Treatments

Please note that as of April 2023, this website is no longer actively being updated.Copy Link!

COVID-19 Guidelines DashboardCopy Link!

Please see our Dashboard for color-coded evidence based summary of guidance from multiple institutions on all major treatments. New updates weekly!

Overview by SeverityCopy Link!

Updated Date: November 13, 2022
Literature Review (Therapeutics): Gallery View, Grid View
Tool: Medication Interactions with COVID-19 Treatments; COVID-19 (Therapeutics) Guidelines Dashboard

Oral Antiviral Outpatient Test-to-Treat AlgorithmCopy Link!

Full downloadable algorithm (that is available for re-use) can be found here

A second example of an outpatient treatment algorithm, from Mass General Brigham, can be found here

CorticosteroidsCopy Link!

Updated Date: April 3, 2021
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

RecommendationsCopy Link!

1. Low-dose systemic corticosteroids are recommended for COVID-19 positive patients who require supplemental oxygen or are critically ill
2. Clinical considerations in patients when initiating steroids:

1. Monitor glucose, WBC, mental status, blood pressure, risk of myopathy (especially in those who are paralyzed for > 48 hours)
2. Assess for risk of Strongyloides and test and/or empirically treat as needed.
3. If patient has other risk factors requiring initiation of stress ulcer prophylaxis, initiate famotidine or a proton pump inhibitor as indicated
4. Contraindications:

1. Hypersensitivity to steroids
2. Relative contraindication: invasive fungal infection

EvidenceCopy Link!

1. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial found that dexamethasone dosed at 6 mg daily for up to 10 days (n=2104) had lower rates of 28-day mortality compared to usual care (n=4321) (22.9% vs. 25.7%; age-adjusted RR 0.83, 95% CI 0.75-0.93, p<0.001). Dexamethasone reduced deaths in mechanically ventilated patients (29.3% vs. 41.4%, RR 0.64, 95% CI 0.51-0.81) and patients receiving supplemental oxygen (23.3% vs. 26.2%, RR 0.82, 95% CI 0.72-0.94), but not among patients who did not require respiratory support (17.8% vs. 14%, RR 1.19, 95% CI 0.91-1.55) (Horby et al).
2. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis of 7 randomized trials in which 647 of 1703 COVID-19 patients died (38%). 28-day all-cause mortality was lower among patients who received corticosteroids compared to those who received usual care or placebo (OR 0.66, 95% CI 0.53-0.82, p<0.001). Of note, this meta-analysis included the RECOVERY trial results (Sterne et al).
3. Additional data on corticosteroids for COVID-19 is evolving

1. Additional randomized controlled trials: Jeronimo et al; Angus et al; Dequin et al; Tomazini et al; Edalatifard et al; Ghanei et al
2. Non-randomized cohorts: Fadel et al; Fernández-Cruz et al; Keller et al; Wu et al; Nelson et al; Lu et al; Wang et al; Bani-Sadr et al; Sanz-Herrero et al; Yuan et al; Wu et al; Bartoletti et al; Monreal et al; Salton et al; Li et al; Liu et al; Fatima et al.
3. Additional meta-analyses: Yang et al; Cano et al; Pasin et al.
4. Previous studies have shown negative effects of corticosteroids on similar viruses, albeit without the hyperinflammatory response frequently seen in COVID-19. There is no clinical evidence of net benefit from steroids in SARS-CoV, MERS-CoV or influenza infection. Observational data show increased mortality, more secondary infections, impaired viral clearance and more adverse effects in survivors (e.g., psychosis, diabetes, avascular necrosis) with steroid use at varying doses compared to usual care (Lee et al; Stockman et al; Lansbury et al; Arabi et al).

4. The WHO makes a strong recommendation for corticosteroids in patients with severe and critical COVID-19 and a conditional recommendation not to use corticosteroids in patients with nonsevere COVID-19 (WHO COVID-19 Living Guidance, September 2020). The National Institutes of Health, Infectious Diseases Society of America, American Thoracic Society, and Society of Critical Care Medicine all suggest the use of steroids in patients requiring supplemental oxygen or on mechanical ventilation (NIH Treatment Guidelines, February 2021; IDSA Treatment Guidelines, September 2020; ATS COVID-19 Updated Guidance, July 2020, SCCM COVID-19 Guidelines, March 2021).

DosingCopy Link!

Dosing regimens to consider include:

1. If also treating shock, hydrocortisone 50mg IV Q6h is recommended until improvement in shock, followed by consideration of steroid dosing as above to complete 10 days of total treatment. Indications for steroids in shock include:

1. Any shock in a patient with chronic steroid use >10mg prednisone daily
2. Multipressor (>2 pressor) shock without history of chronic steroid use

1. Some patients with adrenal suppression may need higher doses of supplemental corticosteroids

AntiviralsCopy Link!

RemdesivirCopy Link!

Updated Date: November 13, 2022
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

RecommendationsCopy Link!

1. Remdesivir, if available, is recommended for outpatients within 7 days of symptom onset and at high risk for progression to severe disease (see an example of an outpatient treatment algorithm here), or hospitalized patients with COVID-19 disease, but not yet requiring intubation (NIH Treatment Guidelines, August 2022; IDSA Treatment Guidelines, November 2022; WHO Treatment Guidelines, September 2022).

PharmacologyCopy Link!

Remdesivir is a nucleotide prodrug metabolized to an analog of adenosine triphosphate, which inhibits viral RNA-dependent RNA polymerase, causing premature termination of RNA transcription

EvidenceCopy Link!

1. Key inpatient randomized controlled trials: Beigel et al; Pan et al; Spinner et al; Ader et al
2. Key outpatient randomized controlled trial: Gottlieb et al
3. Additional randomized controlled trials: Goldman et al; Wang et al; Barrat-Due et al
4. Key meta-analyses: Rochwerg et al
5. Non-randomized cohorts: Mozaffari et al; Garcia-Vidal et al; Holshue et al; Grein et al; Antinori et al; Pasquini et al; Olender et al; Kalligeros et al; Garibaldi et al; Lapadula et al
6. Pharmacology reviews: Aleissa et al; Jorgensen et al

DosingCopy Link!

1. 200 mg IV loading dose, followed by 100 mg IV daily for 4-9 days for a total 5 to 10-day duration The package insert notes an infusion time of 30-120 minutes. If the patient is able to tolerate it, shorter infusion times (30-60 minutes) are preferred as remdesivir's active metabolite (GS-443902) is active intracellularly and achieves higher intracellular AUCs if infused over 30 minutes compared to 120 minutes (Humeniuk et al).

1. 5-day duration is preferred in the majority of patients
2. For outpatients or patients hospitalized for non-COVID-19 indications incidentally found to be COVID positive and mildly symptomatic, but without an oxygen requirement, a 3-day course of remdesivir should be sufficient (Gottlieb et al)

Monitoring and ToxicityCopy Link!

1. Elevated transaminases (AST, ALT), acute kidney injury, phlebitis, constipation, headache, and nausea
2. Remdesivir is co-formulated with sulfobutyl ether β-cyclodextrin (SBECD), so there is a theoretical risk of accumulation in renal failure promoting further renal injury, similar to intravenous voriconazole. If remdesivir is being considered in patients with renal impairment, the expected benefits of treatment should outweigh the potential risks prior to initiation (Adamsick et al). If remdesivir is used in renal impairment (eGFR <30 mL/min), the powder formulation is preferred as it has less SBECD content/vial than the liquid formulation (3 grams vs. 6 grams of SBECD)

Nirmatrelvir/ritonavirCopy Link!

Updated Date: March 2, 2022
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

RecommendationsCopy Link!

1. If available, nirmatrelvir/ritonavir is recommended for the treatment of mild-to-moderate COVID-19 in outpatients ≥ 12 years old who are at high risk for progression and within 5 days of symptom onset
2. More information on the FDA’s nirmatrelvir/ritonavir EUA can be found here
3. An example of an outpatient treatment algorithm can be found here

PharmacologyCopy Link!

1. Nirmatrelvir is a SARS-CoV-2 main protease (Mpro) inhibitor. Inhibition of Mpro renders SARS-CoV-2 incapable of processing polyprotein precursors, preventing viral replication.
2. Co-packaged with ritonavir to inhibit CYP3A4 metabolism of nirmatrelvir, which is required for the protease inhibitor to achieve therapeutic levels

EvidenceCopy Link!

1. Key randomized controlled trial: Hammond et al
2. Non-randomized cohorts: Arbel et al; Najjar-Debbiny et al; Malden et al

DosingCopy Link!

