Coronavirus disease 2019 (COVID-19)
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Isolate patients with suspected or confirmed mild disease (i.e., symptomatic patients meeting the case definition for COVID-19 without evidence of hypoxia or pneumonia) and asymptomatic patients to contain virus transmission.[79]
Manage patients in a healthcare facility, in a community facility, or at home. Home isolation can be considered in most patients, with telemedicine or remote visits as appropriate.[79][479] This decision requires careful clinical judgment and should be informed by an assessment of the patient’s home environment to ensure that: infection prevention and control measures and other requirements can be met (e.g., basic hygiene, adequate ventilation); the caregiver is able to provide care and recognize when the patient may be deteriorating; the caregiver has adequate support (e.g., food, supplies, psychological support); the support of a trained health worker is available in the community.[774] The location of care will depend on guidance from local health authorities and available resources.
Pregnant women with suspected or confirmed mild disease may not require acute care in a hospital unless there is concern for rapid deterioration or an inability to return to hospital promptly.[79]
Advise patients and household members to follow appropriate infection prevention and control measures:
CDC: COVID-19 – if you are sick or caring for someone Opens in new window
Guidance on when to stop isolation varies widely across locations. Isolation periods may depend on various factors including vaccination status, circulating SARS-CoV-2 variants, and patient factors (e.g., immunocompetent/immunocompromised, asymptomatic/symptomatic, disease severity). The World Health Organization recommends discontinuing transmission-based precautions (including isolation) and releasing patients from the care pathway 10 days after positive test (asymptomatic patients), or 10 days after symptom onset plus at least 3 days without fever and respiratory symptoms (symptomatic patients).[79] However, some countries now recommend isolation periods as short as 5 days to 7 days.[772] Consult your local public health guidance for more information.
Treatment recommended for ALL patients in selected patient group
Closely monitor patients with risk factors for severe illness and counsel patients about signs and symptoms of deterioration or complications that require prompt urgent care (e.g., difficulty breathing, chest pain).[79][479]
Pulse oximetry monitoring at home is recommended in symptomatic patients with risk factors for progression to severe disease who are not hospitalized. Patient education and appropriate follow-up are required.[79]
Treatment recommended for ALL patients in selected patient group
Advise patients to avoid lying on their back as this makes coughing ineffective. Use simple measures first (e.g., a teaspoon of honey in patients ages 1 year and older) to help cough.[537] A meta-analysis found that honey is superior to usual care (e.g., antitussives) for the improvement of upper respiratory tract infection symptoms, particularly cough frequency and severity.[775]
Advise patients about adequate nutrition and appropriate rehydration. Advise patients to drink fluids regularly to avoid dehydration. Fluid intake needs can be higher than usual because of fever. However, too much fluid can worsen oxygenation.[79][537]
Advise patients to improve air circulation by opening a window or door.[537]
Provide basic mental health and psychosocial support for all patients, and manage any symptoms of insomnia, depression, or anxiety as appropriate.[79]
Consider treatment for olfactory dysfunction (e.g., olfactory training) if it persists beyond 2 weeks. There is no evidence to support the use of these treatments in patients with COVID-19.[776] A Cochrane review found there is very limited evidence regarding the efficacy of different interventions at preventing persistent olfactory dysfunction following infection. The only evidence available is for intranasal corticosteroids, and this is of very low certainty, so no conclusions could be drawn.[777]
Most children with mild disease can be managed with supportive care alone.[479]
Treatment recommended for SOME patients in selected patient group
Primary options
acetaminophen: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 325-1000 mg orally (immediate-release) every 4-6 hours when required, maximum 4000 mg/day
OR
ibuprofen: children 6 months to 11 years of age: 5-10 mg/kg orally every 6-8 hours when required, maximum 40 mg/kg/day; children ≥12 years of age and adults: 200-400 mg orally every 4-6 hours when required, maximum 2400 mg/day
Acetaminophen or ibuprofen are recommended.[79][537]
Ibuprofen should only be taken at the lowest effective dose for the shortest period needed to control symptoms. It is not recommended in pregnant women (especially in the third trimester) or children <6 months of age (age cut-offs vary by country).
