NOTE: The Panel has a new update on prioritization of monoclonal antibodies when there are logistical constraints. 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
• Outpatient pharmacologic Management
• Post-Exposure Prophylaxis (PEP)
• Monoclonal Antibodies and Logistical Constraints
• Concomitant Medications in Patients with COVID-19
• Coagulopathy Considerations

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
  • Overall, despite promising data, it is unclear which hypoxemic, nonintubated patients with COVID-19 pneumonia will benefit | Data also unclear as length of time and clinical utility in preventing intubation or improving survival
  • Appropriate candidate for awake prone positioning: Patients who can adjust their own position independently and tolerate lying prone
  • 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

Remdesivir

• Only drug that is approved by FDA for the treatment of COVID-19
• Recommended for use in hospitalized patients who require supplemental oxygen
  • The Panel recommends using remdesivir for 5 days (200 mg IV for 1 day followed by 100 mg IV once daily for 4 days) or until hospital discharge, whichever comes first
  • May extend treatment duration up to 10 days if no substantial clinical improvement by day 5
  • If a patient who is on supplemental oxygen while receiving remdesivir progresses to requiring delivery of oxygen through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or ECMO, the course of remdesivir should be completed
• Not routinely recommended for patients who require mechanical ventilation due to the lack of data showing benefit at this advanced stage of the disease

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
• Dose
  • 6 mg IV or PO once daily for 10 days or until hospital discharge
  • If dexamethasone unavailable, equivalent dose of other corticosteroids (e.g., prednisone) may be used
• Combination of dexamethasone and remdesivir has not been studies in clinical trials
• Inhaled corticosteroid
  • There is insufficient evidence for the Panel to recommend either for or against the use of inhaled budesonide for the treatment of COVID-19

Tocilizumab

• Humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)
  • FDA approved to treat inflammatory diseases
• The Panel recommends the use of tocilizumab: Single dose IV 8 mg/kg of actual body weight (up to 800 mg) in combination with dexamethasone (6 mg daily for up to 10 days) “in certain hospitalized patients who are exhibiting rapid respiratory decompensation due to COVID-19″
• Recently hospitalized patients
  • Admitted to ICU: Within the prior 24 hours and who require invasive mechanical ventilation, noninvasive mechanical ventilation, or HFNC oxygen (>0.4 FiO₂/30 L/min of oxygen flow) or
  • Not in ICU: With rapidly increasing oxygen needs who require noninvasive mechanical ventilation or HFNC and have significantly increased markers of inflammation (Note: The RECOVERY trial inclusion criterion for inflammation was CRP ≥75 mg/L
• 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

Note: Some Panel members would also give tocilizumab to patients who are exhibiting rapidly increasing oxygen needs while on dexamethasone and have a CRP ≥75 mg/L but who do not yet require noninvasive mechanical ventilation or HFNC

Baricitinib

• Baricitinib is an oral Janus kinase (JAK) inhibitor that is selective for JAK1 and JAK2
  • FDA approved to treat rheumatoid arthritis
• Hospitalized patients with COVID-19 on high-flow oxygen or noninvasive ventilation who have evidence of clinical progression or increased markers of inflammation
  • The Panel recommends that baricitinib (as an alternative to tocilizumab) can be used in combination with dexamethasone alone or dexamethasone plus remdesivir 
• Hospitalized patients with hypoxemia who require supplemental oxygen therapy
  • Insufficient evidence to identify which patients would benefit from the addition of baricitinib or tocilizumab to dexamethasone (with or without remdesivir)
• Hospitalized patients who require invasive mechanical ventilation
  • Insufficient evidence for the Panel to recommend either for or against the use of baricitinib in combination with dexamethasone for the treatment of COVID-19
• Do not use baricitinib in combination with tocilizumab for the treatment of COVID-19, except in a clinical trial 

Note: Some Panel members would add either baricitinib 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

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

Medications for Non-Hospitalized Mild to Moderate COVID-19

Anti-SARS-CoV-2 Monoclonal Antibodies

• For patients with mild to moderate COVID-19 who are at high risk of clinical progression, the Panel recommends one of the following combinations
  • Casirivimab 600 mg plus imdevimab 600 mg | Same doses of casirivimab and imdevimab may be administered by subcutaneous (SQ) injection when IV infusion is not feasible or may delay treatment | SQ administration requires four injections (2.5 mL per injection) at four different sites
  • Sotrovimab 500 mg IV infusion
• High risk of clinical progression definitions
  • Strong representation in clinical trials: Older age (aged ≥65 years) | Obesity (BMI >30) | Diabetes | Cardiovascular disease (including congenital heart disease) or hypertension | Chronic lung diseases (e.g., chronic obstructive pulmonary disease, moderate-to-severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)
  • Limited representation in clinical trials but are considered risk factors for progression: An immunocompromising condition or immunosuppressive treatment | Overweight (BMI 25 to 30) as the sole risk factor | Chronic kidney disease | Pregnancy | Sickle cell disease | Neurodevelopmental disorders (e.g., cerebral palsy) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes and severe congenital anomalies) | Medical-related technological dependence (e.g., tracheostomy, gastrostomy, or positive pressure ventilation [not related to COVID-19])
• Start treatment as soon as possible after positive SARS-CoV-2 antigen or NAAT test report becomes available and within 10 days of symptom onset
• Use of anti-SARS-CoV-2 monoclonal antibodies should be considered for patients with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 if they otherwise meet the EUA criteria for outpatient treatment

Note: On June 25, 2021, a pause was placed on all distribution of bamlanivimab and etesevimab together and etesevimab alone until further notice | No safety issues were identified, but there is concern regarding lack of effectiveness against particular variants (Gamma variant [first identified in Brazil] and Beta variant [first identified in South Africa])

