COVID-19 Guidelines Dashboard

Guidelines and available data recommend the use of dexamethasone or an alternative equivalent corticosteroid for hospitalized patients with COVID-19 who require supplemental oxygen, including those who are mechanically ventilated.

Multiple high-quality clinical trials have shown that a 5-10 day course of 6-20mg dexamethasone (or equivalent corticosteroid) reduces mortality in patients with COVID-19 who require supplemental oxygen, including those who are mechanically ventilated. Accordingly, all major guidelines currently recommend this practice. Guidelines and available evidence do not support the use of doses higher than 20mg dexamethasone (or equivalent) per day or recurrent courses of systemic steroids for progressive or resistant critical COVID-19.

Recent data indicates that neutralizing monoclonal antibodies may prevent symptomatic infection in persons who had very close and prolonged contact with an individual with COVID-19. The antibodies studied for this indication, casirivimab plus imdevimab, are the same that are currently approved by the US FDA's Emergency Use Authorization for certain patients with mild-moderate COVID-19 with high risk for progression, and the US FDA extended this authorization to include post-exposure prophylaxis in July 2021. Data on the use of monoclonal antibodies for post-exposure prophylaxis is still limited, and the cost-effectiveness of prophylactic therapy is unknown.

Agents that interfere with IL-6 signaling pathways, such as tocilizumab or sarilumab, have been investigated in severe COVID-19 because of their potent anti-inflammatory properties. Multiple clinical trials of IL-6 inhibitors have now been published. Results from these trials are heterogeneous with some suggesting benefit and others not, but a recent meta-analysis demonstrated improved survival at 28 days with the use of IL-6 inhibitors when combined with corticosteroids in the treatment of severe COVID-19 pneumonia. Multiple authorities now support the use of tocilizumab and/or sarilumab as an adjunctive treatment to corticosteroids in patients with severe COVID-19 pneumonia.

There are inadequate data to recommend routine use of the anti-JAK1/JAK2 drug baricitinib in hospitalized patients with COVID-19, although newer trial data suggest improvement in time to recovery in patients who received remdesivir and baricitinib. As such, guidelines are evolving. Current guideline recommendations depend on whether steroids are available or contraindicated, whether remdesivir is available, and whether patients are on supplemental oxygen.

Lab-generated SARS-CoV-2-specific antibodies, such as bamlanivimab-etesevimab or casirivimab-imdevimab (also known as the "Regeneron cocktail"), have been investigated as a therapy to prevent progression of mild-moderate COVID-19 in non-hospitalized patients. Some trials have shown decreased viral load with use of these therapies and potentially lower rates of progression of disease, but the robustness and clinical significance of these findings remains uncertain. The US FDA has approved some therapies for use under Emergency Use Authorizations, although the EUA for bamlanivimab *monotherapy* has been withdrawn due to concerns about efficacy against novel variants like the Delta variant. Several US institutions offer guidance on how to select appropriate patients for use. See separate topics on this dashboard for information about neutralizing antibodies for outpatient prophylaxis or for hospitalized patients.

Lung protective ventilation should be pursued for all ARDS patients undergoing mechanical ventilation. This includes targeting tidal volumes of 4-6mL/kg Ideal Body Weight, targeting Plateau Pressure < 30cmH2O, and titrating FiO2 and PEEP per ARDSnet protocols. Available guidelines do not support significant deviations from existing ARDS ventilation protocols in the care of COVID-19 patients.

Chemical prophlyaxis with heparin or LMWH to prevent venous thromboembolism is recommended for all hospitalized patients with COVID-19 in absence of contraindications. Existing guidelines do not support the use of high-dose or "therapeutic" (in contrast to "prophylactic") dosing for routine DVT prophylaxis in patients hospitalized with COVID-19, but large international RCTs comparing “therapeutic” to “prophylactic” anti-thrombotic dosing and anti-platelet therapies are ongoing and results are anticipated in the coming weeks/months.

High Flow Nasal Oxygen/Cannula (HFNO/HFNC) may be used to maintain SpO2 >90-94% in patients with hypoxemic respiratory failure who otherwise do not meet criteria for intubation and have escalating conventional oxygen requirements. HFNO/HFNC is considered an Aerosol Generating Procedure by many organizations; appropriate PPE and precautions should be used. Guideline support for this therapy is largely based on its efficacy in trials on non-COVID hypoxemic respiratory failure.

For mechanically ventilated patients with moderate to severe ARDS (P:F<150) despite optimized mechanical ventilation, prone positioning for 12-16 hours per day may improve outcomes. Continuous infusions of neuromuscular blockade are not always required. Guideline support for this therapy is largely based on its efficacy in trials on non-COVID hypoxemic respiratory failure.

