NOTE: The FDA has addressed the use of bebtelovimab among nonhospitalized patients in light of an increase in subvariants. Due to resistance, bebtelovimab is not currently authorized for emergency use in any US region. Information and guidelines may change rapidly. Check in with listed reference in ‘Learn More – Primary Sources’ to best keep up to date.

SUMMARY:

NIH has released guidance on the diagnosis, management and treatment of COVID-19. A Panel was convened to develop recommendations, with the understanding that there is still much that is unknown and the guidelines will be updated as additional data become available

• Critical Care Treatment
• Inpatient Pharmacologic Management
• Therapeutic Management of Nonhospitalized Adults With COVID-19
• Serologic or Antibody Testing
• Concomitant Medications in Patients with COVID-19
• Coagulopathy Considerations
• Influenza and COVID-19

Critical Care Treatment

Infection Control When Caring for Patients with COVID-19

• Aerosol-generating procedures
  • Use fit-tested respirators (N-95 respirators) or powered air-purifying respirators rather than surgical masks
  • The above masks should be used in addition to other PPE (gloves, gown, and eye protection such as a face shield or safety goggles)
• Endotracheal intubation
  • Should be done by healthcare professionals “with extensive airway management experience, if possible”
  • Intubation should be done with video laryngoscopy, if possible

Hemodynamic Support

• First-choice vasopressor: Norepinephrine
• To assess fluid responsiveness
  • Use dynamic parameters, skin temperature, capillary refilling time, and/or lactate levels vs static parameters
• Acute resuscitation of adults with COVID-19 and shock
  • Use buffered/balanced crystalloids over unbalanced crystalloids
  • Panel recommends against initial use of albumin
• Septic shock and steroids
  • IV hydrocortisone 200 mg per day administered either as an infusion or in intermittent doses
  • Duration of hydrocortisone is typically a clinical decision
  • Patients who are receiving corticosteroids for COVID-19 are receiving sufficient replacement therapy such that they do not require additional hydrocortisone

Ventilatory Support for Patients with COVID-19

• Oxygen saturation (SpO2) target
  • Optimal goal is uncertain
  • A target SpO2 of 92% to 96% “seems logical”
  • Experience suggests that SpO2 <92% or >96% may be harmful
• Prone position
  • Appropriate candidate for awake prone positioning: Patients who can adjust their own position independently and tolerate lying prone
  • Awake proning should not be used as a substitute for intubation and invasive mechanical ventilation in patients with refractory hypoxemia who otherwise meet the indications for these interventions
  • Pregnancy: Acceptable and can be done in left lateral decubitus or fully prone
• Refractory hypoxemia in patients who otherwise require intubation and mechanical ventilation
  • Panel recommends against using awake prone positioning as a rescue therapy to avoid intubation 
• Acute hypoxemic respiratory failure despite conventional oxygen therapy
  • Options for providing enhanced respiratory support include high-flow nasal cannula (HFNC), NIPPV, intubation and invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)
  • Use HFNC oxygen rather than noninvasive positive pressure ventilation (NIPPV)
  • If HFNC is unavailable and there is no indication of intubation: Use a closely monitored trial of NIPPV
• For patients on supplemental oxygen
  • Monitor closely for worsening of respiratory status
  • If respiratory status worsens, the Panel recommends early intubation by an experienced practitioner in a controlled setting
• For patients mechanically ventilated with ARDS
  • Use low tidal volume (VT) ventilation (VT 4 to 8 mL/kg of predicted body weight) vs higher tidal volumes (VT >8 mL/kg)
  • If refractory hypoxemia despite optimized ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone ventilation
  • In the setting of hypoxemia and severe ARDS despite optimized ventilation and other rescue strategies, a trial of inhaled pulmonary vasodilators is recommended as a rescue therapy| Taper if there is no rapid improvement in oxygenation

Inpatient Pharmacologic Management

Note: For patients who are hospitalized for reasons other than COVID-19 and who are found to have mild to moderate COVID-19 and a high risk of disease progression, the Panel recommends following its recommendations for treating nonhospitalized patients with COVID-19 (section below)

The following applies to individuals admitted for the treatment of COVID-19

Therapeutic Management of Hospitalized Adults With COVID-19 Based on Disease Severity

Remdesivir

• Recommended for use in hospitalized patients who require supplemental oxygen
  • 200 mg IV once, then RDV 100 mg IV once daily for 4 days or until hospital discharge
  • If the patient progresses to more severe illness, complete course