NIH: Therapeutic Management of NonHospitalized Adults With COVID-19

Other Medications and Therapies

HIV Protease Inhibitors

• The panel recommends against lopinavir/ritonavir or other HIV protease inhibitors (except in a clinical trial), because of unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19

Chloroquine/Hydroxychloroquine

• Inpatient
  • The Panel  recommends against the use of chloroquine  or hydroxychloroquine for the treatment of COVID-19
• Outpatient
  • The Panel recommends against the use of chloroquine  or  hydroxychloroquine for the treatment of COVID-19 except in a clinical trial

Convalescent Plasma and Immune Globulins

• Insufficient data to recommend either for or against the use of COVID-19 convalescent plasma or SARS-CoV-2 immune globulins
  • Panel recommends against the use of non-SARS-CoV-2-specific IVIG for the treatment of COVID-19 except in the context of a clinical trial
  • IVIG should be used when indicated for the treatment of complications that arise during the course of COVID-19

Immunomodulators

• Interferons: Panel recommends against use except in a clinical trial
• The panel recommends against the use of other JAK inhibitors other than baricitinib except in a clinical trial

Empiric Broad-Spectrum Antimicrobial Therapy for Severe or Critical Illness

• In absence of another indication, there is insufficient data to recommend

Mesenchymal Stem Cells

• The Panel recommends against the use of mesenchymal stem cells outside of a clinical trial

Ivermectin

• There are insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19

Post-Exposure Prophylaxis (PEP)

Individuals recently exposed to SARS-CoV-2 but negative NAAT or antigen test

Administer casirivimab 600 mg plus imdevimab 600 mg SQ injections or IV infusion for people who meet the following 3 criteria

• At high risk for progression to severe COVID-19 if infected with SARS-CoV-2 (see above in section on monoclonal antibodies)  
• Vaccination Status
  • Not fully vaccinated: Never vaccinated or 2^nd dose <2 weeks from first dose
  • Fully vaccinated, but not expected to mount an adequate immune response (e.g., those with immunocompromising conditions or immunosuppressive medications)
• Exposure History to SARS-CoV-2
  • Recent exposure to an individual with SARS-CoV-2 infection (using CDC close contact criteria of being within 6 feet of an infected person, for a cumulative total of 15 minutes or more over a 24 hour period)
  • At high risk of exposure to an individual with SARS-CoV-2 infection because of recent occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (e.g., nursing homes, prisons)

Note: Administer as soon as possible and preferably within 7 days of high-risk exposure | Casirivimab 600 mg plus imdevimab 600 mg should be given as four SQ injections (2.5 mL per injection) at four different sites  or as a single IV infusion | Observe patient for at least 1 hour after the injections or infusion | There is insufficient to recommend for or against repeat dosing

KEY POINTS:

Prioritization of Monoclonal Antibodies When There Are Logistical Constraints

• While currently there are no monoclonal antibody shortages, logistical constraints may arise due to
  • Limited space
  • Not enough staff who can administer therapy
• In the case of logistical constraints, the Panel suggests the following prioritization
  • Prioritize the treatment of COVID-19 over PEP of SARS-CoV-2 infection
  • Unvaccinated or incompletely vaccinated individuals who are at high risk of progressing to severe COVID-19
  • Vaccinated individuals who are not expected to mount an adequate immune response (e.g., immunocompromised individuals)
• If there are no logistical constraints, the above suggestions should not limit the use of anti-SARS-CoV-2 monoclonal antibodies when indicated

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 that “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

Laboratory Testing

• Non-hospitalized patients
  • No data to support measurement of coagulation markers
• Hospitalized patients with COVID-19
  • Coagulation markers are commonly measured, but insufficient data to recommend for or against use to guide management

VTE Prophylaxis and Screening

• Non-hospitalized patients
  • Anticoagulants and antiplatelet therapy should not be initiated for COVID-19 alone without other indications
• Hospitalized patients
  • Hospitalized nonpregnant adults with COVID-19 should receive prophylactic dose anticoagulation
  • Anticoagulant or antiplatelet therapy should not be used to prevent arterial thrombosis outside of the usual standard of care for patients without COVID-19
  • 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
• Discharge
  • Hospitalized patients with COVID-19 should not routinely be discharged from the hospital while on VTE prophylaxis
  • Continuing anticoagulation can be considered in patients who are at low risk for bleeding and high risk for VTE, as per the protocols for patients without COVID-19
• DVT screening in COVID-19 patients
  • Insufficient data to recommend for or against routine DVT screening if there are no signs or symptoms of VTE, regardless of the status of their coagulation markers
• Consider thromboembolic disease in the following clinical scenarios
  • Rapid deterioration of pulmonary, cardiac, or neurological function, or of sudden, localized loss of peripheral perfusion

Pregnancy and Lactation

• If antithrombotic therapy is prescribed during pregnancy prior to a diagnosis of COVID-19, this therapy should be continued
• For pregnant patients hospitalized for severe COVID-19, prophylactic dose anticoagulation is recommended if there are no contraindications to its use
• VTE prophylaxis after hospital discharge is not recommended for pregnant patients
  • Decisions to continue VTE prophylaxis in the pregnant or postpartum patient after discharge should be individualized, considering concomitant VTE risk factors
• During labor
  • Specialized care and planning is required and anticoagulation 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 
• Lactation
  • Unfractionated heparin, low molecular weight heparin, and warfarin do not accumulate in breast milk and do not induce an anticoagulant effect in the newborn and can be used in during breastfeeding (in mothers with or without COVID-19)
  • Direct-acting oral anticoagulants are not routinely recommended due to lack of safety data

Learn More – Primary Sources:

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

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