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ACEP COVID-19 Field Guide

Table of Contents

Management of Patients With COVID-19

Treatment

Currently, no FDA-approved drugs exist to specifically treat patients with COVID-19.

Table 10.1 Recommendation rating scheme.

Table_10.2_Recommendation_rating_scheme.png

For more information, see the NIH’s “COVID-19 Treatment Guidelines.”

Also refer to the “Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19” published on April 11, 2020.

Definition of COVID-19 Disease Severity

  • Mild: A variety of symptoms (eg, fever, cough, sore throat, malaise, headache, muscle pain, malaise) without shortness of breath/dyspnea or abnormal chest imaging (if obtained). 
  • Moderate: Evidence of lower respiratory disease by clinical assessment or imaging with SaO2 >94% on room air (sea level).
  • Severe: Having a SaO2 <94% on room air (sea level), respiratory frequency >30 breaths/minute, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50%.
  • Critical: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.
  • In pediatric patients, radiographic abnormalities are common and, for the most part, should not be used as the sole criteria to define COVID-19 illness category. Normal values for respiratory rate also vary with age in children, thus hypoxia should be the primary criteria to define severe illness, especially in younger children.

Management of Nonhospitalized Patients With Acute COVID-19

General Management of Nonhospitalized Patients With Acute COVID-19

  • Management of nonhospitalized patients with acute COVID-19 should include providing supportive care, taking steps to reduce the risk of SARS-CoV-2 transmission (including isolating the patient), and advising patients on when to contact a health care provider and seek an in-person evaluation (AIII).
  • When possible, patients with symptoms of COVID-19 should be triaged via telehealth visits before receiving in-person care. Patients with dyspnea should be referred for an in-person evaluation by a health care provider and should be followed closely during the initial days after the onset of dyspnea to assess for worsening respiratory status (AIII).
  • Management plans should be based on a patient’s vital signs, physical exam findings, risk factors for progression to severe illness, and the availability of health care resources (AIII).
  • Anticoagulants and antiplatelet therapy 
    • Anticoagulants and antiplatelet therapy should not be initiated in the ED for the prevention of venous thromboembolism (VTE) or arterial thrombosis if the patient is not being admitted to the hospital, unless the patient has other indications for the therapy or is participating in a clinical trial (AIII).
    • Hospitalized patients with COVID-19 should not be routinely discharged while receiving VTE prophylaxis, unless they have another indication or are participating in a clinical trial (AIII).

Therapeutic Management of Nonhospitalized Adults With COVID-19

  • Anti-SARS-CoV-2 Monoclonal Antibodies
      • The NIH COVID Guidelines recommend using one of the following anti-SARS-CoV-2 monoclonal antibodies to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression (treatments are listed in alphabetical order):
        • Casirivimab plus imdevimab; or
        • Sotrovimab
      • At this time, the NIH COVID Guidelines recommend against the use of bamlanivimab plus etesevimab (AIII) because of the increase in the proportion of the variants of concern Gamma (P.1) and Beta (B.1.351), 
        • These variants have shown a reduced susceptibility to both bamlanivimab and etesevimab.
  • Dexamethasone
      • The NIH COVID Guidelines recommend against the use of dexamethasone or other systemic glucocorticoids to treat outpatients with mild to moderate COVID-19 who do not require hospitalization or supplemental oxygen (AIII). 
        • There is currently a lack of safety and efficacy data on the use of these agents, and systemic glucocorticoids may cause harm in these patients.
      • Patients who are receiving dexamethasone or another corticosteroid for other indications should continue therapy for their underlying conditions as directed by their health care providers (AIII).
      • The NIH COVID Guidelines recommend against the use of dexamethasone or other systemic glucocorticoids in this population, as there are no clinical trial data to support their use (AIII).
      • For hospitalized patients with COVID-19 who do not require supplemental oxygen after discharge, the NIH COVID Guidelines recommend against the continuation of dexamethasone (AIIa).
      • In rare cases, patients with COVID-19 who require supplemental oxygen and hospital admission may need to be discharged from the ED due to scarce resources (e.g., in cases where hospital beds or staff are not available). 
        • For these patients, the NIH COVID Guidelines recommend using dexamethasone 6 mg PO once daily for the duration of supplemental oxygen (dexamethasone use should not exceed 10 days) with careful monitoring for adverse events (BIII).
  • Remdesivir
      • The NIH COVID Guidelines recommend against the continuation of remdesivir (AIIa) in hospitalized patients with COVID-19 who are stable enough for discharge and who do not require supplemental oxygen.
  • Baricitinib
      • The NIH COVID Guidelines recommend against the continuation of baricitinib (AIIa) in hospitalized patients with COVID-19 who are stable enough for discharge and who do not require supplemental oxygen.
      • The NIH COVID Guidelines recommend against the use of baricitinib in these patients, except in a clinical trial (AIII).
  • Other Agents 
      • The NIH COVID Guidelines recommend against the use of chloroquine or hydroxychloroquine with or without azithromycin (AI), lopinavir/ritonavir, and other HIV protease inhibitors (AIII) for outpatient treatment of COVID-19.
      • The NIH COVID Guidelines recommend against the use of antibacterial therapy (e.g., azithromycin, doxycycline) for outpatient treatment of COVID-19 in the absence of another indication (AIII).
      • Anticoagulants and antiplatelet therapy should not be initiated in the outpatient setting for the prevention of venous thromboembolism or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial (AIII). 
      • Health care providers should provide information about ongoing clinical trials of investigational therapies to eligible outpatients with COVID-19 so they can make informed decisions about participating in clinical trials (AIII).
  • Concomitant Medication Management
    • In general, a patient’s usual medication and/or supplement regimen should be continued after the diagnosis of COVID-19. Angiotensin-converting enzyme inhibitors, statin therapy, nonsteroidal anti-inflammatory drugs, and oral, inhaled, and intranasal corticosteroids that are prescribed for comorbid conditions should be continued as directed (AIII). 
    • In patients with HIV, antiretroviral therapy should not be switched or adjusted for the purpose of preventing or treating SARS-CoV-2 infection (AIII).

