to severe disease. These include, but are not limited to, vitamin C, vitamin D, zinc, and quercetin.61,63,64
Vitamin C is a water-soluble vitamin with a proposed mechanism of providing anti-inflammatory properties and supplementation to provide added support in times of high oxidative stress. In a study conducted to determine the ability of vitamin C to reduce the number of days required to reach a 50% reduction of symptoms, it was concluded there was no significant difference compared to standard of care.61
Vitamin D is a fat-soluble vitamin crucial for bone metabolism with receptors found on immune cells, such as B cells and T cells. Its use is based on its implications on potential immunomodulatory effects. In a randomized clinical trial with a primary outcome of length of hospital stay, the length of stay of the vitamin D group was not significantly different from that of the placebo group.61
Zinc deficiency has potentially been indicated in relation to COVID-19 severity. Several clinical trials examining the use of zinc supplementation have concluded there is no clinical benefit and there is actual potential harm with long-term zinc supplementation, including copper deficiency with reversible hematologic pathologies and potentially irreversible neurologic pathologies. Hence, zinc supplementation currently is not recommended.61
Quercetin is a flavonoid commonly used as a dietary supplement, which also gained popularity as a possible preventative oral supplement. Although currently under investigation, a recently published study found no difference between quercetin and placebo in disease outcomes.63,64
Early in the pandemic, there were suggested antiviral capabilities for hydroxychloroquine and azithromycin, but since then these have since been heavily studied, with no suggestion of clinical benefit for patients with COVID-19 in the outpatient setting.65-70
Ivermectin received a lot of attention in the media as a remedy for COVID-19 infection; however, studies show no clear benefit reported from its use.71-76 A July 2021 meta-analysis identified four ivermectin trials with placebo comparisons. These four trials found no reduction in all-cause mortality, need for invasive ventilation, or effect on symptom resolution. Other studies found that ivermectin did not improve the time to resolution of symptoms when compared to placebo, nor did it prevent progression to severe disease.73,74 In a recent study published in the New England Journal of Medicine, researchers concluded that treatment with ivermectin did not lower the incidence of admission to the hospital or prolonged observation in the emergency department in outpatients with early diagnosis of COVID-19.75 Furthermore, ivermectin is available over the counter for veterinary use. Although not intended for human use, these veterinary formulations can be obtained by the public without a prescription. Some of these veterinary formulations are intended for large animals and may be in concentrated form. In 2021, concordant with the waves of COVID-19 infection, retail pharmacies in the United States reported up to a 24-fold increase in ivermectin sales. Concordant with the waves of COVID-19 infection, there were increased calls to the poison control center and emergency rooms related to ivermectin overdose and toxicity.76,77
Colchicine was evaluated for use in early mild to moderate COVID-19 disease; however, there was no reduction in mortality, and increased adverse effects were observed.78
Guiding Patients to Treatment
Access to Therapy
The fact that several EUA authorized or approved therapies exist does not necessarily imply that access exists for both patients and healthcare providers. Determining access to therapies, including monoclonal antibodies and oral antivirals, can best be accomplished by visiting the COVID-19 Therapeutics Locator (https://covid-19-test-to-treat-locator-dhhs.hub.arcgis.com) via the Office of the Assistant Secretary for Preparedness & Response (ASPR).79 This national map displays public locations that have received COVID-19 therapeutics acquired under the FDA EUA, mainly the aforementioned monoclonal antibody formulations and the oral antiviral therapies. Maps available on the ASPR site reflect updated supplies made within the last seven days. Using your state’s department of health website also may provide similar supply resources to assist in directing your patients to the appropriate therapy.
Determining the Appropriate Therapy for the Appropriate Patient
After triaging patients and determining their risk factors and current disease state (i.e., hypoxia, dyspnea, altered mental status), determining the best therapeutic approach ultimately may come down to affordability and access. However, a chart (https://aspr.hhs.gov/COVID-19/Therapeutics/Documents/side-by-side-overview.pdf) created by the ASPR helps to compare different treatment modalities, the appropriate populations, and the best treatment window. 80
Approaching Patients Who Are Vaccine-Hesitant
The mainstay for preventing death or severe disease from COVID-19 is to get vaccinated, primarily with one of the two approved mRNA vaccines. In reality, the circumstances surrounding the COVID-19 pandemic and the rapid development of vaccines using emergent mRNA and vector technologies has led to an exacerbation of preexisting vaccine hesitancy.