1. Nirmatrelvir 300 mg (two 150 mg tablets) with ritonavir 100 mg by mouth twice daily for 5 days, initiated within 5 days of symptoms onset

1. Dose reduction for moderate renal impairment (eGFR ≥ 30 to < 60 mL/min): Nirmatrelvir 150 mg (one 150 mg tablet) with ritonavir 100 mg by mouth twice daily for 5 days
2. Not recommended in patients with severe renal impairment (eGFR <30 mL/min) or severe hepatic impairment (Child-Pugh class C)

Monitoring and ToxicityCopy Link!

1. Ritonavir, as a strong CYP3A4 inhibitor, interacts with many medications. Please refer to the University of Liverpool drug-drug interaction checker to assess potential drug interactions. An example one-pager of drug interactions from Mass General Brigham can be found here
2. Adverse reactions occurring in more than 1% of patients in clinical trials included dysgeusia, diarrhea, hypertension, and myalgias
3. Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir
4. While highly unlikely, nirmatrelivir/ritonavir use may lead to a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1

MolnupiravirCopy Link!

Updated Date: February 15, 2022
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

RecommendationsCopy Link!

1. If available, molnupiravir is recommended for the treatment of mild-to-moderate COVID-19 in adult outpatients who are at high risk for progression and within 5 days of symptom onset only if other outpatient treatments (COVID monoclonal antibodies, nirmatrelvir/ritonavir, remdesivir) are not accessible or clinically appropriate
2. Not recommended during pregnancy

1. Women of child-bearing potential should use contraception during treatment and for 4 days after course completion
2. Men of reproductive potential sexually active with females of child-bearing potential should use contraception during treatment and for at least 3 months after course completion

3. More information on the FDA’s molnupiravir EUA can be found here
4. An example of an outpatient treatment algorithm can be found here

PharmacologyCopy Link!

1. Molnupiravir is an oral ribonucleotide prodrug that is metabolized into N4-hydroxycytidine (NHC), which is then phosphorylated to form the active ribonucleoside triphosphate NHC-TP. NHC-TP inhibits SARS-CoV-2 replication by inducing RNA mutagenesis

EvidenceCopy Link!

1. Key randomized controlled trial: Bernal et al
2. Other randomized controlled trials: Fischer et al; Arribas et al; Caraco et al

DosingCopy Link!

1. Molnupiravir 800 mg (four 200 mg capsules) by mouth every 12 hours for 5 days, initiated within 5 days of symptom onset

Monitoring and ToxicityCopy Link!

1. Molnupiravir is not recommended for use during pregnancy due to potential embryo-fetal toxicity
2. Molnupiravir is not authorized for patients < 18 years old as it may affect bone and cartilage growth
3. Adverse reactions occurring in more than 1% of patients in clinical trials included diarrhea, nausea, and dizziness

Other AntiviralsCopy Link!

FavipiravirCopy Link!

Literature Review: Gallery View, Grid View

Not recommended for routine use

See BWH Summary

Umifenovir (Arbidol)Copy Link!

Literature Review: Gallery View, Grid View

Not recommended for routine use

See BWH Summary

Lopinavir/RitonavirCopy Link!

Literature Review: Gallery View, Grid View

Not recommended for routine use

For patients on Antiretrovirals for HIV, we do not recommend changing existing ART regimens for the purposes of prophylaxis or treatment of COVID-19

See BWH Summary

InterferonsCopy Link!

Literature Review: Gallery View, Grid View

Not recommended for routine use

See BWH Summary

AntibodiesCopy Link!

Monoclonal AntibodiesCopy Link!

Updated Date: November 13, 2022
Literature Review: Gallery View, Grid View

Tool: COVID-19 (Therapeutics) Guidelines Dashboard

RecommendationsCopy Link!

1. The United States Food and Drug Administration (FDA) has issued emergency use authorizations (EUA) for five investigational monoclonal antibody therapies, bamlanivimab-etesevimab, casirivimab-imdevimab, sotrovimab, tixagevimab-cilgavimab, and bebtelovimab. However, no monoclonal antibody products are currently active against the circulating SARS-CoV-2 variants and thus are not recommended at this time.
2. Bamlanivimab-etesevimab, casirivimab-imdevimab, sotrovimab, and bebtelovimab are authorized for the treatment of outpatients with mild to moderate COVID-19 disease who are at high risk for progressing to severe COVID-19 and/or hospitalization. More information on the EUAs can be found here for bamlanivimab-etesevimab, here for casirivimab-imdevimab, here for sotrovimab, and here for bebtelovimab.
3. Currently, no monoclonal antibody products are available for post-exposure prophylaxis as casirivimab-imdevimab and bamlanivimab-etesevimab are not active against the Omicron SARS-CoV-2 variant Casirivimab-imdevimab and bamlanivimab-etesevimab were authorized for post-exposure prophylaxis in patients who have a recent confirmed SARS-CoV-2 exposure, are at high risk for progression to severe COVID-19 disease, AND are immunocompromised or unvaccinated
4. Tixagevimab-cilgavimab is authorized for pre-exposure prophylaxis in patients who:

1. Are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to an individual infected with SARS-CoV-2, and

1. Have moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medications and may not mount an adequate immune response to vaccination, or
2. For whom vaccination with any available COVID-19 vaccine is not recommended due to a history of severe adverse reaction

2. More information on the tixagevimab-cilgavimab EUA can be found here

5. Monoclonal antibody products have varying activity depending on the most prevalent SARS-CoV-2 variant in your local area. If located in the United States, please refer to the HHS/ASPR website for the most up-to-date information.
6. An example of an outpatient treatment algorithm can be found here

PharmacologyCopy Link!

1. Tixagevimab and cilgavimab (AZD7442, Evusheld) are recombinant human IgG1κ monoclonal antibodies that bind to non-overlapping regions of the receptor binding domain of SARS-CoV-2 spike protein, blocking viral entry into host cells
2. Bebtelovimab (LY-CoV1404) is a recombinant human IgG1κ monoclonal antibody to the spike protein of SARS-CoV-2, blocking viral entry into host cells
3. Other monoclonal antibody products are not currently authorized by the FDA due to the current circulating variants

1. Bamlanivimab-etesevimab (LY-CoV555 and LY-CoV016) are two recombinant neutralizing human IgG1κ monoclonal antibodies to the spike protein of SARS-CoV-2, blocking viral entry into host cells
2. Casirivimab-imdevimab (REGN10933-REGN10987) are two recombinant human monoclonal antibodies to the spike protein of SARS-CoV-2 (IgG1κ and IgG1λ, respectively), blocking viral entry into host cells
3. Sotrovimab (VIR-7831) is a recombinant human IgG1κ monoclonal antibody to the spike protein receptor binding domain of SARS-CoV-2, blocking viral entry into host cells

EvidenceCopy Link!

Outpatient Treatment

1. Key randomized controlled trials: Weinreich et al; Dougan et al; Weinreich et al; Gupta et al; O’Brien et al
2. Other randomized controlled trials: Chen et al; Gottlieb et al

Inpatient Treatment

1. Key randomized controlled trials: RECOVERY; Lundgren et al; Self et al; Lundgren et al

Post-exposure Prophylaxis

1. Key randomized controlled trials: Cohen et al; O’Brien et al

Pre-exposure Prophylaxis

1. Levin et al

DosingCopy Link!

1. Tixagevimab 300 mg and cilgavimab 300 mg IM once as two separate injections.

1. For patients who previously received 150-150 mg dosing, an additional 150 mg of tixagevimab and 150 mg of cilgavimab administered as two separate IM injections may be given
2. Redosing with 300-300 mg is recommended every 6 months, timed from the most recent tixagevimab-cilgavimab dose

2. Bebtelovimab 175 mg IV once over at least 30 seconds as soon as possible after a positive SARS-CoV-2 test and within 7 days of symptom onset
3. Other monoclonal antibody products are not currently authorized by the FDA due to the current circulating variants

1. Bamlanivimab 700 mg and etesevimab 1400 mg IV once over at least 21 minutes administered as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset While the 2800-mg dose was the only dose to show a significant reduction in viral load at day 11 in BLAZE-1, the FDA’s EUA authorized the 700-mg dose for use due to issues with limited drug supply
2. Casirivimab 600 mg and imdevimab 600 mg IV (or subcutaneous, but IV is strongly preferred) once over at least 20 minutes as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset
3. Sotrovimab 500 mg once over 30 minutes as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset

Monitoring and ToxicityCopy Link!

1. Patients must be monitored during administration and for at least 60 minutes following the infusion or injection of any of the monoclonal antibody cocktails to assess for signs of hypersensitivity
2. The most common adverse events reported in clinical trials have been nausea, diarrhea, dizziness, headache, pruritus, and vomiting
3. Understanding the local incidence of SARS-CoV-2 variants can help guide which monoclonal antibody product may be most appropriate for use.