Care of Critically Ill Adult Patients With COVID-19 - Summary Recommendations

Infection Control

  • For health care workers who are performing aerosol-generating procedures on patients with COVID-19, the COVID-19 Treatment Guidelines NIH (the NIH) recommends using an N95 respirator (or equivalent or higher-level respirator) rather than surgical masks, in addition to other personal protective equipment (PPE) (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) (AIII).
  • The NIH recommends minimizing the use of aerosol-generating procedures on intensive care unit patients with COVID-19 and carrying out any necessary aerosol-generating procedures in a negative-pressure room, also known as an airborne infection isolation room, when available (AIII).
  • For health care workers who are providing usual care for nonventilated patients with COVID-19, the NIH recommends using an N95 respirator (or equivalent or higher-level respirator) or a surgical mask in addition to other PPE (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) (AIIa).
  • For health care workers who are performing non-aerosol-generating procedures on patients with COVID-19 who are on closed-circuit mechanical ventilation, the NIH recommends using an N95 respirator (or equivalent or higher-level respirator) in addition to other PPE (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) because ventilator circuits may become disrupted unexpectedly (BIII).
  • The NIH recommends that endotracheal intubation in patients with COVID-19 be performed by health care providers with extensive airway management experience, if possible (AIII).
  • The NIH recommends that intubation be performed using video laryngoscopy, if possible (CIIa).

Hemodynamics

  • For adults with COVID-19 and shock, the NIH recommends using dynamic parameters, skin temperature, capillary refilling time, and/or lactate levels over static parameters to assess fluid responsiveness (BIIa).
  • For the acute resuscitation of adults with COVID-19 and shock, the NIH recommends using buffered/balanced crystalloids over unbalanced crystalloids (BIIa).
  • For the acute resuscitation of adults with COVID-19 and shock, the NIH recommends against the initial use of albumin for resuscitation (BIIa).
  • The NIH recommends against using hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock (AIIa).
  • The NIH recommends norepinephrine as the first-choice vasopressor (AIIa). The NIH recommends adding either vasopressin (up to 0.03 units/min) (BIIa) or epinephrine (CIIb) to norepinephrine to raise mean arterial pressure to target or adding vasopressin (up to 0.03 units/min) (CIIa) to decrease norepinephrine dosage.
  • When norepinephrine is available, the NIH recommends against using dopamine for patients with COVID-19 and shock (AIIa).
  • The NIH recommends against using low-dose dopamine for renal protection (BIIa).
  • The NIH recommends using dobutamine in patients who show evidence of cardiac dysfunction and persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents (BIII).
  • The NIH recommends that all patients who require vasopressors have an arterial catheter placed as soon as practical, if resources are available (BIII).
  • For adults with COVID-19 and refractory septic shock who are not receiving corticosteroids to treat their COVID-19, the NIH recommends using low-dose corticosteroid therapy (“shock-reversal”) over no corticosteroid therapy (BIIa).