Dexamethasone

• Found to improve survival in hospitalized patients who require supplemental oxygen
  • Greatest effect observed in patients who require mechanical ventilation
  • The Panel recommends against using dexamethasone among patients who do not require supplemental oxygen
• Primary immunomodulator for all patients who require high-flow nasal canula oxygen, noninvasive ventilation, mechanical ventilation, or ECMO
• Dose
  • 6 mg IV or PO once daily for up to 10 days or until hospital discharge
  • If dexamethasone is not available, an equivalent dose of another corticosteroid may be used

Tocilizumab

• Humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)
  • FDA approved to treat inflammatory diseases
• Dose
  • 8 mg/kg actual body weight (up to 800 mg) administered as a single IV dose
  • In clinical trials, a third of the participants received a second dose of tocilizumab 8 hours after the first dose if no clinical improvement was observed
• Avoid tocilizumab for the following
  • Significant immunosuppression | Alanine transaminase >5 times the upper limit of normal | High risk for gastrointestinal perforation | Uncontrolled, serious bacterial, fungal, or non-SARS-CoV-2 viral infection | Absolute neutrophil count <500 cells/µL | Platelet count <50,000 cells/µL

Baricitinib

• Oral Janus kinase (JAK) inhibitor that is selective for JAK1 and JAK2
  • FDA approved to treat rheumatoid arthritis
• Dose
  • Baricitinib dose is dependent on eGFR; duration of therapy is up to 14 days or until hospital discharge
  • eGFR ≥60 mL/min/1.73 m2: Baricitinib 4 mg PO once daily
  • eGFR 30 to <60 mL/min/1.73 m2: Baricitinib 2 mg PO once daily
  • eGFR 15 to <30 mL/min/1.73 m2: Baricitinib 1 mg PO once daily
  • eGFR <15 mL/min/1.73 m2: Baricitinib is not recommended

Tofacitinib

• Oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis
• Dose
  • 10 mg PO twice daily for up to 14 days or until hospital discharge
  • Use as an alternative immunomodulatory drug if baricitinib is not available or not feasible to use (BIIa)
  • eGFR <60 mL/min/1.73 m2: Tofacitinib 5 mg PO twice daily

Sarilumab

• Humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)
  • FDA approved to treat rheumatoid arthritis
• Dose
  • Use the single-dose, prefilled syringe (not the prefilled pen) for SQ injection
  • Reconstitute sarilumab 400 mg in 100 cc 0.9% NaCl and administer as an IV infusion over 1 hour
  • Use as an alternative immunomodulatory drug if tocilizumab is not available or not feasible to use

Therapeutic Management of Nonhospitalized Adults With COVID-19

NIH refers to the CDC guidance to determine at increased risk for progression | See ‘Learn More – Primary Care’ for reference

In Order of Preference

• Paxlovid (for more information, see ‘oral antivirals below’)
  • Orally twice daily for 5 days, initiated as soon as possible and within 5 days of symptom onset in those aged ≥12 years and weighing ≥40 kg
• Remdesivir
  • 200 mg IV on Day 1, followed by remdesivir 100 mg IV daily on Days 2 and 3, initiated as soon as possible and within 7 days of symptom onset in those aged ≥12 years and weighing ≥40 kg 

Alternative Therapies to be used ONLY if none of the preferred therapies are available, feasible to deliver, or clinically appropriate (listed in alphabetical order)

Molnupiravir

800 mg orally twice daily for 5 days, initiated as soon as possible and within 5 days of symptom onset in those aged ≥18 years ONLY when none of the above options can be used

Note: BQ.1 and BQ.1.1 subvariants appear to be resistant to bebtelovimab and as of 11/30/2022, bebtelovimab is not currently authorized for emergency use in any US region | The Panel continues to recommend Paxlovid, followed by remdesivir for treatment of mild to moderate COVID-19 in nonhospitalized adults who are at high risk for progression

More on Oral Antivirals

• Ritonavir-Boosted Nirmatrelvir (Paxlovid)
  • Nirmatrelvir
    • Orally bioavailable protease inhibitor
    • Works by inhibiting viral protease M^PRO (protease that plays an essential role in viral replication)
    • Active against all coronaviruses known to infect humans
  • Packaged with ritonavir (as Paxlovid)
    • Ritonavir is a cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic boosting agent
    • Boosts nirmatrelvir concentrations to the target therapeutic ranges