Treatment recommended for SOME patients in selected patient group
Primary options
sotrovimab: children ≥12 years of age and adults: consult specialist for guidance on dose
OR
casirivimab and imdevimab: children ≥12 years of age and adults: consult specialist for guidance on dose
OR
bebtelovimab: children ≥12 years of age and adults: consult specialist for guidance on dose
OR
bamlanivimab: children and adults: consult specialist for guidance on dose (administered with etesevimab)
Consider a monoclonal antibody. Options may include sotrovimab, casirivimab/imdevimab, bamlanivimab/etesevimab, bebtelovimab, and regdanvimab, depending on your location. Guideline recommendations vary.
The World Health Organization recommends sotrovimab or casirivimab/imdevimab for patients with nonsevere disease who are at highest risk of hospitalization. Casirivimab/imdevimab should only be used where viral genotyping can confirm a susceptible SARS-CoV-2 variant (i.e., excluding Omicron). Monoclonal antibodies probably reduce the risk of hospitalization and duration of symptoms in patients with nonsevere disease, based on moderate-certainty evidence. While monoclonal antibodies achieve a substantial reduction in the relative risk of hospitalization, the absolute benefit will be trivial or unimportant in absolute terms for all but those who are at highest risk of disease (e.g., unvaccinated, older people, immunodeficiencies, and/or chronic disease). Treatment is in addition to the current standard of care. The applicability of this recommendation to children is currently uncertain.[769][770][771]
BMJ rapid recommendations: a living WHO guideline on drugs for COVID-19 Opens in new window
In the UK, the National Institute for Health and Care Excellence recommends offering a neutralizing monoclonal antibody to patients ≥12 years of age who are not in hospital and are thought to be at high risk of progression to severe disease. Consult local guidance for monoclonal antibodies with current UK access.[537]
In the US, the National Institutes of Health guidelines panel recommends bebtelovimab for the treatment of nonhospitalized patients with mild to moderate disease who are at high risk of clinical progression. However, it is only recommended when preferred therapies (i.e., antivirals) are not available, feasible to use, or clinically appropriate as it has not been evaluated in patients at high risk of progression in placebo-controlled trials. Use may be considered in patients with mild to moderate disease who are hospitalized for a reason other than COVID-19 provided that they otherwise meet the criteria for outpatient treatment. The panel currently recommends against the use of casirivimab/imdevimab, bamlanivimab/etesevimab, and sotrovimab because Omicron is the dominant variant in the US, and these monoclonal antibodies are predicted to have markedly reduced susceptibility to Omicron and its subvariants.[479] These monoclonal antibodies are not currently authorized for use in the US.[778][779]
The Infectious Diseases Society of America supports the use of monoclonal antibodies with activity against the predominant regional variants within 7 days of symptom onset in ambulatory patients with mild to moderate disease who are at high risk for progression to severe disease.[480]
Choice of monoclonal antibody depends on availability, as well as clinical and contextual factors including emerging information about efficacy with different variants. Preclinical evidence has emerged suggesting that casirivimab/imdevimab and bamlanivimab/etesevimab lack neutralization activity against the Omicron variant in vitro. Sotrovimab and bebtelovimab appear to retain activity against Omicron; however, sotrovimab is not active against the Omicron BA.2 subvariant. Consult local guidance for details regarding specific variants and resistance. Logistical or supply constraints may make patient triage necessary. Treatment should be prioritized for patients who are at the highest risk of progressing to severe disease.[479][537][769]
Evidence for the use of monoclonal antibodies in nonhospitalized patients is uncertain. A Cochrane review found that the evidence is insufficient to draw meaningful conclusions about any specific monoclonal antibody, and the disease stage in which it should be used. Information on outcomes in nonhospitalized patients such as mortality, quality of life, and serious adverse events is either inconclusive or entirely lacking, although casirivimab/imdevimab, sotrovimab, bamlanivimab (alone or in combination with etesevimab), and regdanvimab may reduce the occurrence of hospital admission or death (low-certainty evidence).[781]
Monoclonal antibodies are administered by intravenous infusion. Casirivimab/imdevimab is also available in a subcutaneous formulation, but intravenous administration is recommended. However, if intravenous infusions are not feasible or would cause a delay in treatment, subcutaneous administration may be considered.[479] Evidence for subcutaneous administration is emerging.[780] Outpatient administration in specialized clinics is required, which may limit the feasibility of these treatments.[769] Administer as soon as possible after a positive test and within 7 days of symptom onset.[479] Dose varies across guidelines; consult local protocols.