1. The NIH has an OpenData Portal with further information if looking for more information than the below table
2. Monoclonal antibody products have varying activity depending on the most prevalent SARS-CoV-2 variant in your local area. If located in the United States, please refer to the HHS/ASPR website for the most up-to-date information and CDC’s Nowcast for current variant estimates in your region

No change: < 5-fold reduction in susceptibility for all except < 2-fold reduction for casirivimab-imdevimab

* Performed in pseudotyped virus-like particles rather than authentic SARS-CoV-2 virus

Convalescent PlasmaCopy Link!

Updated Date: September 13, 2021
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

RecommendationsCopy Link!

1. The FDA has issued an Emergency Use Authorization (EUA) for convalescent plasma for the treatment of hospitalized COVID-19 patients.
2. Despite the EUA, convalescent plasma is not routinely recommended for COVID-19 patients given the lack of conclusive evidence. This stance is also supported by both the National Institutes of Health (NIH) Guidelines and Infectious Diseases Society of America Guidelines.
3. Because of the feasibility of local production, convalescent plasma may be a particularly appealing therapeutic option in low and middle-income countries. However, given the unproven benefits and potential risks, the International Society of Blood Transfusion recommends that convalescent plasma use be limited to the context of clinical research studies (Smid et al).

PathophysiologyCopy Link!

1. Convalescent plasma originates from patients who have previously recovered from a viral infection and are now able to donate their immunoglobulin-containing blood
2. The presumed mechanism of action is that antibodies present in convalescent plasma may suppress viremia

EvidenceCopy Link!

1. The first multicenter randomized clinical trial was published on June 3, 2020, in which 103 COVID-19 patients were randomized to receive convalescent plasma (n=52) or standard of care (n=51). In this open label trial, clinical improvement occurred within 28 days in 51.9% of the convalescent plasma patients compared to 43.1% of the standard of care patients (HR 1.4, 95% CI 0.79-2.49). There was also no significant difference in mortality between groups, with 15.7% mortality in the convalescent plasma group compared to 24% with standard of care (OR 0.65, 95% CI 0.29-1.46). The findings of this study are limited however due to early termination of the trial. To provide 80% power, 200 patients were required in the analysis, but only half of that number were enrolled. Further studies are still warranted (Li et al).
2. In a 160-patient, randomized, double-blind, placebo-controlled trial among older patients (≥65 years with comorbidities or ≥75 years without comorbidities), early receipt of high-titer convalescent plasma (<72 hours of symptoms) reduced the incidence of severe COVID-19 (RR 0.52, 95% CI 0.29-0.94) (Libster et al).
3. PlasmAr randomized 333 hospitalized COVID-19 patients to receive convalescent plasma (with a minimum SARS-CoV-2 antibody titer of 1:400, n=228) or placebo (n=105). At day 30, there were no significant differences between groups in clinical status (OR 0.83, 95% CI 0.52 to 1.35) or overall mortality (10.96% in convalescent plasma group vs. 11.43% in placebo group, -0.46 percentage points, 95% CI -7.8 to 6.8) (Simonovich et al).
4. PLACID randomized 464 hospitalized COVID-19 patients to receive convalescent plasma in addition to standard of care (n=235) or standard of care alone (n=229). Progression to severe disease or death by day 28 occurred in 19% of patients in the convalescent plasma arm compared to 18% in the control arm (RR 1.04, 95% CI 0.71 to 1.54) (Agarwal et al)
5. CONCOR-1 randomized hospitalized patients 2:1 to receive convalescent plasma (n=625) or standard of care (n=313). Intubation or death occurred in 32.4% of patients in the convalescent plasma arm compared to 28% patients in the standard of care arm (RR 1.16, 95% CI 0.94-1.43, p=0.18). Patients receiving convalescent plasma had more serious adverse events (33.4% versus 26.4%; RR 1.27, 95% CI 1.02-1.57, p=0.034) (Bégin et al)
6. The Mayo Clinic has published on their expanded access program, which to-date has analyzed 20,000 hospitalized COVID-19 patients who received convalescent plasma. In the cohort, the risk of serious adverse events was low and the seven-day mortality rate was 8.6% (8.2 to 9%). Noted side effects included cardiac events (0.37%), sustained hypotension (0.27%), thrombotic/thromboembolic complications (0.16%), transfusion-associated circulatory overload (TACO) (0.18%), transfusion-related acute lung injury (TRALI) (0.1%), and allergic transfusion reactions (0.13%), (Joyner et al; previous report with 5,000 patients: Joyner et al).

1. A subgroup of 3,082 patients had anti-SARS-CoV-2 IgG antibody levels determined prior to transfusion. In the high-titer group (defined as a signal-to-cutoff ratio of >18.45), 22.3% of patients died within 30 days, compared to 27.4% in the medium-titer group and 29.6% in the low-titer group. These retrospective results hint that high-titer convalescent plasma may be more effective than plasma with lower antibody levels (Joyner et al).

7. Numerous smaller case series and cohort studies have been published to-date without reaching definitive conclusions on the use of convalescent plasma in COVID-19 (Shen et al; Duan et al; Zhang et al; Salazar et al; Salazar et al; Rogers et al; Liu et al; Tworek et al)

DosingCopy Link!

1. Optimal therapeutic dosing is not yet known. Most ongoing studies are assessing one infusion of 1-2 units (200-500 mL)

Monitoring and ToxicityCopy Link!

1. Plasma transfusions in general are safe and well-tolerated in most patients. Potential side effects however include:

1. Mild fever
2. Allergic reactions, including serum sickness on rare occasions
3. Transfusion-associated circulatory overload (TACO)
4. Transfusion-related acute lung injury (TRALI) (Gajic et al)
5. Potential risk of another infectious disease from donor, although risk is incredibly low with modern blood bank techniques

2. There is a theoretical concern that convalescent plasma may lower a patient’s INR if on warfarin, similar to (but to a lesser degree than) fresh frozen plasma.

ImmunomodulatorsCopy Link!

Anti-IL-6 Agents (e.g. Tocilizumab)Copy Link!

Literature Review (Tocilizumab):Gallery View, Grid View
Literature Review (Sarilumab):Gallery View, Grid View
Literature Review (Siltuximab):Gallery View, Grid View

Tool: See BWH Summary

Tool: COVID-19 (Therapeutics) Guidelines Dashboard

Primarily based on the RECOVERY and REMAP-CAP trials, tocilizumab may be considered in patients with severe COVID-19 in addition to corticosteroids if early in the patient’s hospital admission and with no contraindications to its use (Horby et al, Gordon et al). The WHO now makes a strong recommendation in favor of using tocilizumab in severe or critical COVID-19 based on the results of their meta-analysis, which found that 28-day all-cause mortality was lower among those receiving IL-6 inhibitors (21.8%) compared to usual care or placebo (25.8%) (OR 0.86, 95% CI 0.79-0.95) (Shankar-Hari et al). BWH’s example algorithm for use of tocilizumab or baricitinib in addition to corticosteroids can be found here.

JAK Inhibitors (e.g. Baricitinib)Copy Link!

Literature Review (Baricitinib):Gallery View, Grid View

Literature Review (Tofacitinib):Gallery View, Grid View

Literature Review (Ruxolitinib):Gallery View, Grid View

Tool: See BWH Summary

Tool: COVID-19 (Therapeutics) Guidelines Dashboard

Based on the ACTT-2 and COV-BARRIER trials, baricitinib may be considered in patients with severe COVID-19 in addition to corticosteroids on a case-by-case basis if early in the patient’s hospital admission and with no contraindications to its use (Kalil et al, Marconi et al, Ely et al). BWH’s example algorithm for use of tocilizumab or baricitinib in addition to corticosteroids can be found here.

Anti-IL-1 Agents (e.g. Anakinra)Copy Link!

Literature Review (Anakinra): Gallery View, Grid View
Literature Review (Canakinumab): Gallery View, Grid View
Literature Review (Rilonacept): Gallery View, Grid View

Tool: See BWH summary

Based on the SAVE-MORE trial, anakinra may be considered in patients with severe COVID-19 in addition to corticosteroids on a case-by-case basis if early in the patient’s hospital admission and with no contraindications to its use (Kyriazopoulou et al). BWH’s example algorithm for use of tocilizumab or baricitinib in addition to corticosteroids (in which anakinra is now a part of) can be found here.

Symptomatic TreatmentsCopy Link!

CoughCopy Link!

Updated Date: December 7, 2020

Non-Pharmacologic Therapy

1. Drink plenty of fluids, preferably warm if possible
2. A teaspoon of honey may help ease coughing symptoms
3. Cough drops or hard candy may also be used

Pharmacologic Therapy

1. Wet cough, difficulty clearing thick sputum: cough expectorant such as guaifenesin
2. Dry cough: cough suppressant such as dextromethorphan
3. Severe cough that disrupts sleep or results in pain, dyspnea, or vomiting: opioid such as morphine at same doses as used for refractory dyspnea.

