Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can experience a wide range of clinical manifestations, ranging from no symptoms to critical illness and death.1 Research on the pathophysiology of COVID-19 indicates that early in the course of infection, the severity of illness is primarily driven by replication of the SARS-CoV-2 virus. Later, an exaggerated immune/inflammatory response by the host is the major driver for tissue damage.2 Therefore, monoclonal antibodies that target the spike protein and antiviral therapies are believed to be more beneficial in the early stages of the illness, whereas immunosuppressive/anti-inflammatory therapies are expected to be more beneficial in the later stages.2 The optimal approach to the treatment of COVID-19 continues to evolve rapidly.2,3 As of October 2021, the antiviral drug remdesivir is the only US Food and Drug Administration (FDA)-approved drug for the treatment of COVID-19.2,4 Several other therapies (eg, casirivimab plus imdevimab, bamlanivimab plus etesevimab, sotrovimab, baricitinib, tocilizumab) are available for the treatment of COVID-19 under emergency use authorizations (EUAs) from the FDA.5–7
Mild illness. Patients with mild illness may present with any signs or symptoms of COVID-19 (eg, fever, cough, muscle pain, sore throat, malaise, headache, nausea, vomiting, diarrhea, loss of taste and smell); however, they do not exhibit shortness of breath, dyspnea on exertion, or abnormal chest imaging results.1 Most cases of mild illness can be managed through telemedicine or in the ambulatory setting. No imaging or laboratory testing is routinely indicated in otherwise healthy patients with mild COVID-19.1 Any patient with risk factors for severe disease should be monitored closely because the clinical course of the disease may progress rapidly in some patients (about 1 week after illness onset).1,2,9,10 Risk factors for severe COVID-19 include, but are not limited to, cardiovascular disease, chronic lung disease, sickle cell disease, diabetes, cancer, obesity, and chronic kidney disease, as well as being 65 years or older, pregnant, a smoker, or a recipient of transplant or immunosuppressive therapy.1 Anti–SARS-CoV-2 monoclonal antibodies (casirivimab plus imdevimab, bamlanivimab plus etesevimab, and sotrovimab) are available under EUAs for outpatients with mild COVID-19 who are at high risk for progressing to severe disease and/or hospitalization. These therapies should be administered as soon as possible and within 10 days of symptom onset. In clinical trials, monoclonal antibodies have been shown to reduce viral load and decrease the number of patients requiring medical care and hospitalization.5,6
Moderate illness. Moderately ill patients have clinical or imaging evidence of lower respiratory disease, with SpO2 ≥94% on room air at sea level.1 These patients should be monitored closely, given the risk of rapid disease progression that may require hospitalization. The optimal pulmonary evaluation technique has not been defined yet, but the initial evaluation should include chest imaging by x-ray, ultrasound, or computed tomography (CT). An electrocardiogram should be performed if indicated.1 Complete blood count (CBC) with differentials and a metabolic profile, including liver and renal function tests, should be performed. Measurements of inflammatory markers, such as C-reactive protein (CRP), D-dimer, and ferritin, may have prognostic value.1 Anti–SARS-CoV-2 monoclonal antibodies (casirivimab plus imdevimab, bamlanivimab plus etesevimab, and sotrovimab) are available under EUAs for outpatients with moderate COVID-19 who are at high risk for progressing to severe disease and/or hospitalization.2,5,6 Monoclonal antibodies should be administered as soon as possible after a positive viral test for SARS-CoV-2 and within 10 days of symptom onset.5,6 Administer empiric antibiotics for community-acquired pneumonia if bacterial pneumonia or sepsis is strongly suspected and reevaluate the patient’s condition daily.1
Severe illness. Severely ill patients have SpO2 <94% on room air at sea level, respiratory rate >30/min, PaO2/FiO2 <300 mm Hg, or lung infiltrates >50%.1 Oxygen therapy should be initiated immediately, using a nasal cannula or high-flow oxygen. These patients should be admitted to a healthcare facility.1,2 Evaluation should include chest imaging, CBC, and a metabolic panel. Measurements of inflammatory markers may have prognostic value.1 Available treatment options for hospitalized patients with severe COVID-19 who require supplemental oxygen include remdesivir, dexamethasone, baricitinib, or tocilizumab.2,4 Administer empiric antibiotics if bacterial pneumonia or sepsis is suspected and reevaluate the patient’s condition daily.1 Patients with severe COVID-19 may experience rapid disease progression and will likely need to undergo aerosol-generating procedures. These patients should be placed in an airborne-infection isolation room (AIIR).2 Given the potential of a hypercoagulable state and the high incidence of thrombosis in hospitalized patients with COVID-19, clinicians should have a high clinical suspicion for thrombotic events. All hospitalized patients with COVID-19 should receive prophylactic dose anticoagulation.11,12
Critical illness. Critically ill patients may have acute respiratory distress syndrome (ARDS), virus-induced distributive septic shock, cardiac dysfunction, cytokine storm from elevations in inflammatory cytokines, multiorgan dysfunction, and/or exacerbation of underlying comorbidities. In addition to pulmonary disease, patients with critical COVID-19 may also develop cardiac, hepatic, renal, central nervous system, or thrombotic disease.1 Care of critically ill patients with COVID-19 requires treating both the medical condition that initially resulted in the critical illness (ie, COVID-19 from SARS-CoV-2 infection) plus other comorbidities and nosocomial complications.1 Available treatment options for critically ill patients with COVID-19 include dexamethasone, remdesivir, baricitinib, or tocilizumab.2,4 All critically ill patients with COVID-19 should receive prophylactic dose anticoagulation.11,12 Whether critically ill patients should receive therapeutic anticoagulation in the absence of confirmed or suspected venous thromboembolism is currently under investigation.11,12
Use the Monoclonal Antibody Eligibility Tool to find out if your patient is a candidate for this treatment
Pharmacologic Management of COVID-19
Casirivimab plus imdevimab (REGN-COV2). Casirivimab and imdevimab are neutralizing monoclonal antibodies that target the receptor-binding domain of the spike protein of SARS-CoV-2 and prevent the virus from entering host cells.2,13 The FDA issued an EUA for casirivimab plus imdevimab for the treatment of nonhospitalized patients with mild-to-moderate COVID-19 who are at high risk for progressing to severe disease and/or hospitalization (see table 1 below).6 This authorization is largely based on data from a randomized trial showing that treatment with casirivimab plus imdevimab was associated with a reduction in viral load, as well as COVID-19–related hospitalizations or death.6,13 Infrequent infusion-related reactions to treatment with casirivimab plus imdevimab were reported.6
Casirivimab plus imdevimab is also authorized for individuals 12 and older for post-exposure prophylaxis against COVID-19.6 This authorization is based on the results from the phase 3 COV-2069 trial in which casirivimab plus imdevimab was associated with an 81.4% risk reduction in the development of COVID-19 when administered as post-exposure prophylaxis in seronegative household contacts of individuals infected with SARS-CoV-2.14
Bamlanivimab plus etesevimab. Bamlanivimab and etesevimab are neutralizing monoclonal antibodies that bind to the receptor-binding domain of the spike protein of SARS-CoV-2 and prevent the virus from entering host cells.15,16 The FDA granted an EUA for bamlanivimab plus etesevimab for the treatment of nonhospitalized patients with mild to moderate COVID-19 who are at high risk for progressing to severe disease and/or hospitalization (see table below).5 Data from the BLAZE-1 trial showed that compared to placebo, combination therapy with bamlanivimab and etesevimab, but not bamlanivimab monotherapy, decreased viral load among outpatients with mild-to-moderate COVID-19.16 Compared with the placebo group, the rate of COVID-19–related hospitalizations or emergency department visits at day 29 was numerically lower for the monotherapy groups as well as the combination therapy group, but the difference was only significant for the combination group (5.8% vs 0.9%).16 The EUA for bamlanivimab monotherapy was revoked, given the increasing incidence of SARS-CoV-2 viruses that are resistant to single monoclonal antibody therapy.17 Due to viral resistance, bamlanivimab plus etesevimab is authorized only in states in which the combined frequency of resistant variants, including the South African (B.1.352; Beta) and Brazilian (P.1; Gamma) variants, does not exceed 5%. This combination currently is authorized in all US mainland states due to the high prevalence of the Delta variant; it currently is not authorized in Hawaii.5,18
Bamlanivimab and etesevimab is also authorized for individuals 12 and older for post-exposure prophylaxis against COVID-19.5 This authorization is based on the results of a trial of bamlanivimab in nursing-home residents at high-risk for severe COVID-19. Compared with placebo, bamlanivimab was associated with a significant reduction in incident SARS-CoV-2 infection by day 29 (15.1% vs 31.9%; odds ratio = 0.24).19
Remdesivir – Remdesivir is an inhibitor of SARS-CoV-2 nucleotide analog RNA polymerase.4 It is approved by the FDA for the treatment of COVID-19 requiring hospitalization, based on data from clinical trials (ACTT-1 and others) showing that it can reduce time to recovery in hospitalized patients with COVID-19.4,20–23 Remdesivir is recommended for use in hospitalized patients who require supplemental oxygen. The Infectious Diseases Society of America (IDSA) guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19.24 Among patients who do not need supplemental oxygen and have oxygen saturation >94% on room air, IDSA suggests against the routine use of remdesivir.24 The National Institutes of Health (NIH) guidelines recommend the use of remdesivir in hospitalized patients with COVID-19 who require supplemental oxygen.2 Remdesivir is given by IV injection and should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care.4 The most common adverse reactions observed with treatment with remdesivir are nausea and elevated levels of aspartate aminotransferase and alanine aminotransferase.4
Dexamethasone. Early in the pandemic, systemic corticosteroids were not recommended as part of the treatment of COVID-19.25 However, RECOVERY and some other clinical trials showed that treatment with dexamethasone improves survival among hospitalized patients with severe COVID-19 who require supplemental oxygen, including critically ill patients on ventilatory support.26–28 Patients receiving dexamethasone should be monitored for its adverse effects, including hyperglycemia, secondary infections, psychiatric effects, and avascular necrosis.29
Baricitinib. Baricitinib is an oral Janus kinase (JAK) inhibitor with anti-inflammatory as well as potential antiviral activity.30 The FDA issued an EUA for the use of baricitinib for the treatment of hospitalized patients aged 2 years or older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).7
The ACTT-2 trial showed that baricitinib plus remdesivir is superior to remdesivir alone in reducing recovery time among hospitalized patients with COVID-19, especially those receiving high-flow oxygen or noninvasive ventilation. Patients receiving baricitinib plus remdesivir were also more likely to have a better clinical status at day 15 compared with patients assigned to placebo plus remdesivir.7,30 The phase 3 COV-BARRIER study found a significant reduction in the proportion of hospitalized patients who died by day 28 with baricitinib versus placebo (8% vs 13%, respectively; hazard ratio = 0.57 (95% CI, 0.41–0.78)).31 Known adverse effects of baricitinib include serious venous thrombosis, such as pulmonary embolism, and serious infections.7
Management of Acute Respiratory Distress Syndrome from COVID-19
The leading cause of mortality with COVID-19 is respiratory failure from ARDS; without an effective therapy, current management of this viral infection is supportive.4 A trial of high-flow nasal oxygen should be considered in patients with moderately severe hypoxemia. This procedure provides high concentrations of humidified oxygen, low levels of positive end-expiratory pressure, and can facilitate the elimination of carbon dioxide, potentially avoiding the need for intubation or mechanical ventilation. Patients should be closely monitored for clinical deterioration to reduce the need of emergent intubations that may increase the risk of infection to healthcare workers.5
Prone positioning should be applied early, given its association with reduced mortality in other causes of severe ARDS. Veno-venous extracorporeal membrane oxygenation (ECMO) is reserved for the most severe cases of ARDS. In one report, out of 28 patients who received ECMO, 14 died, 9 were still on ECMO, and only 5 were successfully weaned.6 Additional therapeutic options for the management of severe ARDS in patients with COVID-19 are summarized in the table below.
- National Institutes of Health (NIH). Clinical spectrum of SARS-CoV-2 infection. In: Coronavirus disease 2019 (COVID-19) treatment guidelines. Available at www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/
- NIH. Therapeutic management of patients with COVID-19. In: Coronavirus disease 2019 (COVID-19) treatment guidelines. https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf
- Infectious Diseases Society of America (IDSA). Guidelines on the treatment and management of patients with COVID-19. Available at www.idsociety.org/globalassets/idsa/practice-guidelines/covid-19/treatment/tx-and-mgmt-v5.4.1-1.pdf
- US Food and Drug Administration (FDA). Remdesivir prescribing information. Available at www.gilead.com/-/media/files/pdfs/medicines/covid-19/veklury/veklury_pi.pdf
- FDA. Emergency use authorization (EUA) of Bamlanivimab and etesevimab. Available at www.fda.gov/media/145802/download
- FDA. Emergency use authorization (EUA) of casirivimab and imdevimab. Available at www.fda.gov/media/145611/download
- FDA. Emergency use authorization (EUA) of baricitinib. Available at www.fda.gov/media/143823/download
- Gandhi RT, Lynch JB, Del Rio C. Mild or moderate COVID-19. N Engl J Med. 2020;383:1757-1766.
- Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med.2020;382:1708-1720.
- Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.
- IDSA. COVID-19 real-time learning network. Thrombosis. Available at www.idsociety.org/covid-19-real-time-learning-network/disease-manifestations–complications/thrombosis/
- NIH. Antithrombotic therapy in patients with COVID-19. In: Coronavirus disease 2019 (COVID-19) treatment guidelines. Available at www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/antithrombotic-therapy/
- Weinreich DM, Sivapalasingam S, Norton T, et al; Trial Investigators. REGEN-COV antibody combination and outcomes in outpatients with Covid-19. N Engl J Med. 2021;Sept 29:Epub ahead of print.
- O’Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med. 2021;385:1184-1195.
- Chen P, Nirula A, Heller B, et al; BLAZE-1 Investigators. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 2021;384:229-237.
- Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021;325:632-644.
- FDA. Coronavirus (COVID-19) update: FDA revokes emergency use authorization for monoclonal antibody bamlanivimab. 4/16/2021. Available at www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-monoclonal-antibody-bamlanivimab
- FDA. Bamlanivimab and etesevimab authorized states, territories, and US jurisdictions. 10/8/2021. Available at www.fda.gov/media/151719/download
- Cohen MS, Nirula A, Mulligan MJ, et al. Effect of bamlanivimab vs placebo on incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities: a randomized clinical trial. JAMA. 2021;326:46-55.
- Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19–final report. N Engl J Med. 2020;383:1813-1826.
- Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-1578.
- Spinner CD, Gottlieb RL, Criner GJ, et al; GS-US-540-5774 Investigators. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324:1048-1057.
- Goldman JD, Lye DCB, Hui DS, et al; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020;383:1827-1837.
- IDSA. COVID-19 real-time learning network. Remdesivir. Available at www.idsociety.org/covid-19-real-time-learning-network/therapeutics-and-interventions/remdesivir/
- Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395:473-475.
- Horby P, Lim WS, Emberson JE, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384:693-704.
- Tomazini BM, Maia IS, Cavalcanti AB, et al; COALITION COVID-19 Brazil III Investigators. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial. JAMA. 2020;324:1307-1316.
- WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324:1330-1341.
- NIH. Corticosteroids. In: Coronavirus disease 2019 (COVID-19) treatment guidelines. Available at www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/
- Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021;384:795-807.
- Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Resp Med. 2021;Aug 31: Epub ahead of print.