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported. Administer in a setting where severe hypersensitivity reactions can be managed. Monitor patients during the infusion and observe for at least 1 hour after infusion.
Treatment recommended for SOME patients in selected patient group
Primary options
remdesivir: children ≥12 years of age and ≥40 kg and adults: 200 mg intravenously as a loading dose on day 1, followed by 100 mg every 24 hours for 2 days
Consider the antiviral agent remdesivir. Guideline recommendations vary.
The World Health Organization conditionally recommends remdesivir for patients ≥12 years of age (weighing ≥40 kg) with nonsevere disease who are at highest risk of hospitalization.[769][770][771] In the UK, the National Institute for Health and Care Excellence recommends remdesivir for patients ≥12 years of age (weighing ≥40 kg) who do not need supplemental oxygen, and are within 7 days of symptom onset, and are thought to be at high risk of progression to severe disease (based on low-certainty evidence).[537] In the US, the National Institutes of Health guidelines panel recommends remdesivir to treat nonhospitalized patients with mild to moderate disease who are at high risk of clinical progression.[479] Remdesivir is approved in pediatric patients ≥28 days of age (weighing at least 7 lbs [3 kg]) in the US.[782] The Infectious Diseases Society of America supports the use of remdesivir in ambulatory patients with mild to moderate disease who are at high risk for progression to severe disease.[480]
Remdesivir should be initiated as soon as possible, ideally within 7 days of symptom onset. The treatment course for this indication is 3 days. If a patient requires hospitalization after starting treatment, the full treatment course can be completed at the healthcare provider’s discretion. Logistical constraints may make it difficult to administer the drug in some outpatient settings as it requires administration via intravenous infusion. Renal and/or hepatic monitoring may be required.[479][537][769]
Adverse effects include nephrotoxicity and hepatotoxicity. Remdesivir is not recommended in patients with an estimated glomerular filtration rate <30 mL/minute. Monitor renal function before starting treatment and during treatment as clinically appropriate. Intravenous formulations contain the solubility enhancer sulfobutyl ether beta-cyclodextrin sodium (SBECD), which is renally cleared. Accumulation of SBECD in patients with renal impairment may result in liver and renal toxicities. Consider preferential use of the lyophilized powder formulation in patients with renal impairment if available, as it contains less SBECD. Remdesivir may have little or no effect on acute kidney injury compared with placebo; however, the certainty of evidence is low.[883] Transaminase elevations have been reported. Monitor liver function before starting treatment and during treatment as clinically appropriate. Consider discontinuing treatment if alanine aminotransferase (ALT) levels increase to ≥10 times the upper limit of normal. Discontinue treatment if ALT elevation is accompanied by signs or symptoms of liver inflammation. Monitor prothrombin time before starting treatment and during treatment as clinically appropriate as increases in prothrombin time have been reported.
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported. Administer in a setting where severe hypersensitivity reactions can be managed. Monitor patients during the infusion and observe for at least 1 hour after infusion.