DyspneaCopy Link!

Updated Date: December 7, 2020

Dyspnea is a common physical symptom of severe COVID-19. Dyspnea may be severe. Dyspnea from COVID-19 should first be treated with oxygen and/or medications as discussed in other sections. Other underlying causes (such as severe anemia, pleural effusion, pneumothorax, or acidemia) should be ruled out and/or treated.

Non-Opioid ManagementCopy Link!

1. Non-Pharmacologic Therapy for Dyspnea

1. Positioning: sitting patient up in bed, if possible.
2. Bedside fan to blow air onto face.
3. Relaxation techniques (see section on Anxiety).

2. Pharmacologic Therapy

1. NSAIDs and/or acetaminophen may be used.
2. Lorazepam can be used to ease the anxiety associated with dyspnea, but would avoid in patients who have had a previous paradoxical reaction (i.e. worsened agitation).

Opioid ManagementCopy Link!

Tool: Partners In Health Decision Tree for Opioid Treatment of Severe Dyspnea

Opioids are effective for relief of dyspnea that does not respond to treatment of underlying causes (e.g. severe anemia, severe anemia, pleural effusion, pneumothorax, or acidemia). Opioid therapy is an important component of the Essential Package for Palliative Care, which can be accessed here

1. Candidates for Opioid Treatment of Dyspnea

1. Opioids should be used to treat dyspnea in patients for whom survival is unlikely and treatment is focused solely on comfort and control of symptoms.
2. Other patients with significant refractory dyspnea despite maximal treatment but expected to survive can receive opioids to treat dyspnea, although this should be done carefully in order to minimize the side effect of respiratory suppression.

2. General Principles:

1. Always use as needed (PRN) boluses to address acute, uncontrolled symptoms. PRN bolus dosing should be 10-20% of the 24-hour opioid dose

3. For Opioid Naive Patients:

2. If frequent doses are needed, schedule an effective morphine dose Q4H and add a rescue dose as needed at 10% of the total daily dose
3. If patient is not well-managed with the above, add opioid infusion:

1. Consider drip If > 3 bolus doses in 8 hours
2. Calculate initial dose with total mg used/8 hours

1. e.g. 1+2+2+2= 7 mg; begin drip at 7mg/8 hr = 1 mg/h
2. Depending on symptoms and goals of care, consider reducing hourly rate by 30-50%. If patient is at end of life, would use 100% of hourly rate.

3. Continue PRN dosing at current dose (if effective) or titrate as per above

4. For Opioid tolerant patients:

1. If able to take PO:

1. Continue current long-acting doses if renal and hepatic function tolerate
2. Continue current oral PRN dose if effective q4h prn

1. If ineffective, increase dose by 50% and order range of up to 3 x basal dose

1. e.g. 5 mg PO MS q3h prn; increase to 7.5 mg; 7.5-22 mg PO q3h PRN

2. If unable to take PO, severe or rapidly escalating symptoms:

1. Convert as-needed PO doses to IV pushes as needed

1. Use the IV Conversion chart (see chart below)
2. Decrease PRN dose by ⅓ for incomplete cross-tolerance when switching between opioid classes

1. e.g. to convert 20 mg of oxycodone to IV hydromorphone: 20 mg oxy = 1.5 mg IV hydromorphone; 1.5 mg x ⅔ =1 mg IV

2. Convert PO long-acting/ sustained release opioids to an infusion:

1. Calculate 24-hour dose of PO sustained release (SR) morphine

1. Divide by 3 for the total 24h mg IV (Morphine PO/IV = 3:1)

2. Divide the 24h mg IV total by 24h for the hourly drip rate (mg)

1. e.g. 30 mg SR PO morphine q8 hr= 90 mg PO in 24 h; 90 mg /3 = 30 mg IV dose; 30 mg / 24 h ~1 mg/hr IV morphine infusion

3. Continue PRN dosing. PRN dose should be 100-200% of opioid drip rate

1. e.g. 1 mg/hr IV morphine infusion; PRN dose is 1-2 mg IV q2h

Abbreviated Opioid Equianalgesic Table (for complete table and an example conversion see DFCI Pink Book)

PainCopy Link!

Pharmacologic:Copy Link!

Opioid management of pain should be managed similarly to Opioid Management for Dyspnea.

AnxietyCopy Link!

Updated Date: December 7, 2020
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NonpharmacologicCopy Link!

Feelings of uncertainty and fear can fuel anxiety

1. Important to first acknowledge and normalize distress reactions
2. Correct misinformation. Provide accurate information (regarding patient’s current medical condition and next steps, regarding hospital protocols and measures being taken for safety)
3. Offer counseling (Spiritual, Psychocological, Social Work)
4. Offer mindfulness strategies
5. Strategies for reducing distress

1. Restful sleep, eating regular meals, exercising
2. Talking to loved ones (by telephone or video chat)
3. Diaphragmatic breathing (breathing to inflate the abdomen)
4. Muscle relaxation

PharmacologicCopy Link!

1. Continue home psychotropic medication regimen if possible
2. For patients with evidence of delirium

1. Quetiapine 12.5-25mg TID PRN or Haloperidol 1-2.5 mg orally or IV Q4H as needed (can also be scheduled Q6 – 8 H)

3. For patients without evidence of delirium

1. Quetiapine 12.5-25mg TID PRN
2. Lorazepam 0.5-2 mg PO/SL TID PRN; 0.5-2 mg IV TID PRN or Diazepam 2.5-5mg every 6 to 24 hours

4. For patients with risk of respiratory depression or history of respiratory illness

1. Buspirone 5-15mg PO TID

5. For moderate or severe anxiety in a patient expected to survive

1. Fluoxetine 20mg orally daily. Increase dose as needed every 7 days to achieve good effect, maximum 80mg per day. Other selective serotonin uptake inhibitors (SSRIs) that can be used instead of fluoxetine include sertraline (50mg orally QD, increase weekly as needed to a maximum of 200mg QD) and citalopram. Beware of QTc prolongation with some SSRIs.

Anxiety Related to Dyspnea or End of LifeCopy Link!

1. Benzodiazepines (if patient is not delirious; can use in either intubated or non-intubated pts — use with caution in older patients)

1. Lorazepam (longer half-life) 0.5-2 mg PO/SL q4-6h PRN; 0.5-2 mg IV q2h PRN
2. Midazolam (shorter half-life) 0.2-0.5 mg IV slowly q 15 min PRN or 0.1-0.3 mg/hr IV infusion
3. Diazepam 2.5-5mg every 6 to 24 hours

2. SSRI/SNRI: Continue home dose if possible. If NPO, replace with prn benzodiazepine

Respiratory SecretionsCopy Link!

Updated Date: December 7, 2020
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1. Patients can develop thick secretions from Covid-19 itself or secondary bacterial pneumonia
2. Nebulized treatments may help with airway secretion management, but published evidence is not available
3. Options include:

1. Normal (0.9%) saline nebulizer BID
2. N-acetylcysteine (“Mucomyst”) nebulizer BID or TID

1. N-acetylcysteine can cause bronchoconstriction
2. Pre-treat with inhaled albuterol just prior to delivery

3. Nebulized hypertonic (3-7%) saline once daily

1. Hypertonic saline can cause bronchoconstriction
2. If using, start with 3% saline to assess response and bronchoconstriction.
3. Pre-treat with inhaled albuterol just prior to delivery

4. Dornase alfa 2.5mg nebulizer once daily
5. Dornase can cause bronchoconstriction, mucosal bleeding, and can clog the HEPA filter, requiring intermittent replacement by RT
6. Avoid in the setting of bloody secretions
7. Pre-treat with inhaled albuterol just prior to delivery
8. It would be reasonable to consider other agents, including N-acetylcysteine, first given the need to change HEPA filters. In addition, a RCT for dornase nebulizer versus saline will begin shortly at BWH. However, if persistent secretions, it is reasonable to try dornase nebulizer

4. Although avoided if possible since it is an aerosol generating procedure, bronchoscopy for pulmonary clearance can be performed if needed on COVID-19 confirmed or PUI patients.

Secretions at the End of LifeCopy Link!

Pharmacologic management (not to be used with secretions with significant mucus). Avoid using > 2 of these at the same time; if more than one is required, monitor for development of anticholinergic crisis

1. Glycopyrrolate 0.2 – 0.4mg IV q2hrs prn secretions, rattling sound
2. Hyoscyamine sulfate 0.125-0.25mg PO q4hrs prn secretions, rattling sound
3. Scopolamine 1.5mg TD q72hrs if patient not awake and no apparent delirium or history of delirium. Note that the patch will take ~ 12 hours to take effect
4. Hyoscine butylbromide (alternative formulation of scopolamine) 20mg orally/IV/SC Q6H PRN or scheduled.

Nausea and VomitingCopy Link!