Oxygenation and Ventilation

  • For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the NIH recommends high-flow nasal cannula (HFNC) oxygen over noninvasive positive pressure ventilation (NIPPV) (BIIa).
  • In the absence of an indication for endotracheal intubation, the NIH recommends a closely monitored trial of NIPPV for adults with COVID-19 and acute hypoxemic respiratory failure and for whom HFNC is not available (BIIa).
  • For patients with persistent hypoxemia despite increasing supplemental oxygen requirements in whom endotracheal intubation is not otherwise indicated, the NIH recommends considering a trial of awake prone positioning to improve oxygenation (CIIa).
  • The NIH recommends against using awake prone positioning as a rescue therapy for refractory hypoxemia to avoid intubation in patients who otherwise meet the indications for intubation and mechanical ventilation (AIII).
  • If intubation becomes necessary, the procedure should be performed by an experienced practitioner in a controlled setting due to the enhanced risk of severe acute respiratory syndrome coronavirus 2 exposure to health care practitioners during intubation (AIII).
  • For mechanically ventilated adults with COVID-19 and acute respiratory distress syndrome (ARDS):
    • The NIH recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body weight) over higher VT ventilation (VT >8 mL/kg) (AI).
    • The NIH recommends targeting plateau pressures of <30 cm H2O (AIIa).
    • The NIH recommends using a conservative fluid strategy over a liberal fluid strategy (BIIa).
    • The NIH recommends against the routine use of inhaled nitric oxide (AIIa).
  • For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:
    • The NIH recommends using a higher positive end-expiratory pressure (PEEP) strategy over a lower PEEP strategy (BIIa).
    • For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized ventilation, the NIH recommends prone ventilation for 12 to 16 hours per day over no prone ventilation (BIIa).
  • For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:
    • The NIH recommends using, as needed, intermittent boluses of neuromuscular blocking agents (NMBA) or continuous NMBA infusion to facilitate protective lung ventilation (BIIa).
    • In the event of persistent patient-ventilator dyssynchrony, or in cases where a patient requires ongoing deep sedation, prone ventilation, or persistently high plateau pressures, the NIH recommends using a continuous NMBA infusion for up to 48 hours as long as patient anxiety and pain can be adequately monitored and controlled (BIII).
  • For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and other rescue strategies:
    • The NIH recommends using recruitment maneuvers rather than not using recruitment maneuvers (CIIa).
    • If recruitment maneuvers are used, the NIH recommends against using staircase (incremental PEEP) recruitment maneuvers (AIIa).
    • The NIH recommends using an inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in oxygenation is observed, the treatment should be tapered off (CIII).

Acute Kidney Injury and Renal Replacement Therapy

  • For critically ill patients with COVID-19 who have acute kidney injury and who develop indications for renal replacement therapy, the NIH recommends continuous renal replacement therapy (CRRT), if available (BIII).
  • If CRRT is not available or not possible due to limited resources, the NIH recommends prolonged intermittent renal replacement therapy rather than intermittent hemodialysis (BIII).

Pharmacologic Interventions

  • In patients with COVID-19 and severe or critical illness, there are insufficient data to recommend empiric broad-spectrum antimicrobial therapy in the absence of another indication.
  • If antimicrobials are initiated, the NIH recommends that their use should be reassessed daily in order to minimize the adverse consequences of unnecessary antimicrobial therapy (AIII).

Extracorporeal Membrane Oxygenation

  • There are insufficient data to recommend either for or against the use of extracorporeal membrane oxygenation in patients with COVID-19 and refractory hypoxemia.

Additional information can be found on the NIH COVID-19 Treatment Guidelines for Care of Critically Ill Adult Patients With COVID-19

Therapeutic Management of Adults With COVID-19

Patients With Mild to Moderate COVID-19 Who Are Not Hospitalized

  • For patients who are not at high risk of disease progression:
    • The NIH recommends providing supportive care and symptomatic management (AIII).
  • For patients who are at high risk of disease progression, as defined by the EUA criteria for treatment with anti-SARS-CoV-2 monoclonal antibodies:
    • Bamlanivimab 700 mg plus etesevimab 1,400 mg (AIIa); or
    • Casirivimab 1,200 mg plus imdevimab 1,200 mg (AIIa).
    • The NIH recommends using one of the following combination anti-SARS-CoV-2 monoclonal antibodies (treatments are listed in alphabetical order):
    • Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen test or a nucleic acid amplification test and within 10 days of symptom onset.

Patients Who Are Hospitalized With Moderate COVID-19 but Who Do Not Require Supplemental Oxygen

  • The NIH recommends against the use of dexamethasone or other corticosteroids (AIIa). Patients who are receiving dexamethasone or another corticosteroid for other indications should continue therapy for their underlying conditions as directed by their health care provider.
  • There are insufficient data to recommend either for or against the routine use of remdesivir in these patients. The use of remdesivir may be appropriate in patients who have a high risk of disease progression.

For Hospitalized Patients With COVID-19 Who Require Supplemental Oxygen but Who Do Not Require Oxygen Delivery Through a High-Flow Device, Noninvasive Ventilation, Invasive Mechanical Ventilation, or Extracorporeal Membrane Oxygenation

  • The NIH recommends one of the following options for these patients:
    • Remdesivir (e.g., for patients who require minimal supplemental oxygen) (BIIa);
    • Dexamethasone plus remdesivir (e.g., for patients who require increasing amounts of oxygen) (BIII); or
    • Dexamethasone (e.g., when combination therapy with remdesivir cannot be used or is not available) (BI).
  • Additional Considerations
    • If dexamethasone is not available, an alternative corticosteroid such as prednisone, methylprednisolone, or hydrocortisone can be used (BIII). See Corticosteroids for dosing recommendations.
    • In the rare circumstances when corticosteroids cannot be used, baricitinib plus remdesivir can be used (BIIa). Baricitinib should not be used without remdesivir.
    • There is insufficient evidence to determine which patients in this group would benefit from adding tocilizumab to dexamethasone treatment. Some Panel members would add tocilizumab to a patient’s dexamethasone treatment in cases where the patient has rapidly increasing oxygen needs and C-reactive protein (CRP) levels ≥75 mg/L but does not yet require oxygen through high-flow nasal canula (HFNC) or noninvasive ventilation.

For Hospitalized Patients With COVID-19 Who Require Delivery of Oxygen Through a High-Flow Device or Noninvasive Ventilation but Not Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation

  • The NIH recommends one of the following options for these patients:
    • Dexamethasone alone (AI); or
    • A combination of dexamethasone plus remdesivir (BIII).
  • For recently hospitalized patients (i.e., those who are within 3 days of hospital admission) who have rapidly increasing oxygen needs, require high-flow oxygen or noninvasive ventilation, and have increased markers of inflammation, add baricitinib (BIIa) or tocilizumab (BIIa) (drugs are listed alphabetically) to one of the two options above.
  • The NIH Guidelines recommend against the use of baricitinib in combination with tocilizumab for the treatment of COVID-19, except in a clinical trial (AIII). Because both baricitinib and tocilizumab are potent immunosuppressants, there is the potential for an additive risk of infection.
  • Additional Considerations
    • Immunosuppressive therapy (e.g., dexamethasone with or without baricitinib or tocilizumab) may increase the risk of opportunistic infections or reactivation of latent infections; however, randomized trials have not demonstrated an increase in the frequency of infections.
    • Prophylactic treatment with ivermectin should be considered for patients who are from areas where strongyloidiasis is endemic.
  • Using Corticosteroids
    • The combination of dexamethasone and remdesivir has not been rigorously studied in clinical trials. Because there are theoretical reasons for combining these drugs, the NIH Guidelines consider both dexamethasone alone and the combination of remdesivir and dexamethasone to be acceptable options for treating COVID-19 in this group of patients.
    • The NIH Guidelines recommend against the use of remdesivir alone because it is not clear whether remdesivir confers a clinical benefit in this group of patients (AIIa).
    • For patients who initially received remdesivir monotherapy and progressed to requiring high-flow oxygen or noninvasive ventilation, add dexamethasone and complete the treatment course of remdesivir.
    • If dexamethasone is not available, equivalent doses of other corticosteroids such as prednisone, methylprednisolone, or hydrocortisone may be used (BIII). 
  • Using Baricitinib and Tocilizumab
    • Some clinicians may choose to assess a patient’s clinical response to dexamethasone before deciding whether adding baricitinib or tocilizumab is necessary.
    • Baricitinib or tocilizumab should only be given in combination with dexamethasone or another corticosteroid at an equivalent dose. 
    • The NIH Guideline has insufficient evidence to recommend one drug over the other. Treatment decisions should be made based on local guidance, drug availability, and patient comorbidities.

For Hospitalized Patients With COVID-19 Who Require Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation

  • The NIH recommends the use of dexamethasone in hospitalized patients with COVID-19 who require invasive mechanical ventilation or ECMO (AI).
  • Additional Considerations
    • If dexamethasone is not available, equivalent doses of alternative corticosteroids such as prednisone, methylprednisolone, or hydrocortisone may be used (BIII).
    • For patients who initially received remdesivir monotherapy and progressed to requiring invasive mechanical ventilation or ECMO, dexamethasone should be initiated and remdesivir should be continued until the treatment course is completed.
    • The NIH recommends against the use of remdesivir monotherapy (AIIa).
    • Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid at an equivalent dose).
    • Although some patients in the REMAP-CAP and RECOVERY trials received a second dose of tocilizumab at the discretion of their treating physicians, there are insufficient data to determine which patients, if any, would benefit from an additional dose of the drug.
    • The combination of dexamethasone and tocilizumab may increase the risk of opportunistic infections or reactivation. Prophylactic treatment with ivermectin should be considered for patients who are from areas where strongyloidiasis is endemic.