Evidence for this indication is emerging. Remdesivir probably reduces hospital admission (moderate-certainty evidence), and may have little or no impact on mortality (low-certainty evidence). The effect on mechanical ventilation and time to symptom resolution is very uncertain. The balance between benefits and potential harms favors treatment, but only in the highest risk group.[769][770][771] A randomized, double-blind, placebo-controlled trial of 562 patients found that a 3-day course of remdesivir resulted in an 87% lower risk of hospitalization or death among nonhospitalized patients who were at high risk for disease progression compared with placebo. The most common coexisting conditions were diabetes, obesity, and hypertension.[783]
Logistical or supply constraints may make patient triage for antiviral treatment necessary. Therapy should be prioritized for patients who are at the highest risk of progressing to severe disease.
Oral antiviral agents (e.g., molnupiravir, nirmatrelvir/ritonavir) are also available and may be recommended. The World Health Organization states that nirmaltrelvir/ritonavir may represent a superior choice to remdesivir (and monoclonal antibodies).[769][770][771] See the Emerging section for more information on oral antiviral agents.
Isolate patients with suspected or confirmed moderate disease (i.e., clinical signs of pneumonia but no signs of severe pneumonia) to contain virus transmission.[79]
Manage patients in a healthcare facility, in a community facility, or at home. Home isolation, with telemedicine or remote visits as appropriate, can be considered in low-risk patients. Manage patients at high risk of deterioration and pregnant women in a healthcare facility.[79][479]
Implement local infection prevention and control procedures when managing patients with COVID-19. For patients in home isolation, advise patients and household members to follow appropriate infection prevention and control measures:
CDC: COVID-19 – if you are sick or caring for someone Opens in new window
Guidance on when to stop isolation varies widely across locations. Isolation periods may depend on various factors including vaccination status, circulating SARS-CoV-2 variants, and patient factors (e.g., immunocompetent/immunocompromised, asymptomatic/symptomatic, disease severity). The World Health Organization recommends discontinuing transmission-based precautions (including isolation) and releasing patients from the care pathway 10 days after positive test (asymptomatic patients), or 10 days after symptom onset plus at least 3 days without fever and respiratory symptoms (symptomatic patients).[79] However, some countries now recommend isolation periods as short as 5 days to 7 days.[772] Consult your local public health guidance for more information.
Treatment recommended for ALL patients in selected patient group
Closely monitor patients for signs or symptoms of disease progression. If the patient is being managed at home, counsel them about signs and symptoms of deterioration or complications that require prompt urgent care (e.g., difficulty breathing, chest pain).[79][479] Pulse oximetry monitoring at home is recommended in symptomatic patients with risk factors for progression to severe disease who are not hospitalized. Patient education and appropriate follow-up are required.[79] If the patient is being managed in hospital, monitor patients closely for signs of clinical deterioration using medical early warning scores (e.g., National Early Warning Score 2 [NEWS2]), and respond immediately with appropriate supportive care interventions.[79]
Treatment recommended for ALL patients in selected patient group
Advise patients to avoid lying on their back as this makes coughing ineffective. Use simple measures first (e.g., a teaspoon of honey in patients ages 1 year and older) to help cough.[537] A meta-analysis found that honey is superior to usual care (e.g., antitussives) for the improvement of upper respiratory tract infection symptoms, particularly cough frequency and severity.[775]
Advise patients about adequate nutrition and appropriate rehydration. Advise patients to drink fluids regularly to avoid dehydration. Fluid intake needs can be higher than usual because of fever. However, too much fluid can worsen oxygenation.[79][537]
Advise patients to improve air circulation by opening a window or door.[537]
Provide basic mental health and psychosocial support for all patients, and manage any symptoms of insomnia, depression, or anxiety as appropriate.[79]
Consider treatment for olfactory dysfunction (e.g., olfactory training) if it persists beyond 2 weeks. There is no evidence to support the use of these treatments in patients with COVID-19.[776] A Cochrane review found there is very limited evidence regarding the efficacy of different interventions at preventing persistent olfactory dysfunction following infection. The only evidence available is for intranasal corticosteroids, and this is of very low certainty, so no conclusions could be drawn.[777]
Most children with moderate disease can be managed with supportive care alone.[479]
Treatment recommended for SOME patients in selected patient group
Consider empiric antibiotics only if there is clinical suspicion of secondary bacterial infection. Start treatment as soon as possible, and refer to local guidelines for choice of regimen.[79][479][537] The regimen should be based on the clinical diagnosis, local epidemiology and susceptibility data, and local treatment guidelines.