Although vaccine hesitancy continues to emerge in different areas of social media and the press, having open and honest discussions with patients who are vaccine-hesitant and addressing their individual concerns remains an effective method of combatting their perception.81 Often, sharing personal stories with patients, whether in the hospital or at the clinic, also may help underscore the importance of getting vaccinated.
The CDC has launched its own campaign, called “Vaccinate with Confidence,” to better build community confidence in COVID-19 vaccines. Their website contains helpful resources for clinician use in their practice to promote understanding the needs of the community, identifying community leaders and channels for communication, and interventional strategies for increasing COVID-19 vaccine uptake. In addition to these resources, the website also includes resources specifically targeted toward addressing misinformation and disinformation, such as “social listening,” which is a method of collecting data from multiple media platforms to track online discussions, trends, and sentiments to inform an approach.82
Management of COVID-19 in the outpatient setting should be incorporated in the practice of primary care. Advocating for vaccination always should be considered and administered when appropriate. Early identification and treatment of patients with COVID-19 who are at risk of progressing to severe disease have been shown to help prevent hospitalization and death. Although there are many therapies currently available, several therapies remain under investigation and under the ire of controversy. Staying informed with the latest evidence-based treatments and relying on clinical judgment based on available material will ensure the best outcomes for all patients, especially those at risk for progression.
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- World Health Organization. Statement on Omicron sublineage BA.2. Published Feb. 22, 2022. https://www.who.int/news/item/22-02-2022-statement-on-omicron-sublineage-ba.2
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- Peacock RP, Brown JC, Zhou J, et al. The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry. bioRxiv 2022; Jan 3. [Preprint]. https://www.biorxiv.org/content/10.1101/2021.12.31.474653v1.full.pdf
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- Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N Engl J Med 2021;384:1412-1423.
- U.S. Food and Drug Administration. Emergency use authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). Revised May 5, 2022. https://www.fda.gov/media/146304/download
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- U.S. Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes second booster dose of two COVID-19 vaccines for older and immunocompromised individuals. Published March 29, 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-second-booster-dose-two-covid-19-vaccines-older-and
- Centers for Disease Control and Prevention. COVID-19 vaccine recommendations for children and teens. Updated April 6, 2022. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/vaccines-children-teens.html
- Park A, Ducharme J. FDA panel recommends Moderna and Pfizer COVID-19 vaccines for children 6 months and older. Updated June 15, 2022. https://time.com/6187674/covid-19-vaccines-kids-under-five-fda/
- Centers for Disease Control and Prevention. Use of COVID-19 vaccines in the United States. Updated April 21, 2022. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html
- Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021. MMWR Morb Mortal Wkly Rep 2021;70:977-982.
- Centers for Disease Control and Prevention. Healthcare workers: Information on COVID-19. Updated Dec. 27, 2021. https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html
- Cohen P, Gebo K. COVID-19: Outpatient evaluation and management of acute illness in adults. UpToDate. Updated April 15, 2022. https://www.uptodate.com/contents/covid-19-outpatient-evaluation-and-management-of-acute-illness-in-adults
- Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency department: A single ED’s experience during the COVID-19 pandemic. Acad Emerg Med 2020;27:375-378.
- National Institutes of Health. Therapeutic management of nonhospitalized adults with COVID-19. Updated April 8, 2022. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/
- U.S. Food and Drug Administration. Coronavirus (COVID-19) update: FDA limits use of certain monoclonal antibodies to treat COVID-19 due to the Omicron variant. Published Jan. 24, 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-limits-use-certain-monoclonal-antibodies-treat-covid-19-due-omicron
- U.S. Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes additional monoclonal antibody for treatment of COVID-19. Published May 26, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-monoclonal-antibody-treatment-covid-19
- Agarwal A, Rochwerg B, Lamontagne F, et al. A living WHO guideline on drugs for covid-19. BMJ 2020;370:m3379.
- Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med 2022;386:305-315.
- Pfizer. Pfizer announces additional phase 2/3 study results confirming robust efficacy of novel COVID-19 oral antiviral treatment candidate in reducing risk of hospitalization or death. Published Dec. 14, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results
- Rubin R. From positive to negative to positive again—The mystery of why COVID-19 rebounds in some patients who take Paxlovid. JAMA 2022; Jun 8. doi:10.1001/jama.2022.9925. [Online ahead of print].
- U.S. Food and Drug Administration. Fact sheet for healthcare providers: Emergency use authorization for Lagevrio (molnupiravir) capsules. Revised March 2022. https://www.fda.gov/media/155054/download
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- National Institutes of Health. NIH halts trial of COVID-19 convalescent plasma in emergency department patients with mild symptoms. Published March 2, 2021. https://www.nih.gov/news-events/news-releases/nih-halts-trial-covid-19-convalescent-plasma-emergency-department-patients-mild-symptoms
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- Schwartz I, Boesen ME, Cerchiaro G, et al. Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: A randomized controlled trial. CMAJ Open 2021;9:E693-E702.
- Oldenberg CE, Pinsky BA, Brogdon J, et al. Effect of oral azithromycin vs placebo on COVID-19 symptoms in outpatients with SARS-CoV-2 infection: A randomized clinical trial. JAMA 2021;326:490-498.
- Popp M, Stegemann M, Metzendorf MI, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev 2021;7:CD015017.
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- López-Medina E, López P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: A randomized clinical trial. JAMA 2021;325:1426-1435.
- Lim SCL, Hor CP, Tay KH, et al. Efficacy of ivermectin treatment on disease progression among adults with mild to moderate COVID-19 and comorbidities: The I-TECH randomized clinical trial. JAMA Intern Med 2022;182:426-435.
- Reis G, Silva EASM, Silva DCM, et al. Effect of early treatment with ivermectin among patients with Covid-19. N Engl J Med 2022;386:1721-1731.
- Temple C, Hoang R, Hendrickson RG. Toxic effects from ivermectin use associated with prevention and treatment of Covid-19. N Engl J Med 2021;385:2197-2198.
- Centers for Disease Control and Prevention. Rapid increase in ivermectin prescriptions and reports of severe illness associated with use of products containing ivermectin to prevent or treat COVID-19. Published Aug. 26, 2021. https://emergency.cdc.gov/han/2021/han00449.asp#:~:text=HAN%20Archive-,Rapid%20Increase%20in%20Ivermectin%20Prescriptions%20and%20Reports%20of%20Severe%20Illness,Prevent%20or%20Treat%20COVID%2D19&text=Ivermectin%20is%20a%20U.S.%20Food,by%20internal%20and%20external%20parasites
- Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): A phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med 2021;9:924-932.
- Office of the Assistant Secretary for Preparedness & Response. COVID-19 therapeutics locator. https://covid-19-therapeutics-locator-dhhs.hub.arcgis.com/
- Office of the Assistant Secretary for Preparedness & Response. Side-by-Side overview of therapeutics authorized or approved for the prevention of COVID-19 infection or treatment of mild-moderate COVID-19. Published March 1, 2022. https://aspr.hhs.gov/COVID-19/Therapeutics/Documents/side-by-side-overview.pdf
- Centers for Disease Control and Prevention. Foster support for vaccination in your practice. Last reviewed Nov. 2, 2020. https://www.cdc.gov/vaccines/hcp/conversations/your-practice.html
- Centers for Disease Control and Prevention. How to address COVID-19 vaccine misinformation. Last reviewed Nov. 3, 2021. https://www.cdc.gov/vaccines/covid-19/health-departments/addressing-vaccine-misinformation.html
The COVID-19 pandemic continues to be a major public health concern. The availability of new therapies, as well as their use, continues to be shrouded in confusion. This discussion provides a brief clinical overview of COVID-19, followed by a focus on outpatient management and therapy based on our current understanding and available therapies.
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