Note: Review other medications to assess drug interactions including OTCs and herbal supplements | University of Liverpool has a site with COVID-19 Drug Interactions (included in the NIH Panel guidelines – see “Learn More – Primary Resources’ below)

• Molnupiravir
  • Oral prodrug of beta-D-N4-hydroxycytidine (NHC)
  • NHC is a ribonucleoside with antiviral activity against RNA viruses
  • NHC uptake by viral RNA-dependent RNA-polymerases results in viral mutations and lethal mutagenesis

Note: Pregnancy and COVID-19 Oral Antivirals

• Paxlovid
  • SMFM supports the use of Paxlovid in pregnancy as indicated (see ‘Primary Sources – Learn More’ below)
• Molnupiravir
  • Although FDA concluded that there is a low risk for genotoxicity, due to concern regarding mutagenesis, the FDA EUA recommends against use during pregnancy
  • The NIH Panel states “However, when other therapies are not available, pregnant people with COVID-19 who are at high risk of progressing to severe disease may reasonably choose molnupiravir therapy after being fully informed of the risks, particularly those who are beyond the time of embryogenesis (i.e., >10 weeks’ gestation). The prescribing clinician should document that a discussion of the risks and benefits occurred and that the patient chose this therapy”

KEY POINTS:

Serologic or Antibody Testing for Diagnosis of SARS-CoV-2 Infection

The Panel does not recommend using serologic testing as the sole basis for diagnosing acute SARS-CoV-2 infection 

• Serologic or antibody tests can detect recent or prior SARS-CoV-2 infection
• It may take ≥21 days after symptoms for seroconversion to occur (i.e., IgM and/or IgG antibodies to SARS-CoV-2)
• NAATs and antigen tests for SARS-CoV-2 occasionally yield false negative results
  • Serologic tests have been used in some settings as an additional diagnostic test for patients who are strongly suspected to have SARS-CoV-2 infection
  • Using a serologic test in combination with a NAAT to detect IgG or total antibodies 3 to 4 weeks after symptom onset maximizes the sensitivity and specificity to detect past infection

Concomitant Medications in Patients with COVID-19

Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARBs) and Statins (HMG-CoA Reductase Inhibitors)

• Continue taking these medications as prescribed
• The Panel recommends against the use of ACE inhibitors or ARBs for the treatment of COVID-19 outside of the setting of a clinical trial

Chronic Corticosteroids

• For patients on oral corticosteroid therapy used prior to COVID-19 diagnosis for another underlying condition (e.g., rheumatological diseases)
  • Corticosteroids should not be discontinued
  • Supplemental or stress-dose steroids: Determine use on a case-by-case basis
• Asthma and chronic obstructive pulmonary disease for control of airway inflammation (daily use)
  • Should not be discontinued

Pregnancy Considerations

• Betamethasone and dexamethasone cross the placenta and are therefore used for fetal benefit to decrease the risk of RDS in the setting or threatened preterm delivery
• The Panel recommends “using dexamethasone in pregnant women with COVID-19 who are mechanically ventilated or who require supplemental oxygen but who are not mechanically ventilated”

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Continue taking NSAIDs for a co-morbid condition as previously directed by physician
• “The Panel recommends that there be no difference in the use of antipyretic strategies (e.g., with acetaminophen or NSAIDs) between patients with or without COVID-19”

Coagulopathy Considerations

Antithrombotic Therapy for Nonhospitalized Patients without VTE

• The Panel recommends against the use of anticoagulants and antiplatelet therapy (aspirin or P2Y12 inhibitors) for the prevention of VTE or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial
• The Panel recommends against routinely continuing VTE prophylaxis for patients with COVID-19 after hospital discharge, except in a clinical trial 
• For patients who are at high risk for VTE and low risk for bleeding, there is insufficient evidence to recommend either for or against continuing anticoagulation after hospital discharge unless another indication for VTE prophylaxis exists

General Considerations for Hospitalized Patients

• The Panel recommends against using anticoagulant or antiplatelet therapy to prevent arterial thrombosis outside of the usual standard of care for patients without COVID-19 
• In hospitalized patients, low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) is preferred over oral anticoagulants, because these 2 types of heparin have shorter half-lives and the effect can be reversed quickly, can be administered intravenously or subcutaneously, and have fewer drug-drug interactions 
• When heparin is used, LMWH is preferred over UFH

Hospitalized, Nonpregnant Adults Who Require Low-Flow Oxygen and Are Not Receiving Intensive Care Unit Level of Care

• Use therapeutic-dose heparin for patients who have a D-dimer above the upper limit of normal and have no increased bleeding risk
• LMWH is preferred over unfractionated heparin
• Contraindications for therapeutic anticoagulation for COVID-19 due to an increased bleeding risk
  • Platelet count <50 x 10⁹/L
  • Hemoglobin <8 g/dL
  • Need for dual antiplatelet therapy
  • Known bleeding within the last 30 days requiring an emergency room visit or hospitalization
  • Known history of a bleeding disorder
  • Inherited or active acquired bleeding disorder
• If no VTE
  • Continue therapeutic treatment for 14 days or until hospital discharge, whichever comes first
• The Panel recommends using prophylactic-dose heparin (LMWH or unfractionated heparin) for patients who are not administered therapeutic heparin unless a contraindication exists 

Note: Oral anticoagulants for VTE prophylaxis or prevention of COVID-19 progression are not recommended for hospitalized patients, except in a clinical trial 

Hospitalized, Nonpregnant Adults Who Are Receiving ICU Level of Care (Including Patients Who Are Receiving High-Flow Oxygen)

• Use prophylactic-dose heparin as VTE prophylaxis unless a contraindication exists 
• The Panel recommends against the following except in a clinical trial
  • Use of intermediate-dose (e.g., enoxaparin 1 mg/kg daily)
  • Therapeutic-dose anticoagulation for VTE prophylaxis
• For patients who start on therapeutic-dose heparin while on low-flow oxygen due to COVID-19 and then transfer to the ICU
  • Switch from therapeutic to prophylactic-dose heparin unless a VTE is confirmed 
• There is insufficient evidence for the Panel to recommend either for or against antiplatelet therapy in critically ill patients with COVID-19

Pregnant Adults

• The Panel recommends that pregnant patients who are receiving anticoagulant or antiplatelet therapies for underlying conditions continue these medications after they receive a diagnosis of COVID-19
• Use prophylactic-dose anticoagulation for pregnant patients hospitalized for manifestations of COVID-19 unless otherwise contraindicated
• Because pregnant patients have not been included in most clinical trials evaluating therapeutic anticoagulation in the setting of COVID-19, there is currently insufficient evidence to recommend either for or against therapeutic anticoagulation for pregnant patients with COVID-19 in the absence of a known VTE

Influenza and COVID-19

Vaccine Considerations

• It is important to ensure that vaccination programs to protect against influenza continue during the pandemic
• Patients with COVID-19 can receive inactivated influenza vaccine
• Moderately or Severely Ill with SARS-CoV-2
  • Consider deferring influenza vaccination until the patients have completed the COVID-19 isolation period and are no longer moderately or severely ill
• Asymptomatic or not moderately or severely ill with SARS-CoV-2
  • Influenza vaccination can be given when infected individual no longer require isolation
  • Vaccinate sooner if they are in a health care setting for other reasons

Note: Influenza vaccine and a COVID-19 vaccine may be administered concurrently at different injection sites

Testing for Influenza

• Test for both viruses in all hospitalized patients with acute respiratory illness 
• The Panel recommends influenza testing in addition to SARS-CoV-2 testing in outpatients with acute respiratory illness if
  • Results will change the clinical management strategy for the patient such as initiating antiviral treatment for influenza 
• Consider testing patients for other pathogens based on their specific clinical circumstances
  • Additional testing is especially important for patients with influenza who have a high risk of acquiring bacterial superinfections

Treatment for Influenza

• Antiviral treatment of influenza is the same in all patients with or without SARS-CoV-2 coinfection 
• Hospitalized patients with suspected influenza
  • Start on empiric treatment for influenza with oseltamivir as soon as possible 
  • Do not wait for influenza test results 
  • Stop antiviral treatment for influenza when influenza has been ruled out by nucleic acid detection assay
    • Nonintubated: Negative report for upper respiratory tract specimens
    • Intubated: Negative report for both upper and lower respiratory tract specimens

Learn More – Primary Sources:

NIH: Coronavirus Disease 2019 (COVID-19) Treatment Guidelines

Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: Information for Healthcare Providers (cdc.gov)

Liverpool COVID-19 Interactions (covid19-druginteractions.org)

SMFM: FDA Issues EUA for the Treatment of Mild-to-Moderate COVID-19 (Paxlovid)

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