Antibiotics may also be considered in older people (particularly those in long-term care facilities) and children <5 years of age to provide empiric antibiotic treatment for possible pneumonia.[79]
Do not offer an antibiotic for preventing secondary bacterial pneumonia in people with COVID-19.[537]
Advise patients to seek medical help without delay if their symptoms do not improve, or worsen rapidly or significantly. Reconsider whether the person has signs and symptoms of more severe disease on reassessment, and whether to refer them to hospital, other acute community support services, or palliative care services.[537]
Treatment recommended for SOME patients in selected patient group
Primary options
acetaminophen: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 325-1000 mg orally (immediate-release) every 4-6 hours when required, maximum 4000 mg/day
OR
ibuprofen: children 6 months to 11 years of age: 5-10 mg/kg orally every 6-8 hours when required, maximum 40 mg/kg/day; children ≥12 years of age and adults: 200-400 mg orally every 4-6 hours when required, maximum 2400 mg/day
Acetaminophen or ibuprofen are recommended.[79][537]
Ibuprofen should only be taken at the lowest effective dose for the shortest period needed to control symptoms. It is not recommended in pregnant women (especially in the third trimester) or children <6 months of age (age cut-offs vary by country).
Treatment recommended for SOME patients in selected patient group
Primary options
sotrovimab: children ≥12 years of age and adults: consult specialist for guidance on dose
OR
casirivimab and imdevimab: children ≥12 years of age and adults: consult specialist for guidance on dose
OR
bebtelovimab: children ≥12 years of age and adults: consult specialist for guidance on dose
OR
bamlanivimab: children and adults: consult specialist for guidance on dose (administered with etesevimab)
Consider a monoclonal antibody. Options may include sotrovimab, casirivimab/imdevimab, bamlanivimab/etesevimab, bebtelovimab, and regdanvimab, depending on your location. Guideline recommendations vary.
The World Health Organization recommends sotrovimab or casirivimab/imdevimab for patients with nonsevere disease who are at highest risk of hospitalization. Casirivimab/imdevimab should only be used where viral genotyping can confirm a susceptible SARS-CoV-2 variant (i.e., excluding Omicron). Monoclonal antibodies probably reduce the risk of hospitalization and duration of symptoms in patients with nonsevere disease, based on moderate-certainty evidence. While monoclonal antibodies achieve a substantial reduction in the relative risk of hospitalization, the absolute benefit will be trivial or unimportant in absolute terms for all but those who are at highest risk of disease (e.g., unvaccinated, older people, immunodeficiencies, and/or chronic disease). Treatment is in addition to the current standard of care. The applicability of this recommendation to children is currently uncertain.[769][770][771]
BMJ rapid recommendations: a living WHO guideline on drugs for COVID-19 Opens in new window
In the UK, the National Institute for Health and Care Excellence recommends offering a neutralizing monoclonal antibody to patients ≥12 years of age who are not in hospital and are thought to be at high risk of progression to severe disease. Consult local guidance for monoclonal antibodies with current UK access.[537]
In the US, the National Institutes of Health guidelines panel recommends bebtelovimab for the treatment of nonhospitalized patients with mild to moderate disease who are at high risk of clinical progression. However, it is only recommended when preferred therapies (i.e., antivirals) are not available, feasible to use, or clinically appropriate as it has not been evaluated in patients at high risk of progression in placebo-controlled trials. Use may be considered in patients with mild to moderate disease who are hospitalized for a reason other than COVID-19 provided that they otherwise meet the criteria for outpatient treatment. The panel currently recommends against the use of casirivimab/imdevimab, bamlanivimab/etesevimab, and sotrovimab because Omicron is the dominant variant in the US, and these monoclonal antibody combinations are predicted to have markedly reduced susceptibility to Omicron and its subvariants.[479] These monoclonal antibodies are not currently authorized for use in the US.[778][779]
The Infectious Diseases Society of America supports the use of monoclonal antibodies with activity against the predominant regional variants within 7 days of symptom onset in ambulatory patients with mild to moderate disease who are at high risk for progression to severe disease.[480]
Choice of monoclonal antibody depends on availability, as well as clinical and contextual factors including emerging information about efficacy with different variants. Preclinical evidence has emerged suggesting that casirivimab/imdevimab and bamlanivimab/etesevimab lack neutralization activity against the Omicron variant in vitro. Sotrovimab and bebtelovimab appear to retain activity against Omicron; however, sotrovimab is not active against the Omicron BA.2 subvariant. Consult local guidance for details regarding specific variants and resistance. Logistical or supply constraints may make patient triage necessary. Treatment should be prioritized for patients who are at the highest risk of progressing to severe disease.[479][537][769]
Evidence for the use of monoclonal antibodies in nonhospitalized patients is uncertain. A Cochrane review found that the evidence is insufficient to draw meaningful conclusions about any specific monoclonal antibody, and the disease stage in which it should be used. Information on outcomes in nonhospitalized patients such as mortality, quality of life, and serious adverse events is either inconclusive or entirely lacking, although casirivimab/imdevimab, sotrovimab, bamlanivimab (alone or in combination with etesevimab), and regdanvimab may reduce the occurrence of hospital admission or death (low-certainty evidence).[781]
Monoclonal antibodies are administered by intravenous infusion. Casirivimab/imdevimab is also available in a subcutaneous formulation, but intravenous administration is recommended. However, if intravenous infusions are not feasible or would cause a delay in treatment, subcutaneous administration may be considered.[479] Evidence for subcutaneous administration is emerging.[780] Outpatient administration in specialized clinics is required, which may limit the feasibility of these treatments.[769] Administer as soon as possible after a positive test and within 7 days of symptom onset. Dose varies across guidelines; consult local protocols.
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported. Administer in a setting where severe hypersensitivity reactions can be managed. Monitor patients during the infusion and observe for at least 1 hour after infusion.
Treatment recommended for SOME patients in selected patient group
Primary options
remdesivir: children ≥12 years of age and ≥40 kg and adults: 200 mg intravenously as a loading dose on day 1, followed by 100 mg every 24 hours for 2 days
Consider the antiviral agent remdesivir. Guideline recommendations vary.
The World Health Organization conditionally recommends remdesivir for patients ≥12 years of age (weighing ≥40 kg) with nonsevere disease who are at highest risk of hospitalization.[769][770][771] In the UK, the National Institute for Health and Care Excellence recommends remdesivir for patients ≥12 years of age (weighing ≥40 kg) who do not need supplemental oxygen, and are within 7 days of symptom onset, and are thought to be at high risk of progression to severe disease (based on low-certainty evidence).[537] In the US, the National Institutes of Health guidelines panel recommends remdesivir to treat nonhospitalized patients with mild to moderate disease who are at high risk of clinical progression.[479] Remdesivir is approved in pediatric patients ≥28 days of age (weighing at least 7 lbs [3 kg]) in the US.[782] The Infectious Diseases Society of America supports the use of remdesivir in ambulatory patients with mild to moderate disease who are at high risk for progression to severe disease.[480]
Remdesivir should be initiated as soon as possible, ideally within 7 days of symptom onset. The treatment course for this indication is 3 days. Logistical constraints may make it difficult to administer the drug in some outpatient settings as it requires administration via intravenous infusion. Renal and/or hepatic monitoring may be required.[479][537][769]
Adverse effects include nephrotoxicity and hepatotoxicity. Remdesivir is not recommended in patients with an estimated glomerular filtration rate <30 mL/minute. Monitor renal function before starting treatment and during treatment as clinically appropriate. