Management Strategies

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can experience a wide range of clinical manifestations, 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 rapidly evolve.2,3 As of May 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, baricitinib) 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 (fever, cough, muscle pain, sore throat, malaise, headache, nausea, vomiting, diarrhea, loss of taste and smell); but 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).1,8,9 Risk factors for severe COVID-19 include having cardiovascular disease, chronic lung disease, sickle cell disease, diabetes, cancer, obesity, or 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) 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. Anti–SARS-CoV-2 monoclonal antibodies (casirivimab plus imdevimab, bamlanivimab plus etesevimab) are available under EUAs for outpatients with moderate COVID-19 who are at high risk (Figure) for progressing to severe disease and/or hospitalization.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 re-evaluate 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 Evaluation should include chest imaging, CBC, and a metabolic panel. Measurements of inflammatory markers may have prognostic value. Available treatment options for hospitalized patients with severe COVID-19 who require supplemental oxygen include remdesivir alone, dexamethasone plus remdesivir, dexamethasone alone, or baricitinib plus remdesivir.2,4 Administer empiric antibiotics if bacterial pneumonia or sepsis is suspected and re-evaluate 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 airborne infection isolation rooms (AIIRS).1 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.10,11

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 a 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), as well as other comorbidities and nosocomial complications.1 Available treatment options for critically ill patients with COVID-19 include dexamethasone alone, dexamethasone plus remdesivir, or baricitinib plus remdesivir.2,4 All critically ill patients with COVID-19 should receive prophylactic dose anticoagulation.10,11 Whether critically ill patients should receive therapeutic anticoagulation in the absence of confirmed or suspected venous thromboembolism is currently under investigation.10,11

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.15 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 Figure 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 medically attended visits (hospitalizations, emergency room visits, urgent care visits, or physician office/telemedicine visits).6,15 Infrequent infusion-related reactions to treatment with casirivimab plus imdevimab were reported.6 Benefit of treatment with casirivimab plus imdevimab has not been observed in hospitalized patients with COVID-19.6

Bamlanivimab plus etesevimab – Bamlanivimab and etesevimab are neutralizing monoclonal antibodies that binds to the receptor-binding domain of the spike protein of SARS-CoV-2 and prevents the virus from entering host cells.12 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 Figure 1 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-19.13 Compared to 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%).13 Results from the ACTIV-3 trial suggest that bamlanivimab, when co-administered with remdesivir, is not beneficial for hospitalized patients with COVID-19.14 The EUA for bamlanivimab monotherapy was revoked given the increasing incidence of SARS-CoV-2 viruses that are resistant to single monoclonal antibody therapy.

Remdesivir – Remdesivir is an inhibitor of SARS-CoV-2 nucleotide analog RNA polymerase.16 Remdesivir is approved by the FDA for the treatment of COVID-19 requiring hospitalization, based on data from clinical trials (ACTT-1 and others) that showed that it can reduce time to recovery in hospitalized patients with COVID-19.4,17-20 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-19.21 Among patients who do not need supplemental oxygen and have oxygen saturation >94% on room air, IDSA suggests against the routine use of remdesivir.21 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 aspartate and alanine aminotransferase levels.4

Dexamethasone – Early in the pandemic, systemic corticosteroids were not recommended as part of the treatment of COVID-19.22 However, clinical trials (RECOVERY and others) 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.23-25 Patients receiving dexamethasone should be monitored for its adverse effects, including hyperglycemia, secondary infections, psychiatric effects, and avascular necrosis.26

Baricitinib plus remdesivir – Baricitinib is an oral Janus kinase (JAK) inhibitor with anti-inflammatory as well as potential antiviral activity.27 The FDA issued an EUA for the use of baricitinib in combination with remdesivir for the treatment of hospitalized patients who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).7 This authorization is largely based on data from the ACTT-2 trial showing 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.7,27 It is not clear yet whether the combination of baricitinib plus remdesivir provides the same survival benefit as dexamethasone.3 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.28 In patients with acute hypoxemic respiratory failure despite supplemental oxygen, high-flow nasal oxygen is preferred over noninvasive positive pressure ventilation.29 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 for emergent intubations that may increase the risk of infection to healthcare workers.30

Prone positioning should be applied early, given its association with reduced mortality in other causes of severe ARDS. Veno-venous 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.31 Additional therapeutic options for the management of severe ARDS in patients with COVID-19 are summarized in the table below.

Therapeutic Options for Severe ARDS Related to COVID-192, 3, 27, 30, 32
TherapyImplementation
High-flow nasal oxygenMight prevent or delay the need for intubation
Tidal volumeUse 6 mL/kg per predicted bodyweight (can reduce to 4 mL/kg per predicted bodyweight)
Plateau airway pressureMaintain at <30 cm H2o if possible
Positive end-expiratory pressureConsider moderate to high levels if needed
Recruitment maneuversLittle value
Neuromuscular blockadeFor ventilator dyssynchrony, increased airway pressure, hypoxemia
Prone positioningFor worsening hypoxemia, PaO2:FiO2 <100–150 mm Hg
Inhaled NONot recommended
Fluid managementAim for a negative fluid balance of 0.5-1.0 L per day
Renal replacement therapyFor oliguric renal failure, acid-base management, negative fluid balance
AntibioticsFor secondary bacterial infections
DexamethasoneRecommended (6 mg IV or PO once daily for 10 days or until hospital discharge). Combination with remdesivir may be considered. Consider baricitinib with remdesivir rather than remdesivir alone in patients who cannot receive corticosteroids because of a contraindication.
Extracorporeal membrane oxygenation (ECMO)Use in patients with a Pao2:Fio2 of <50 mm Hg for >3 hours, a Pao2:Fio2 of <80 mm Hg for >6 hours, or an arterial blood pH of <7.25 with a partial pressure of arterial carbon dioxide of ≥60 mm Hg for >6 hours

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.

References

  1. National Institutes of Health (NIH). COVID-19 Treatment Guidelines. Clinical Spectrum of SARS-CoV-2 Infection. Available at https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/.
  2. National Institutes of Health (NIH). COVID-19 Treatment Guidelines. Therapeutic Management of Patients with COVID-19. Available at https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/.
  3. Infectious Diseases Society of America. Guidelines on the Treatment and Management of Patients with COVID-19. Available at https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/.
  4. US Food and Drug Administration (FDA). Remdesivir Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf.
  5. US Food and Drug Administration (FDA). Emergency Use Authorization (EUA) of Bamlanivimab. Fact Sheet for Healthcare Providers. Available at https://www.fda.gov/media/143603/download.
  6. US Food and Drug Administration (FDA). Emergency Use Authorization (EUA) of Casirivimab and Imdevimab. Available at https://www.fda.gov/media/143892/download.
  7. US Food and Drug Administration (FDA). Emergency Use Authorization (EUA) of Baricitinib. Fact Sheet for Healthcare Providers. Available at https://www.fda.gov/media/143823/download.
  8. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-1720.
  9. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. 2020;395:497-506.
  10. Infectious Diseases Society of America. COVID-19 Real-Time Learning Network. Thrombosis. Available at https://www.idsociety.org/covid-19-real-time-learning-network/disease-manifestations–complications/thrombosis/.
  11. National Institutes of Health (NIH). COVID-19 Treatment Guidelines. Antithrombotic Therapy in Patients with COVID-19. Available at https://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/antithrombotic-therapy/.
  12. 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. 2020:NEJMoa2029849. doi: 10.1056/NEJMoa2029849.
  13. 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. doi: 10.1001/jama.2021.0202.
  14. ACTIV-3/TICO LY-CoV555 Study Group. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med. 2020:NEJMoa2033130. doi: 10.1056/NEJMoa2033130.
  15. Weinreich DM, Sivapalasingam S, Norton T, et al; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 2021;384(3):238-251.
  16. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.
  17. 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(19):1813-1826.
  18. 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(10236):1569-1578.
  19. 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(11):1048-1057.
  20. 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(19):1827-1837.
  21. Infectious Diseases Society of America. COVID-19 Real-Time Learning Network. Remdesivir. Available at https://www.idsociety.org/covid-19-real-time-learning-network/therapeutics-and-interventions/remdesivir/.
  22. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-475.
  23. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 – preliminary report. N Engl J Med. 2020:NEJMoa2021436.
  24. 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(13):1307-1316.
  25. 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(13):1330-1341.
  26. National Institutes of Health (NIH). COVID-19 Treatment Guidelines. Corticosteroids. Available at https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/.
  27. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2020:NEJMoa2031994. doi: 10.1056/NEJMoa2031994.
  28. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;3:1-3.
  29. National Institutes of Health (NIH). Oxygenation and Ventilation. Available at https://www.covid19treatmentguidelines.nih.gov/critical-care/oxygenation-and-ventilation/.
  30. Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory distress syndrome from COVID-19. Lancet Respir Med. 2020;8(5):433-434.
  31. Phua J, Weng L, Ling L, et al. Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med. 2020;8:506-517.
  32. Combes A, Hajage D, Capellier G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med. 2018;378:1965-1975.
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Updates in the Treatment and Prevention of COVID-19​

Molnupiravir, an Oral Antiviral, Reduced the Risk of Hospitalization or Death in Patients with Mild-to-Moderate COVID-19

Molnupiravir, an investigational oral antiviral medicine, significantly reduced the risk of hospitalization or death by 50% in an interim analysis of the phase 3 MOVe-OUT trial. The planned analysis evaluated data from 775 at-risk, non-hospitalized adult patients with mild-to-moderate COVID-19. All patients enrolled had at least one risk factor associated with poor COVID-19 outcomes and were randomized within 5 days of symptom onset. At day 29, 7.3% of patients who received molnupiravir were either hospitalized or died, compared with 14.1% of placebo-treated patients (P= .0012). No deaths were reported in patients receiving molnupiravir, compared with 8 deaths in patients who received placebo. The incidence of any adverse event was comparable in the molnupiravir and placebo groups (35% and 40%, respectively). Discontinuation due to adverse events was lower with molnupiravir (1.3%) versus placebo (3.4%).

Reference:

https://www.contagionlive.com/view/molnupiravir-could-become-first-authorized-covid-19-pill