Additional information can be found on the NIH COVID-19 Treatment Guidelines for Therapeutic Management of Adults With COVID-19

Antiviral Drugs That Are Approved or Under Evaluation for the Treatment of COVID-19

Summary Recommendations

Remdesivir is the only Food and Drug Administration-approved drug for the treatment of COVID-19. 

Remdesivir

Chloroquine or Hydroxychloroquine With or Without Azithromycin

  • The NIH COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of chloroquine or hydroxychloroquine and/or azithromycin for the treatment of COVID-19 in hospitalized patients (AI) and in nonhospitalized patients (AIIa).
  • Chloroquine and hydroxychloroquine may decrease the antiviral activity of remdesivir; coadministration of these drugs is not recommended.
  • Hydroxychloroquine, chloroquine, and azithromycin are not approved by the FDA for the treatment of COVID-19.

Lopinavir/Ritonavir and Other HIV Protease Inhibitors

  • The NIH recommends against the use of lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in hospitalized patients (AI). 
  • The NIH recommends against the use of lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in nonhospitalized patients (AIII).  

Ivermectin

  • There are insufficient data for the Panel to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19. 

Additional information can be found on the NIH COVID-19 Treatment Guidelines for Antiviral Drugs That Are Approved or Under Evaluation for the Treatment of COVID-19

Baricitinib for the Treatment of Adults with COVID-19

Summary Recommendations

  • The NIH recommends using either baricitiniba (BIIa) or tocilizumab (BIIa) (listed alphabetically) in combination with dexamethasone alone or dexamethasone plus remdesivir for the treatment of COVID-19 in hospitalized patients on high-flow oxygen or noninvasive ventilation who have evidence of clinical progression or increased markers of inflammation.
    • Among hospitalized patients with hypoxemia who require supplemental oxygen therapy, there is insufficient evidence to identify which patients would benefit from the addition of baricitinib or tocilizumab to dexamethasone (with or without remdesivir). 
    • The NIH Guidelines add that either baricitiniba or tocilizumab to patients who are exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone, but who do not yet require noninvasive ventilation or high-flow oxygen.
  • In the rare circumstance when corticosteroids cannot be used, the NIH recommends using baricitiniba in combination with remdesivir for the treatment of COVID-19 in hospitalized, nonintubated patients who require oxygen supplementation (BIIa).
  • There is insufficient evidence to recommend either for or against the use of baricitinib in combination with dexamethasone for the treatment of COVID-19 in hospitalized patients who require invasive mechanical ventilation.
  • The NIH recommends against the use of baricitinib in combination with tocilizumab for the treatment of COVID-19, except in a clinical trial (AIII). Because both baricitinib and tocilizumab are potent immunosuppressants, there is the potential for an additive risk of infection.
  • There is insufficient evidence for the Panel to recommend either for or against the use of baricitinib for the treatment of COVID-19 in children.

Additional information can be found on the NIH COVID-19 Treatment Guidelines Statement on Baricitinib for the Treatment of Adults with COVID-19

Colchicine

Summary Recommendations

  • There is insufficient evidence for the NIH COVID-19 Treatment Guidelines to recommend either for or against the use of colchicine for the treatment of nonhospitalized patients with COVID-19.
  • The Guideline recommends against the use of colchicine for the treatment of hospitalized patients with COVID-19 (AI).

Anti-SARS-CoV-2 Antibody Products

Anti-SARS-CoV-2 Monoclonal Antibodies

  • The NIH COVID-19 Treatment Guidelines Panel recommends using one of the following anti-SARS-CoV-2 monoclonal antibodies, listed in alphabetical order, to treat nonhospitalized patients with mild to moderate COVID-19 who are at high risk of clinical progression, as defined by the EUA criteria.
    • Bamlanivimab plus etesevimab; or
    • Casirivimab plus imdevimab; or
    • Sotrovimab.
  • Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen or nucleic acid amplification test (NAAT) and within 10 days of symptom onset.
    • There are no comparative data to determine whether there are differences in clinical efficacy or safety between bamlanivimab plus etesevimab, casirivimab plus imdevimab, or sotrovimab.
    • Some SARS-CoV-2 variants, particularly those that contain the mutation E484K (see Anti-SARS-CoV-2 Monoclonal Antibodies), have reduced susceptibility to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro; however, the clinical impact of these mutations is not known.
    • The availability of bamlanivimab plus etesevimab may be restricted in areas that have an elevated prevalence of variants of concern with markedly reduced in vitro susceptibility to these agents (e.g., P.1 [Gamma], B.1.351 [Beta]). 
    • In regions where SARS-CoV-2 variants of concern or interest with modestly reduced in vitro susceptibility to bamlanivimab plus etesevimab (e.g., B.1.427/429 [Epsilon], B.1.526 [Iota]) are common, some NIH Guidelines panel members would preferentially use casirivimab plus imdevimab or sotrovimab while acknowledging that it is not known whether in vitro susceptibility data correlate with clinical outcomes.
  • The NIH recommends against the use of anti-SARS-CoV-2 monoclonal antibodies for patients who are hospitalized because of COVID-19, except in a clinical trial (AIIa). However, their use should be considered for persons with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 and who otherwise meet the EUA criteria.