Data for proning patients non-intubated patients is evolving, although case series and limited pre-COVID studies suggest feasibility and possible benefit of "awake" proning combined with oxygen therapy in avoiding intubation. Patients who are self-proned require close monitoring including pulse oximetry, telemetry, and frequent clinical observation.

Current evidence does not suggest any specific harm of NSAID use in patients with COVID-19 for antipyrexia or pain control. Most guidelines recommend that NSAIDs may be used if clinically appropriate and not otherwise contraindicated.

N95/FFP2/KN95 or higher grade respirators (including powered respirators), as opposed to surgical/medical masks, should be used in addition to other PPE when performing Aerosol Generating Procedures (AGPs) in the care of COVID19 patients.

For patients with mild COVID-19 who are not admitted to the hospital but are at elevated risk for disease progression, home monitoring of arterial blood oxygen saturation with a hand-held pulse oximeter may help alert patients to seek care if disease is progressing or reassure patients if disease is stable. The optimal use of pulse oximetry in the outpatient setting for COVID19 is an evolving area of practice. Patients and caregivers should only utilize certified and approved devices by their local healthcare authority to ensure quality. Some pulse oximeters may provide false reassurance or false alarms in patients with darker skin pigmentation.

All individuals with symptoms consistent with COVID-19 should undergo testing for SARS-CoV2 infection. PCR-based testing, also known as NAAT (Nucleic Acid Amplification Test), is considered the gold standard diagnostic test for COVID-19, although false negative results are possible.

Rapid antigen tests have high specificity during acute symptomatic COVID-19, but sensitivity is low. Available guidelines generally recommend use of antigen tests if NAAT is not available or in high-risk, high-prevalence settings. Rapid antigen testing is not currently recommended for testing asymptomatic individuals.

The duration of coronavirus vaccine efficacy is not known, and there is some concern that the protection from these novel vaccines may decrease over time. Vaccine "boosters," or additional doses of the same vaccine, are used to ensure ongoing immune response against some infections; an example is routine tetanus vaccine boosters. Whether or not coronavirus vaccine boosters are needed to maintain high-level immunity in all previously vaccinated people, for individuals in certain high-risk groups, or for individuals who received single-dose vaccines like the Johnson & Johnson/Janssen vaccine, is a topic of active research (see literature highlights). On Aug 13, the United States CDC recommended that certain immunocompromised individuals receive a booster, and on Aug 18 the United States Dept of Health and Human Services outlined a plan to begin offering vaccine boosters to all vaccinated individuals starting in Fall, 2021.

Tofacitinib, like baricitinib, is an inhibitor of JAK proteins, and was developed as a treatment for rheumatoid arthritis. Because of its anti-inflammatory properties, it has attracted attention for use in patients hospitalized with severe COVID-19 pneumonia. A medium-sized randomized controlled trial was published on tofacitinib for hospitalized patients with COVID-19 in July 2021 which suggested benefit from adding this medication to standard of care (which in almost all patients included systemic corticosteroids).

Guidelines on the use of Remdesivir are mixed. The ACTT-1 trial revealed improved time to recovery with Remdesivir, but another large RCT (SOLIDARITY, funded by WHO) found that Remdesivir did not improve mortality. Current guidelines stratify recommended use of Remdesivir based on illness severity and the Dashboard has broken this category into 2 topics: Remdesivir for patients requiring supplemental oxygen but not mechanically ventilated (severely ill), and Remdesivir for patients who are mechanically ventilated (critically ill).

Guidelines on the use of Remdesivir are mixed. The ACTT-1 trial revealed improved time to recovery with Remdesivir, but another large RCT (SOLIDARITY, funded by WHO) found that Remdesivir did not improve mortality. Current guidelines stratify recommended use of Remdesivir based on illness severity and the Dashboard has broken this category into 2 topics: Remdesivir for patients requiring supplemental oxygen but not mechanically ventilated (severely ill), and Remdesivir for patients who are mechanically ventilated (critically ill).

Favipiravir is a viral RNA-polymerse inhibitor which has been used to treat influenza. It has been the subject of many smaller, methodologically-limited trials investigating its utility in the treatment of COVID-19 and results have been mixed. To date, no major international guidelines have addressed its use. In April 2021, a favipiravir arm was added to the PRINCIPLE adaptive trial on COVID therapeutics in the United Kingdom.

GM-CSF is a pro-inflammatory growth factor and cytokine that plays a part in mediating the inflammatory response to SARS-CoV2 infection in the lungs. Blockade of this pathway is under investigation in COVID-19 pneumonia, and trial data so far, as released in peer-reviewed journals or in pre-print form, show varying results based on the specific population studied. Until more data is available, it is unlikely that any guideline organization will recommend the use of this class of medications outside of a clinical trial.