Updated Date: December 7, 2020

1. Consider reversible etiologies such as gastritis, constipation, anxiety.
2. Match treatment to etiology of nausea:

1. Chemoreceptor Trigger Zone (blood brain barrier breakdown)

1. haloperidol, metoclopramide, ondansetron, olanzapine, aprepitant

2. Gastrointestinal:

1. ondansetron, metoclopramide, dexamethasone (if malignant obstruction)

3. CNS cortical centers:

1. lorazepam for anticipatory nausea, dexamethasone (tumor burden causing ICP)

4. Vestibular:

1. meclizine, scopolamine, diphenhydramine

3. Additional information can be found at the DFCI Green Book (page 11 for more dosing recommendations):

1. Ondansetron 8-24mg/day IV/PO (usually on a q6h PRN schedule, max single dose 16mg) *causes constipation* Beware QTc prolongation.
2. Haloperidol 0.5-2 mg IV/PO q 4-8 hours *extra-pyramidal effects unlikely at these low doses*
3. Metoclopramide 10-40 mg IV/PO TID-QID *pro-motility*
4. Olanzapine 2.5-10 mg PO/dissolvable daily *off label, effective for concurrent anxiety, will not exacerbate constipation*
5. Prochlorperazine 10 mg PO TID-QID (max 40 mg/day) 25 mg PR BID *very sedating, overlaps with haloperidol, metoclopramide, perphenazine*
6. Meclizine 25-50 mg PO daily

DeliriumCopy Link!

Updated Date: December 20, 2020
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1. Non-Pharmacologic:

1. Frequent reorientation when appropriate
2. Early mobilization (getting out of bed)
3. Promotion of sleep-wake cycles via use of room lighting and stimulation and quiet location
4. Timely removal of unnecessary restraints, catheters, lines, and other devices
5. Ensuring use of glasses/hearing aids once patient is sufficiently alert
6. Reverse contributing medical conditions as able
7. Consult psychiatry services if available

2. Pharmacologic

1. Avoid delirium-causing medications (anticholinergics, benzodiazepines, opioids) whenever possible
2. Treat comorbid symptoms and underlying medical illness
3. For agitation/aggression:

1. Antipsychotics

1. Haloperidol: Mild agitation: 0.5-1.0 milligrams intravenously, or 1- 2 milligrams by mouth every 6 hours and 1-2 milligrams every 2 hours as needed; Moderate agitation: 2-4 milligrams intravenously; Severe agitation: 4-10 milligrams; Maximum dose: 20 milligrams / 24 hours
2. If unresponsive to treatment, olanzapine (Zyprexa), 2.5 to 5 milligrams (by mouth, sublingual, or intravenously) every 12 hours. Based on onset (6h), PO/SL olanzapine should not be used PRN for agitated delirium Maximum dose: 30 milligrams / 24 hours. **do not combine with benzodiazepines given by other routes, due to increased risk of respiratory depression**
3. If haloperidol/olanzapine not effective or contraindicated, can try:

1. Quetiapine (Seroquel) 12.5-50 milligrams every night at bedtime, can increase to every 6-12 hours. Titrate up to effect by 50 mg – 100 mg/day. Max dose: 600-800 mg/day
2. Aripiprazole (Abilify) 5 milligrams by mouth daily; maximum dose 30 milligrams daily

2. Alpha 2 Agonists - helpful for patients for ventilator weaning; also good option if prolonged QTc

1. Dexmedetomidine (Precedex) intravenously - easy to adjust dosing given short half-life
2. Consider use of clonidine 0.1 milligrams twice daily (can uptitrate) - available as a transdermal patch as well.

3. Mood Stabilizers

1. Valproic Acid (good option if prolonged QTc): Start at 125-250 milligrams intravenously every 8 hours three times daily, however, COVID patients are seeming to need escalations in doses (up to anti-manic dosing of 15-25 milligrams/kilogram) in combination with antipsychotics (such as haloperidol or olanzapine, as above).

4. Others

1. For regulation of sleep/wake cycle: Mirtazapine (Remeron): 7.5 milligrams (can increase, but it is more sedating at lower doses)

4. Considerations for Geriatrics Patients

1. High risk for delirium given restrictive visitor policy, disorienting effect of PPE use by staff, difficulty hearing/identifying caregivers through masks
2. Avoid delirium-causing medications such as anticholinergics and benzodiazepines (See here for a comprehensive Beers Criteria List)
3. If acutely agitated, not redirectable by non-pharmacologic means, trial 12.5 milligrams trazodone x 1 as needed, repeat dose at 30 min if no effect
4. Use antipsychotics (such as haloperidol, olanzapine, quetiapine) as last resort only, and only if QTc is < 500. Dose reductions should be used (suggestions: Haloperidol, Mild agitation 0.25 -0.5 mg IV or 1 to 2 mg PO q6h and 1 mg q2h PRN; Moderate agitation: 1-2 mg IV; Severe agitation: 2 mg IV Maximum dose: 20 mg / 24 hours)

AnticoagulationCopy Link!

Prophylactic DosingCopy Link!

Updated Date: October 31, 2021
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

For Patients Who are Not Critically IllCopy Link!

1. Background:

1. For non-critically ill inpatients, VTE rates appear to be similar to general ward patients amongst those receiving standard prophylactic anticoagulation (Hill et al).
2. The REMAP-CAP, ACTIV-4a, and ATTACC multi-platform response-adaptive randomized controlled trials evaluated therapeutic versus standard dose heparin prophylaxis in COVID-19 patients, separating by moderate vs critically ill (see below for a discussion of these results in critically ill patients) (REMAP-CAP, ACTIV-4a, and ATTACC (Non-critically ill). The primary outcomes was a composite of organ support-free days and number of days free of cardiovascular or respiratory organ support Respiratory organ support included non-invasive ventilation and high flow nasal cannula up to 21 days among patients who survived to hospital discharge.

1. For moderately ill hospitalized patients, the therapeutic heparin arm appears to have an beneficial effect with an OR of 1.27 (95% credible interval 1.03 - 1.58). Major bleeding events to be 1.9% in the therapeutic arm compared to 0.9% in the standard dose arm. The difference in treatment effect was 4% favoring therapeutic dose, with a 0.7% difference in major bleeding, resulting in an approximately 3% difference in outcome.
2. These results are controversial for several reasons:

1. First, the proportions of participants assigned to each trial arm were recalculated based on a single interim analysis performed on December 15, 2020 to favor randomization to the therapeutic dose arm, which can introduce bias. This approach is called response-adaptive randomization. While this approach theoretically provides therapeutic advantages to study participants and could be more ethical, it can also introduce selection bias, counteract the benefits of initial randomization, actually reduce total absolute numbers of individuals assigned to the favored arm, and can lead to challenges in interpreting the final results (Proschan, et al. Clin Inf Dis 2020, Park, et al., Clin Epidemiol 2018) The chance for bias is greater when based on fewer or a single interim analysis, as was done in this trial.
2. Second, it is challenging for a clinician to gauge whether an individual patient would have qualified for the trial. For example, participants who were thought not to need hospitalization for more than 72 hours were excluded, and some platforms only enrolled patients within 72 hours of hospital admission, while others enrolled patients within 14 days.
3. Third, the composite endpoint does not elucidate individual patient-specific risks and benefits between clotting and bleeding, especially since major bleeding events were higher in the therapeutic dose arm.

2. Recommendations:

1. For mildly-ill outpatients, we do not recommend prophylaxis
2. For moderately-ill inpatients, we recommend standard dose prophylaxis. (American Society of Hematology) This is due to the difficulty in determining which individual patients might benefit from higher doses, the flaws of the study as above, and the bleeding risk. However, clinicians should weigh individual risk factors for VTE and bleeding.

Standard Dosing VTE ProphylaxisCopy Link!

*LBW does not have a universal definition for LMWH dosing, we define it differently in the non-ICU (<50kg) and ICU (<60kg) populations to help achieve our targeted anticoagulant effect, though this remains an active area of research

For Critically Ill PatientsCopy Link!

1. Background:

1. Experts are divided as to whether standard, intermediate, or full dose anticoagulation provides the optimal balance of benefit of anticoagulation with risk of bleeding for COVID patients (Bikdeli et al). ICU patients are at additionally elevated risk for VTE events even on standard prophylaxis (Klok et al.; Middeldorp et al.; Klok et al.; Llitjos et al; Nahum et al.; Moll et al). Therefore, several observational studies and randomized clinical trials have addressed the use of intermediate and therapeutic dose heparin prophylaxis.

1. Intermediate dosing: The INSPIRATION randomized controlled trial (INSPIRATION Investigators) compared intermediate to standard dose heparin prophylaxis in ICU patients and reported no difference in venous or arterial thromboses, need for ECMO, or 30-day mortality. The intermediate dose group had more thrombocytopenia, but no significant differences in major bleeding.
2. Therapeutic dosing: The REMAP-CAP, ACTIV-4a, and ATTACC multi-platform response-adaptive randomized controlled trials evaluated therapeutic versus standard dose heparin prophylaxis in COVID-19 patients (REMAP-CAP, ACTIV-4a, and ATTACC (Critically-ill). The primary outcomes was a composite of organ support-free days and number of days free of cardiovascular or respiratory organ support Respiratory organ support included non-invasive ventilation and high flow nasal cannula up to 21 days among patients who survived to hospital discharge. For ICU patients, the trial was stopped early for futility, though for non-critically ill hospitalized patients there is a possible benefit (see above).

2. Recommendations:

1. Recommendations between different societies are split on anticoagulation in ICU patients.

1. Standard dosing: As of October, 2021 the American Society of Hematology recommends standard dosing. Further data on therapeutic dosing is forthcoming.
2. Intermediate dosing: As of October, 2021 BWH uses intermediate dosing for critically ill patients and post-critically ill patients. Their randomized controlled trial data do not suggest that intermediate dose heparin reduces the risk of progression of COVID-19 or death, but does decrease VTE death, and thus far does not suggest an increase in bleeding rates.
3. Full dosing: As of October, 2021 UCSF has started using full dose anticoagulation for critically ill patients requiring oxygen support.

Intermediate Dosing VTE ProphylaxisCopy Link!

1. Inclusion (BWH recommendations):

1. COVID-19 confirmed and PUI patients with critical illness at any point during hospitalization
2. Platelets >25,000

2. Exclusion:

1. If Platelets <25,000 or bleeding, hold prophylaxis and start thromboembolic deterrent stockings and sequential compression devices

*LBW does not have a universal definition for LMWH dosing, we define it differently in the non-ICU (<50kg) and ICU (<60kg) populations to help achieve our targeted anticoagulant effect, though this remains an active area of research

VTE Prophylaxis in LMICsCopy Link!

Given limited evidence and resource constraints in LMICs, we recommend standard dosing of VTE prophylaxis as opposed to a tiered dosing approach, in accordance with published guidelines (Ahmed et al).

Therapeutic DosingCopy Link!

Updated Date: October 1, 2021
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

1. Recommendations for therapeutic anticoagulation of patients with known DVT or PE remain the same as prior to COVID-19.

1. While some institutions are considering full dose anticoagulation in severe COVID-19 disease without known VTE, our interpretation of the data is that the risks outweigh the benefits at this time, unless documented DVT or PE. Preliminary data from Wuhan suggest that prophylactic LMWH or heparin may be of benefit in those patients with severe COVID-19 and D-dimer levels > 6 times the upper limit of normal (Tang et al).
2. A propensity score-matched cohort study of 3,772 participants compared COVID-19 patients receiving anticoagulation/antithrombotic therapy prior to diagnosis to patients without prior anticoagulation/antithrombotic therapy. No statistically significant difference in survival or time to mechanical ventilation was observed (Tremblay et al.)
3. In settings where diagnostic testing is limited, initiating empiric therapeutic anticoagulation for hospitalized COVID-19 patients with high suspicion of DVT/VTE may be done in accordance with local clinical practice guidelines.
4. Fixed dose subcutaneous heparin may be used for therapeutic anticoagulation in settings where IV heparin or low-molecular weight heparin are unavailable or impractical.

1. Therapeutic subcutaneous unfractionated heparin dosing: 333 units/kg then 250 units/kg SC every 12 hours

2. If the patient is on direct oral anticoagulants (DOACs) or Warfarin for Afib or VTE, assess on an individual basis whether to switch to a parenteral anticoagulant with a shorter half-life (LMWH or heparin) based on clinical status.

1. Consider the same clinical criteria used for non-COVID-19 patients. For example:

1. Consider LMWH or heparin in COVID-19 patients with AKI, procedures that require time off therapeutic anticoagulation or clinical instability (e.g., patients requiring critical care).
2. Continue home anticoagulation regimen in clinically stable COVID-19 patients without other contra-indications, with close monitoring of factors that could influence pharmacokinetics (e.g., antibiotics that could increase the effect of Warfarin; renal function for DOACs).

2. DOACs can be continued in patients on steroids and remdesivir. The benefits likely outweigh the risk of potential interactions between medications (e.g., by the induction of CYP3A4 or the multidrug efflux pump P-glycoprotein by dexamethasone).

3. Speculative use of therapeutic anticoagulation or tissue plasminogen activator (TPA)

1. While therapeutic anticoagulation has been used empirically in some severe COVID-19 patients in Wuhan given the possible microthrombi in pulmonary vasculature, our interpretation of the data is that the risks outweigh the benefits at this time, unless documented DVT or PE (Hardaway et al).

1. Similarly, TPA has been proposed as a possible therapeutic. We recommend against TPA for ARDS

AspirinCopy Link!

Updated Date: December 7, 2020

Aspirin can continue to be used in patients in whom it is indicated (i.e. cardiovascular disease prevention), but at this point in time, there is not enough evidence to support its use strictly for COVID-19 prevention and/or treatment

• A small retrospective study showed a possible improvement with aspirin started before or early during admission. This has yet to change clinical practice (Chow et al).

AntibioticsCopy Link!

Choice of AntibioticsCopy Link!

A discussion of the risks/benefits of empiric antibiosis and suggested initial regimens is found under Bacterial Infections, whether or not to give empiric antibiosis, and choice of agent. A common initial regimen for community acquired pneumonia is ceftriaxone and azithromycin or doxycycline.

Treatments for Comorbid DiseasesCopy Link!

RAAS InhibitorsCopy Link!

Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin II Receptor Blockers (ARB)

Examples: Lisinopril, Enalapril, and Captopril
Updated Date: May 10, 2020
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

RecommendationsCopy Link!

1. For outpatients, ACEi/ARBs should not be discontinued
2. For inpatients, ACEi/ARBs should not be discontinued unless otherwise indicated (e.g., acute kidney injury, hypotension, shock)

Pathophysiology and EvidenceCopy Link!

1. Data so far indicate that use of ACE inhibitors or angiotensin-receptor blockers (ARBs) is not associated with worse outcomes in patients with COVID-19 (Mancia et al, Reynolds et al).

1. The REPLACE COVID and BRACE Corona Trials showed indifferent outcomes regarding hospitalization duration, death, AKI requiring RRT etc.) (Cohen et al; Lopes et al).

2. The evidence that currently exists favors continuing these medications unless otherwise indicated to stop them because their abrupt discontinuation, particularly in those who have heart failure or have had a myocardial infarction, may lead to clinical instability and adverse outcomes (Vaduganathan et al). The American College of Cardiology, American Heart Association and Heart Failure Society of America joint statement recommends against discontinuing ACEi and ARBs in patients with COVID-19 (Bozkurt et al, HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19, 2020)
3. Background: SARS-CoV-2, the virus that causes COVID-19, enters via the same cell-entry receptor as SARS-CoV, namely angiotensin-converting enzyme II (ACE2) (Paules et al). SARS-CoV-2 is thought to have a higher affinity for ACE2 than SARS-CoV. ACE2 is expressed in the heart, lungs, vasculature, and kidneys. ACE-inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) in animal models increase the expression of ACE2 (Zheng et al), though this has not been confirmed in human studies. This has led to the hypothesis that ACEi and ARBs might worsen myocarditis or precipitate ACS. It has also been hypothesized that the upregulation of ACE2 is therapeutic in COVID-19 and that ARBs might be protective during infection (Gurwitz).

StatinsCopy Link!

Examples: Simvastatin, Rosuvastatin, Pravastatin
Updated Date: December 7, 2020

1. Statins can continue to be used in patients in whom they are indicated, but at this point in time, there is not enough evidence to support their use strictly for COVID-19 prevention and/or treatment

Calcium Channel BlockersCopy Link!

Examples: Amlodipine, Nifedipine, Diltiazem, Verapamil

Updated Date: January 7, 2021

1. Calcium channel blockers can continue to be used in patients in whom they are indicated, but there is not enough evidence to support their use for COVID-19 prevention and/or treatment

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)Copy Link!

Updated Date: May 10, 2020
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Tool: COVID-19 Guidelines Dashboard

RecommendationsCopy Link!

1. Concern has been raised that NSAIDs may worsen COVID-19 disease. This has not been proven clinically to-date, so we cannot make a recommendation for or against their use at this time

PharmacologyCopy Link!

1. SARS-CoV-2 binds to cells via ACE2. ACE2 is upregulated by ibuprofen in animal models, and this might contribute to increased pathology (see “Angiotensin Converting Enzyme Inhibitors (ACE-I) and Angiotensin II Receptor Blockers (ARB)” section of this chapter).

EvidenceCopy Link!

1. Reports from France indicate possible increase in mortality with ibuprofen in COVID-19 infection, but these reports have not been corroborated (Fang et al; Day). WHO clarified on March 20, 2020 that it does not recommend avoiding NSAIDs as initially stated March 18th (WHO, COVID-19 Interim guidance, March 2020)

BronchodilatorsCopy Link!

Updated Date: December 7, 2020
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Bronchodilators are not indicated for COVID alone in the absence of other indications, such as asthma or COPD. Some patients may have bronchoconstrictive responses to infection and so they may help some patients, but should not be used as a default treatment for all patients. When using, try to use meter-dose inhalers (MDIs) with a spacer instead of nebulizers where possible to decrease aerosols

NebulizersCopy Link!

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Nebulizers should be used very sparingly as they pose a risk to staff due to aerosolized virus. An inhaler with a spacer will provide similar benefit in most patients. Limit nebulizers to patients with severe wheezing who do not respond to inhalers. Any nebulizers should be done on airborne precautions (e.g. N95 mask use for all staff and private room for the patient, with negative pressure if possible). Airborne precautions should be continued for at least 1-3 hours after the treatment finishes.

Tool: Instructions on How to Make a Spacer With a Water Bottle: WHO-ICRC Basic Emergency Care Course (p.158)

Meter-Dose InhalersCopy Link!

Meter-Dose Inhalers (MDIs) can still be used and normal, and should be used with a spacer for efficacy.

Tool: For simple instructions on how to make a spacer with a water bottle, see page 158 of the WHO-ICRC basic Emergency Care Course.

Inhaled CorticosteroidsCopy Link!

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To treat COVID:

One small study with industry funding suggested a decrease in requiring urgent medical care amongst outpatients with COVID and no underlying lung condition who were treated with Budesonide. (Ramakrishnan et al) Larger studies are ongoing, and this remains experimental.

• At this time is no convincing data to support ICS as a treatment for COVID in patients without underlying asthma or COPD, and negative effects on viral clearance remain unknown. We do not recommend using inhaled corticosteroids routinely unless as part of a clinical trial.

To treat asthma or COPD:

Whether ICSs are harmful or protective against COVID-19 is debated. In theory, ICS use might reduce local lung immunity and increase susceptibility to disease. However, ICS use reduces the frequency of exacerbations of COPD and asthma, and might even and might even reduce replication of the SARS-CoV-2 virus (Jeon et al). In a large retrospective cohort study of over 140,000 COPD and Asthma patients, use of ICS had no bearing on Asthma-related COVID-19 mortality, and may be associated with increased mortality in COPD patients (though this is confounded by COPD severity). Regardless, use does not appear to be associated with any significant benefit (Schultze et al). The Asthma Section discusses ICS use in the setting of asthma and COVID.

• If ICS is indicated for treatment of asthma or COPD, these should be continued (or initiated as needed). We do not recommend changing management related to COVID risk
• If a patient on ICS develops COVID at this time we do not recommend changing withdrawing the ICS

Blood ProductsCopy Link!

Updated Date: May 1, 2020
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1. In general, treat bleeding rather than numbers.
2. We recommend a restrictive transfusion strategy (Hct > 21, Hgb > 7). Randomized controlled trials of ICU patients have shown that a conservative transfusion strategy (Hgb > 7) is associated with less pulmonary edema, fewer cardiac events and no evidence of harm compared to a liberal transfusion strategy (Hébert et al; Holst et al; Gajic et al).
3. If hemodynamically stable, transfuse 1 unit at a time and reassess needs.

1. A conservative approach to transfusions is encouraged given risks associated with blood product transfusions, limited supply (blood drives are limited by social distancing), and volume overload being of particular concern in COVID patients.

4. Fresh frozen plasma (FFP) or 4 factor-PCC (lower volume) should be given for active bleeding in the setting of known or suspected coagulation abnormalities.
5. For warfarin reversal, use 4 factor-PCC given longer effect and lower volume.

1. If PCC is unavailable, FFP and vitamin K (10mg IV administered over 60 minutes) should be given
2. If FFP is unavailable, vitamin K should still be given, although it can take hours to have an effect

6. Massive transfusion protocol, as a very limited resource, will need to be activated only by a senior clinician.
7. Tranexamic acid: only for ongoing oozing/bleeding with over DIC and hyperfibrinolysis.
8. Procedures: If the patient is at high bleeding risk, the most experienced operator should perform the procedure to minimize complications.

1. We recommend avoiding subclavian lines when placing central venous catheters in coagulopathic patients.

* SCDs = sequential compression devices = “pneumoboots”

** ACS = Acute Coronary Syndrome

# Intracranial hemorrhage and massive bleeding are not included here.

ImmunosuppressantsCopy Link!

See Baseline Immunosuppression

Other Miscellaneous AgentsCopy Link!

HydroxychloroquineCopy Link!

Updated Date: November 15, 2020
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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

RecommendationsCopy Link!

1. Hydroxychloroquine and chloroquine are not recommended in the treatment of COVID-19 outside of clinical trials
2. Despite an initial EUA, the FDA concluded that it is unlikely that chloroquine or hydroxychloroquine will be effective in treating COVID-19 and that the benefits do not outweigh the risks for use in COVID-19, thereby revoking EUA 039 originally authorized on March 28, 2020 (FDA EUA Revocation Letter June 15, 2020). The World Health Organization, National Institutes of Health and Infectious Diseases Society of America also recommend against its use (WHO Treatment Guidelines, May 2020; NIH Treatment Guidelines, October 2020; IDSA Treatment Guidelines, August 2020)

PharmacologyCopy Link!

Hydroxychloroquine (HCQ) is an anti-malarial 4-aminoquinoline shown to have in vitro activity against diverse RNA viruses, including SARS-CoV-1 (Touret et al).

EvidenceCopy Link!

1. The first randomized control trial for COVID-19 post-exposure prophylaxis was published on June 3, 2020. Asymptomatic patients who had household or occupational exposures to others with COVID-19 for more than 10 minutes within 4 days of exposure were randomized to receive either placebo (n=407) or hydroxychloroquine 800 mg once, 600 mg in 6-8 hours, then 600 mg daily for 4 additional days (n=414). The incidence of new illness compatible with COVID-19 was 11.8% in the hydroxychloroquine arm and 14.3% in the placebo arm (absolute difference -2.4%, 95% CI -7 to 2.2%, p=0.35). Side effects were more common in the hydroxychloroquine arm (40.1% vs. 16.8%), but no serious adverse reactions were reported (Boulware et al).
2. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial in the United Kingdom has enrolled over 11,500 patients to-date into multiple treatment arms, two of which are hydroxychloroquine and standard of care. While it hasn’t yet been published, the hydroxychloroquine arm of the study ceased enrollment on June 4, 2020 due to lack of benefit. The independent Data Monitoring Committee found that the hydroxychloroquine arm (n=1542) had similar outcomes in terms of 28-day mortality compared to the standard of care arm (n=3132) (25.7% vs. 23.5%, HR 1.11, 95% CI 0.98-1.26, p=0.10) (RECOVERY statement June 5, 2020).
3. The WHO-initiated SOLIDARITY trial was randomized across 30 countries and >11,000 hospitalized COVID-19 patients comparing 5 potential COVID-19 treatment regimens (remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, and combination lopinavir/r with interferon) against placebo. In the hydroxychloroquine portion of the trial, hydroxychloroquine (n=947) did not lead to a significant difference in 28-day mortality compared to placebo (n=906), 11.0% (104 deaths) vs. 9.3% (84 deaths) respectively (RR=1.19, 95% CI 0.89-1.59, p=0.23) (Pan et al).
4. The NIH’s ORCHID trial has also stopped enrolling patients after the data and safety monitoring board (DSMB) determined that while hydroxychloroquine did not cause additional harm, it also was very unlikely to provide benefit to hospitalized patients with COVID-19 (NIH press release June 20, 2020).
5. A number of other studies have also shown no positive impact with the addition of hydroxychloroquine in COVID-19 patients (Tang et al; Geleris et al; Mahevas et al; Borba et al; Magagnoli et al).

AzithromycinCopy Link!

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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

There is not sufficient supporting evidence to use azithromycin for COVID-19 disease outside of clinical trials, unless concomitant community-acquired pneumonia is suspected and atypical coverage is needed. Numerous studies have raised concerns about the deleterious effects of hydroxychloroquine and azithromycin combination therapy (Mercuro et al; Bessière et al; Chorin et al).

For more information on the pharmacology and evidence, please see BWH’s Protocols.

IvermectinCopy Link!

Updated Date: January 2, 2021

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Tool: COVID-19 (Therapeutics) Guidelines Dashboard (New Updates Weekly!)

RecommendationsCopy Link!

1. A small number of low-quality studies have published data on the use of ivermectin as a therapy for COVID-19. At this time, it is not possible to make any conclusions regarding the efficacy of ivermectin therapy for the treatment of COVID-19. We do not recommend ivermectin use for the treatment of COVID-19 at this time. The United States FDA has issued a warning against using ivermectin intended for animals for the treatment of COVID-19
2. Patients should be assessed for risk of concurrent Strongyloides Infection. Ivermectin may be indicated for empiric treatment of strongyloides in patients with COVID-19 to prevent complications from corticosteroid therapy.

PharmacologyCopy Link!

1. The antiviral activity of ivermectin is not entirely clear, but it is postulated that ivermectin may inhibit importin ɑ/β1 receptor, which transmits viral proteins into the host cell nucleus (Caly et al).

EvidenceCopy Link!

1. In vitro, Caly and colleagues infected cells with SARS-CoV-2 and exposed them to 5 μM of ivermectin over 72 hours. At 24 hours, there was a 93% reduction in viral RNA and at 48 hours, the effect increased to loss of essentially all viral material (~5000-fold decrease). The ivermectin concentration resulting in 50% inhibition (IC50) was estimated to be ~2 μM (Caly et al).

1. Multiple subsequent studies have shown that ivermectin dosing would need to be much higher than the current maximum approved dosing in order to reach the needed concentration in vivo (Schmith et al; Jermain et al; Momekov et al).
2. Two letters to the editor have also challenged the initial in vitro study (Bray et al).

2. A small randomized control trial compared ivermectin 12 mg daily for 5 days (n=22) or ivermectin 12 mg x1 and doxycycline daily for 5 days (n=23) against placebo (n=23). Ivermectin monotherapy showed a reduction in time for viral clearance with a mean duration 9.7 days vs. 12.7 days for placebo (p=0.02), but ivermectin + doxycycline did not show a reduction (11.5 days). Further studies are required and conclusions can't be made from this study (Ahmed et al).
3. A small prospective controlled (non-randomized) trial compared 2 to 3 doses of ivermectin in combination with 5 to 10 days of doxycycline (n=70) with standard care (n=70). Ivermectin/doxycycline therapy was associated with reduced time to recovery of 10.6 days compared to 17.9 days for placebo (p<0.0001). These results are not peer-reviewed and further studies are needed in order to make any conclusions regarding ivermectin therapy and COVID-19 (Hashim et al).
4. A retrospective cohort reviewed the impact of ivermectin use in 280 COVID-19 patients in four Florida hospitals. Mortality was less in patients who received ivermectin (n=173, 15% mortality) compared to those who received standard of care (n=107, 25.2% mortality). After adjusting, the mortality difference between groups remained significant (aOR 0.27, 95% CI 0.09-0.80, p=0.03). These findings however require randomized controlled trials for confirmation (Rajter et al).
5. Additional case series have been published on the use of ivermectin in COVID-19 (Camprubi et al).

DosingCopy Link!

1. The dose needed to obtain therapeutics concentrations is likely not feasible (see Evidence above). For parasitic diseases, ivermectin dosing ranges from 150 to 400 μg/kg. Published reports thus far have utilized doses of 200 μg/kg once or 12 mg once daily for 5 days
2. Nausea and vomiting, rash, CNS effects (dizziness, drowsiness, ataxia), itching, eosinophilia, tachycardia, hypersensitivity reactions. Toxicities with higher-than-approved doses are not yet fully understood (Navarro et al).

NitazoxanideCopy Link!

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Nitazoxanide should not be used outside of clinical trials as overall clinical evidence is lacking and optimal dosing is not known.

For more information on the pharmacology and evidence, please see BWH’s Protocols.

FamotidineCopy Link!

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Tool: COVID-19 (Therapeutics) Guidelines Dashboard

Famotidine can be used in patients in whom it is indicated (GERD, stress ulcer prophylaxis), but there is not enough evidence to support its use for COVID-19 prevention and/or treatment at this time

Vitamins & MineralsCopy Link!

ZincCopy Link!

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We do not recommend routine use of zinc for the treatment or prevention of COVID-19, except as part of a clinical trial. For more information on the pharmacology and evidence, please see BWH’s Protocols.

Vitamin CCopy Link!

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While this idea has been popular on social media, there is currently no evidence to support low- or high-dose vitamin C in COVID-19 patients. For more information on the pharmacology and evidence, please see BWH’s Protocols.

Clinical TrialsCopy Link!

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Clinical trials are essential for advancing the management of COVID-19, but are challenging in the setting of a new and evolving virus with an ever-changing standard of care. When able, patients are encouraged to enroll in active clinical trials.

1. National Institute of Allergy and Infectious Diseases (NIAID)-supported COVID-19 studies
2. Mass General Brigham COVID-19 studies
3. World Health Organization COVID-19 studies
4. Clinicaltrials.gov COVID-19 studies
5. Many large adaptive trials are underway, including RECOVERY, SOLIDARITY, DisCoVeRy, REMAP-CAP, and ACTIV

Baseline ImmunosuppressionCopy Link!

Updated Date: May, 2021

COVID-19 Risk by MedicationCopy Link!

The list below summarizes existing data about the risks of severe COVID for patients on baseline immunosuppressive medications used as disease modifying therapies.

**PLEASE NOTE:

• This section applies to patients who were already on these agents when they contracted coronavirus. The use of immunosuppressive medications as therapeutics for COVID-19 specifically (e.g. colchicine, glucocorticoids, tocilizumab/sarilumab, and tofacitinib/baricitinib, are covered in corticosteroids and immunomodulators)
• This review does not include agents for which there is no evidence of true immunosuppression or increased infection risk (such as drugs like interferon beta, glatiramer, or hydroxychloroquine).
• Most of this data is preliminary and rapidly evolving, and much of it is derived from smal@l and/or uncontrolled studies. It is also very challenging to keep up to date, and thus may not include the most recent studies for all drugs. If you

Management of Baseline ImmunosuppressionCopy Link!

These recommendations mostly derive from expert opinion, vary internationally, and are constantly evolving. Please verify with your institution and local guidance.

In general:

• In COVID-negative patients, continuation of baseline immunosuppression is recommended, though corticosteroids may be tapered, but these decisions should be made with the relevant specialist(s).
• In COVID-positive patients, ,anagement of baseline immunosuppressants depends on the type and severity of their chronic illness, the specific immunosuppressants they take, and the severity of their SARS-CoV-2 infection.

DermatologyCopy Link!

Particularly relevant diseases include psoriasis, atopic dermatitis, and hidradenitis suppurativa. This table synthesizes guidelines from the following societies:

• European Academy of Dermatology and Venereology
• International League of Dermatological Societies
• American Academy of Dermatology Association

Consider entering psoriasis patients with COVID in the following registry: PsoPROTECT.

GastroenterologyCopy Link!

Particularly relevant diseases include Crohn’s disease and ulcerative colitis.

This table synthesizes guidelines from the following societies:

• American Gastroenterological Association: AGA Guidelines
• British Society of Gastroenterology: BSG Guidelines
• International Organization for the Study of Inflammatory Bowel Disease: IOIBD Guidelines

Consider entering IBD patients with COVID in the following registry: SECURE-IBD Registry

NeurologyCopy Link!

Particularly relevant disease include multiple sclerosis, myasthenia gravis, Lambert Eaton myasthenic syndrome, and other immune-mediated diseases such as neuromyelitis optica, autoimmune encephalitis, certain myopathies, or neuropathies such as CIDP.

This table synthesizes guidelines from the following groups:

• International MG/COVID-19 Working Group
• European Academy of Neurology: Consensus Statement
• Association of British Neurologists

Consider entering MS patients with COVID in the following registry: COVID-19 Infections in MS and Related Disease

RheumatologyCopy Link!

This table synthesizes guidelines from the following societies:

• American College of Rheumatology: Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID‐19 Pandemic
• European Alliance of Associations for Rheumatology: Provisional Recommendations
• NICE (National Institute for Health and Care Excellence) - UK: COVID-19 rapid guideline: rheumatological autoimmune, inflammatory and metabolic bone disorders

Consider entering patients with rheumatologic diseases who contract COVID into the EULAR registry if in Europe or the Global Provider-Entered Registry if elsewhere, both available through the following link: COVID-19 Global Rheumatology Alliance.

Solid Organ TransplantCopy Link!

This table synthesizes guidelines from the following societies:

• International Society for Heart and Lung Transplantation (ISHLT): Guidance
• American Society of Transplantation: COVID19 FAQ
• European Renal Association—European Dialysis and Transplant Association (ERA-EDTA): Expert Opinion
• British Transplantation Society: Guidance

Consider entering solid transplant patients with COVID in the following registry: COVID-19 Transplant Registry. See also the Transplant Library for an up-to-date compendium of papers surrounding transplant and COVID-19.