Additional information can be found on the NIH COVID-19 Treatment Guidelines Statement on the Emergency Use Authorizations of Anti-SARS-CoV-2 Monoclonal Antibodies for the Treatment of COVID-19

COVID-19 Convalescent Plasma

  • The NIH recommends against the use of low-titer COVID-19 convalescent plasma for the treatment of COVID-19 (AIIb). Low-titer COVID-19 convalescent plasma is no longer authorized through the convalescent plasma EUA.
  • For hospitalized patients with COVID-19 who do not have impaired immunity:
    • The NIH recommends against the use of COVID-19 convalescent plasma for the treatment of COVID-19 in mechanically ventilated patients (AI).
    • The NIH recommends against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients who do not require mechanical ventilation, except in a clinical trial (AI).
  • For hospitalized patients with COVID-19 who have impaired immunity:
    • There are insufficient data for the Panel to recommend either for or against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19.
  • For nonhospitalized patients with COVID-19:
    • There are insufficient data for the Panel to recommend either for or against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19 in patients who are not hospitalized.

Anti-SARS-CoV-2 Specific Immunoglobulin

There are insufficient data for the NIH to recommend either for or against the use of anti-SARS-CoV-2 specific immunoglobin for the treatment of COVID-19.

Additional information can be found on the NIH COVID-19 Treatment Guidelines for Anti-SARS-CoV-2 Antibody Products

Immunomodulators Under Evaluation for the Treatment of COVID-19

Summary Recommendations

See NIH Guidelines for Therapeutic Management of Patients with COVID-19 for the COVID-19 Treatment recommendations on the use of the following:

  • Baricitinib in combination with remdesivir when corticosteroids cannot be used,
  • Dexamethasone (or other corticosteroids) with or without remdesivir, and
  • Tocilizumab with dexamethasone (with or without remdesivir).

See additional recommendations on the use of baricitinib and tocilizumab below.

Other Immunomodulators

There are insufficient data for the NIH to recommend either for or against the use of the following immunomodulators for the treatment of COVID-19:

  • Fluvoxamine
  • Interleukin (IL)-1 inhibitors (e.g., anakinra)
  • Interferon beta for the treatment of early (i.e., <7 days from symptom onset) mild to moderate COVID-19
  • Sarilumab for patients who are within 24 hours of admission to the intensive care unit (ICU) and who require invasive mechanical ventilation, noninvasive ventilation, or high-flow oxygen (>0.4 FiO2/30 L/min of oxygen flow)
  • Tocilizumab for most hospitalized patients with hypoxemia who require conventional oxygen therapy

The NIH recommends against the use of the following immunomodulators for the treatment of COVID-19, except in a clinical trial:

  • Baricitinib without remdesivir (AIII)
  • Colchicine for hospitalized patients with COVID-19 (AIII)
  • Interferons (alfa or beta) for the treatment of severely or critically ill patients with COVID-19 (AIII)
  • Kinase inhibitors:
    • Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib) (AIII)
    • Janus kinase inhibitors other than baricitinib (e.g., ruxolitinib, tofacitinib) (AIII)
  • Non-SARS-CoV-2-specific intravenous immunoglobulin (IVIG) (AIII). This recommendation should not preclude the use of IVIG when it is otherwise indicated for the treatment of complications that arise during the course of COVID-19.
  • Sarilumab for patients who do not require ICU-level care or who are admitted to the ICU for >24 hours but do not require invasive mechanical ventilation, noninvasive ventilation, or supplemental oxygen administered through a high-flow device (BIIa)
  • The anti-IL-6 monoclonal antibody siltuximab (AIII)

Antithrombotic Therapy in Patients With COVID-19

Laboratory Testing

  • In nonhospitalized patients with COVID-19, there are currently no data to support the measurement of coagulation markers (e.g., D-dimers, prothrombin time, platelet count, fibrinogen) (AIII).
  • In hospitalized patients with COVID-19, hematologic and coagulation parameters are commonly measured, although there are currently insufficient data to recommend either for or against using this data to guide management decisions.

Chronic Anticoagulant and Antiplatelet Therapy

  • Patients who are receiving anticoagulant or antiplatelet therapies for underlying conditions should continue these medications if they receive a diagnosis of COVID-19 (AIII).

Venous Thromboembolism Prophylaxis and Screening

  • For nonhospitalized patients with COVID-19, anticoagulants and antiplatelet therapy should not be initiated for the prevention of venous thromboembolism (VTE) or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial (AIII).
  • Hospitalized nonpregnant adults with COVID-19 should receive prophylactic dose anticoagulation (AIII) (see the recommendations for pregnant individuals below). Anticoagulant or antiplatelet therapy should not be used to prevent arterial thrombosis outside of the usual standard of care for patients without COVID-19 (AIII).
  • There are currently insufficient data to recommend either for or against the use of thrombolytics or higher than the prophylactic dose of anticoagulation for VTE prophylaxis in hospitalized COVID-19 patients outside of a clinical trial.
  • Hospitalized patients with COVID-19 should not routinely be discharged from the hospital while on VTE prophylaxis (AIII). Continuing anticoagulation with a Food and Drug Administration-approved regimen for extended VTE prophylaxis after hospital discharge can be considered for patients who are at low risk for bleeding and high risk for VTE, as per the protocols for patients without COVID-19 (see details on defining at-risk patients below) (BI).
  • There are currently insufficient data to recommend either for or against routine deep vein thrombosis screening in COVID-19 patients without signs or symptoms of VTE, regardless of the status of their coagulation markers.
  • For hospitalized COVID-19 patients who experience rapid deterioration of pulmonary, cardiac, or neurological function, or of sudden, localized loss of peripheral perfusion, the possibility of thromboembolic disease should be evaluated (AIII).

Hospitalized Children With COVID-19

  • For hospitalized children with COVID-19, indications for VTE prophylaxis should be the same as those for children without COVID-19 (BIII).

Treatment

  • When diagnostic imaging is not possible, patients with COVID-19 who experience an incident thromboembolic event or who are highly suspected to have thromboembolic disease should be managed with therapeutic doses of anticoagulant therapy (AIII).
  • Patients with COVID-19 who require extracorporeal membrane oxygenation or continuous renal replacement therapy or who have thrombosis of catheters or extracorporeal filters should be treated with antithrombotic therapy as per the standard institutional protocols for those without COVID-19 (AIII).

Special Considerations During Pregnancy and Lactation

  • If antithrombotic therapy is prescribed during pregnancy prior to a diagnosis of COVID-19, this therapy should be continued (AIII).
  • For pregnant patients hospitalized for severe COVID-19, prophylactic dose anticoagulation is recommended unless contraindicated (see below) (BIII).
  • Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not recommended for pregnant patients (AIII). Decisions to continue VTE prophylaxis in the pregnant or postpartum patient after discharge should be individualized, considering concomitant VTE risk factors.
  • Anticoagulation therapy use during labor and delivery requires specialized care and planning. It should be managed in pregnant patients with COVID-19 in a similar way as in pregnant patients with other conditions that require anticoagulation in pregnancy (AIII).
  • Unfractionated heparin, low molecular weight heparin, and warfarin do not accumulate in breast milk and do not induce an anticoagulant effect in the newborn; therefore, they can be used by breastfeeding individuals with or without COVID-19 who require VTE prophylaxis or treatment (AIII). In contrast, use of direct-acting oral anticoagulants during pregnancy is not routinely recommended due to lack of safety data (AIII).

Additional information can be found on the NIH COVID-19 Treatment Guidelines for Antithrombotic Therapy in Patients With COVID-19

Bamlanivimab

The FDA has issued an EUA for the investigational monoclonal antibody therapy bamlanivimab for the treatment of mild-to-moderate COVID-19 in adult and pediatric patients. 

  • Bamlanivimab is a monoclonal antibody that is specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells.
  • Bamlanivimab is authorized for patients with positive results of direct SARS-CoV-2 viral testing who are ≥12 years of age and weighing ≥40 kilograms (about 88 pounds), and who are at high risk for progressing to severe COVID-19 and/or hospitalization (Table 10.2). This includes those who are ≥65 years of age, or who have certain chronic medical conditions.
  • While the safety and effectiveness of this investigational therapy continues to be evaluated, bamlanivimab was shown in clinical trials to reduce COVID-19-related hospitalization or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo.
  • Bamlanivimab is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19. 
    • A benefit of bamlanivimab treatment has not been shown in patients hospitalized due to COVID-19. 
    • Monoclonal antibodies, such as bamlanivimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.

Table 10.2 Bamlanivimab (Eli Lilly) EUA — High-Risk Criteria.

Table 10.3 Bamlanivimab (Eli Lilly) EUA—High-Risk Criteria.png

Link to BMI Calculator

Bamlanivimab Administration

EUA authorizes use of Bamlanivimab for treatment of high risk (Table 10.3) COVID 19 outpatients (ages ≥12 years, weight ≥40 kg) with mild to moderate symptoms at risk for progressing to severe disease/hospitalization.

Key Summary Steps:

  • Direct SARS-CoV-2 test (eg, PCR, rapid antigen test) must be positive
  • Administered as soon as possible after positive test result and within 10 days of symptom onset
  • Provider to review EUA fact sheet
  • Patient/caregiver to be provided with EUA fact sheet
  • Administered in a setting where health care providers have direct access to medications to manage severe reactions

Table 10.3 Dosing and requirements.

Table 10.4 Dosing and Requirements .png

Recently, the FDA authorized revised preparation and administration instructions in the Fact Sheet for Healthcare Providers for bamlanivimab. As seen below, these changes include shortened infusion times, ranging from 16-60 minutes, depending on the size of IV bag used.

These changes were made in response to feedback received from front-line healthcare professionals administering these infusions and are aimed at reducing the burden on the healthcare system.

Table 10.4 Recommended Dilution and Administration Instructions for Bamlanivimab

Recommended Dilution and Administration Instructions for Bamlanivimab.png

Infusion Supplies

  • 250 mL 0.9% NaCl
  • IV Insertion Supplies
  • IV Infusion Tubing
  • 0.2/0.22 µm Filter
  • 20 mL Syringe x2
  • 18 g Sterile Needle x2
  • Alcohol Wipes

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Readiness Checklist: Administration of Outpatient mAbs under EUA

  • Allocate dedicated space and develop plan to manage patient flow
    • Clear process for patients that are coming to clinical site including scheduling requirements
    • Admission process for COVID-19 positive patients designed to minimize risk of spread per facility requirements/directions/guidelines
    • Dedicated room available for treatment 
  • Ensure dedicated source of supplies; which may be difficult to procure
    • Needed infusion components obtained 
    • Example: IV kits, infusion chair, IV pole, vital sign monitoring equipment, emergency medications
  • Assign sufficient personnel to meet expected demand
    • Sufficient staffing plans in place for Nurse/IV tech, Physician, Pharmacist
    • Likely need dedicated team to treat patients
  • Prepare for drug administration process
    • Pre-visit: Clear treatment and monitoring plan developed for during infusion
    • Treatment: 1-hour treatment and up 1-hour post-treatment observation
    • Emergency protocol defined for addressing potential infusion reactions or complications
    • Post-treatment: Clear process for patient follow-up defined using telemedicine as possible
  • Ensure process for reimbursement in place (non-drug administrative costs)
  • Prepare for reporting needs for adverse events and record keeping

Available for download:

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Table 10.5 Safety Bulletin: Covid 19 Monoclonal Antibody Administration

Table 10.5.png

Additional Information and Resources

EUA, Fact Sheets, Lilly Playbook, and FDA Resources

Allocation and Distribution

CMS and Reimbursement     

Casirivimab Plus Imdevimab

The FDA has issued an EUA to permit the emergency use of the unapproved products casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (≥12 years of age and weighing ≥ 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization.

  • Following the initial EUA, the FDA updated the Emergency Use Authorization (EUA) for REGEN-COV™, lowering the dose to 1,200 mg (600 mg casirivimab and 600 mg imdevimab), which is half the dose originally authorized
  • As part of the updated EUA, REGEN-COV should be administered by intravenous (IV) infusion; subcutaneous (SC) injections are an alternative when IV infusion is not feasible and would lead to a delay in treatment.

High-Risk Criteria for Emergency Use Authorization of the Casirivimab Plus Imdevimab Combination

The following medical conditions or other factors may place adults and pediatric patients (age 12-17 years and weighing at least 40 kg) at higher risk for progression to severe COVID-19:

  • Older age (for example, age ≥65 years of age)
  • Obesity or being overweight (for example, BMI >25 kg/m2, or if age 12-17, have BMI ≥85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm
  • Pregnancy
  • Chronic kidney disease
  • Diabetes
  • Immunosuppressive disease or immunosuppressive treatment
  • Cardiovascular disease (including congenital heart disease) or hypertension
  • Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension)
  • Sickle cell disease
  • Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies)
  • Having a medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID 19)) 

Other medical conditions or factors (for example, race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and authorization of REGEN-COV under the EUA is not limited to the medical conditions or factors listed above. For additional information see the CDC website: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medicalconditions.html.  

Casirivimab and imdevimab are not authorized for use in patients:

  • Who are hospitalized due to COVID-19; or
  • Who require oxygen therapy due to COVID-19; or
  • Who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to an underlying non-COVID-19 related-comorbidity.

Benefit of treatment with casirivimab plus imdevimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 who require high-flow oxygen or mechanical ventilation.

Additional Information:

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