Most randomized clinical trials have not shown a benefit of convalescent plasma (from prior survivors of COVID-19 infection) in patients hospitalized with moderate to severe COVID-19, although some data suggests that early use of convalescent plasma in patients with mild disease may help to prevent progression to more severe disease. Given this uncertainty, most guidelines currently recommend use of convalescent plasma only in the setting of a clinical trial.

Given concerns for hypercoagulability in critically ill patients with COVID-19, some institutions recommend "intermediate" (higher than standard dosing, but lower than full-dose therapeutic dosing) anticoagulation dosing in critically-ill patients in the ICU. Data regarding the optimal dose of anticoagulation is forthcoming.

Authorities typically recommend one of two strategies for releasing patients with symptomatic or asymptomatic SARS-CoV2 infection from respiratory isolation: 1. Repeat PCR testing or 2. Clinical criteria that include patient risk factors (such as immunocompromised state), current symptoms, and time since the initial positive SARS-CoV2 test or symptom onset. This category addresses the question "do guidelines recommend repeat PCR testing prior to releasing hospitalized patients from isolation?" Testing availability is generally recommended to be included in institutional decision making.

There are inadequate data regarding the use of empiric antibacterial agents in patients with severe COVID-19. Cohort studies show a low incidence of concurrent bacterial pneumonia in patients who present with COVID-19, but many guidelines recommend empiric antibiotics for critically ill or hypotensive patients admitted with COVID-19, and prompt de-escalation of therapy if no clinical evidence of bacterial infection is found.

Multiple guidelines suggest that the use medical/surgical masks provides adequate protection during routine care (that is, no AGPs are ordered or expected) of COVID19 patients, but many institutions encourage the use of respirators instead of medical/surgical masks at all times when providing direct care for COVID19 patients if adequate supplies of respirators are available.

In adults with acute hypoxemic respiratory failure, if HFNC is not available and intubation/mechanical ventilation is not indicated or available, a trial of CPAP or NIPPV/BiPAP may be considered. Most authorities support this practice only in mild to moderate ARDS patients or subsets of respiratory failure patients (e.g. COPD or heart failure exacerbation). Risks include delayed intubation and some experts believe NIPPV/BiPAP in patients with ARDS can cause direct pulmonary injury. Airborne precautions should be utilized.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has drawn interest in treatment of mild-moderate COVID-19 due to possible anti-inflammatory properties previously observed in mouse models of infection. A small, randomized, placebo-controlled trial of fluvoxamine in outpatients with new-onset, mild COVID-19 suggested that it may prevent progression of mild disease, but larger trials are needed to confirm this effect. Current guidelines do not address fluvoxamine or do not make a recommendation for or against its use due to insufficient data.

Molnupiravir is a prodrug to a nucleoside analog which interrupts viral replication, and is available experimentally in an oral form. As of May, 2021, there is no data available on the efficacy of monupiravir against COVID-19 infection in humans. A trial on molnupiravir in hospitalized patients was stopped after interim analysis in April 2021 showed that the drug was "unlikely to demonstrate a clinical benefit in hospitalized patients," per Merck, the drug's developer. Phase II and III trials on the drug's efficacy in non-hospitalized patients and are underway, but data has not yet been reported. This drug is investigational, is not commercially available, and has not been addressed by any major guideline.

Data on the use of the anti-parasitic agent ivermectin for anti-viral treatment of patients with COVID-19 or infection prophylaxis in high-risk patients are inadequate. In light of emerging, but underpowered RCTs, some guideline bodies have recently changed their recommendations from 'don't' to 'inconclusive.' At present, most guidelines currently either do not address ivermectin or encourage continued research by using it only in the context of a clinical trial. No guidelines surveyed by the COVID Guidelines Dashboard currently recommend ivermectin as prophylaxis against COVID-19.

Tofacitinib, like baricitinib, is an inhibitor of JAK proteins, and was developed as a treatment for rheumatoid arthritis. Because of its anti-inflammatory properties, it has attracted attention for use in patients hospitalized with severe COVID-19 pneumonia. A medium-sized randomized controlled trial was published on tofacitinib for hospitalized patients with COVID-19 in July 2021 which suggested benefit from adding this medication to standard of care (which in almost all patients included systemic corticosteroids).

Nitazoxanide is an anti-parasitic agent which has previously been investigated as an anti-viral medication for patients with influenza, and it has garnered interest as a potential therapy in early COVID-19 disease. However, a randomized, controlled trial of nitazoxanide for treatment of early COVID (within 3 days of symptom onset) did not show efficacy of this medication, and no major guideline organization currently support the use of nitazoxanide for inpatients or outpatients with COVID-19.

Aspirin has attracted attention for use in patients with COVID-19 due to its anti-platelet and anti-inflammatory properties. The adaptive, randomized controlled trial RECOVERY tested aspirin against placebo in over 14,000 patients hospitalized with COVID-19 infection and did not find any difference in mortality, progression to mechanical ventilation, or other clinically relevant endpoints, according to a recently published pre-print. We will attach a link to these findings when they have been peer reviewed. Most guidelines do not address aspirin or advise against its use outside of a clinical trial. Patients with COVID-19 who are on aspirin for a separate indication, e.g. coronary artery disease, should continue taking aspirin.

Colchicine, a medication that inhibits many different inflammatory pathways via disruption of microtubule formation, has garnered interest as a potential therapeutic option for patients with COVID-19. Its efficacy is not yet supported by randomized, clinical trial data, and guidelines do not recommend its routine use outside of a clinical trial. In March 2021, an interim analysis of the multinational RECOVERY trial failed to show benefit of colchicine in hospitalized adults with COVID-19 with respect to mortality, so recruitment to this arm of the study was stopped.

Most existing guidelines recommend against the use hydroxychloroquine (HCQ) for treatment or prevention of COVID-19 in hospitalized patients and outpatients outside of clinical trials. Published randomized trials have not shown efficacy for treatment, or pre- or post-exposure prophylaxis. In June 2020, the US FDA revoked emergency use authorization of hydroxychloroquine for COVID-19. In March 2021, WHO extended its recommendation against HCQ to specifically advise against its use as a preventative medication.

The analysis of 3 large, international randomized controlled trials investigating therapeutic (or "full-dose") anticoagulation in patients hospitalized with COVID-19 suggest that this therapy does not prevent progression of disease or death in patients with critical COVID-19 who are in the ICU, and may be associated with increased rates of significant bleeding. Most existing guidelines do not recommend therapeutic anticoagulation in absence of known DVT/PE, but do recommend prophylactic anticoagulation for all patients with COVID-19 in the ICU. Full results are now published and linked below.

The analysis of 3 large, international randomized controlled trials investigating therapeutic (or "full-dose") anticoagulation in patients hospitalized with COVID-19 who do not have known VTE suggest that this therapy may prevent progression of disease or death in patients with non-critical COVID-19 who are not in the ICU. Existing guidelines have not yet addressed this data, and as such most guidelines currently advice against this practice.

Multiple guidelines recommend against using azithromycin alone or in combination with hydroxychloroquine as part of therapy for COVID-19.

There are inadequate data regarding the use of empiric antibacterial agents in patients with mild or moderate COVID-19. Most guidelines recommend against use of empiric antimicrobials in patients admitted to the hospital with non-severe COVID-19.

Current data and guidelines do not recommend routine use of lab-generated SARS-CoV-2-specific monoclonal antibodies, such as bamlanivimab or casirivimab-imdevimab, in hospitalized patients.

There are inadequate data to inform guidelines on the initiation of ACE inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB) specifically as therapy for COVID-19 among hospitalized patients.

COVID-19 patients already on an ACEi or ARB for cardiovascular disease should continue these medications in the absence of other contraindications.

Authorities typically recommend one of two strategies for releasing patients with symptomatic or asymptomatic SARS-CoV2 infection from isolation: 1. Repeat PCR testing or 2. Clinical criteria that include patient risk factors (such as immunocompromised state), current symptoms, and time since the initial positive SARS-CoV2 test or symptom onset. This category addresses the question "do guidelines recommend repeat PCR testing prior to releasing non-hospitalized patients from isolation?" Testing availability is generally included in institutional decision making.

Guidelines to not recommend discontinuing or holding NSAIDs as antipyretic or analgesic therapy in patients with COVID-19 unless there are known contraindications for use of NSAIDs in individual patients.

There are inadequate data to recommend use of the H2-blocker famotidine as an antiviral therapy among patients with COVID-19.

Several large trials indicate that the antiviral agent lopinavir alone or in combination with ritonavir among patients with COVID-19 is an ineffective therapy. All major guidelines currently recommend against the use of lopinavir/ritonavir as treatment for COVID-19.

Testing for antibodies against SARS-CoV2 virus to diagnose acute COVID-19 is generally not recommended, but may be used in patients presenting >7-14 days after initial symptoms who have had multiple negative PCR tests but still have high clinical suspicion of COVID-19. Data are lacking to establish whether that a positive test for SARS-CoV2 antibodies confers immunity from recurrent infection.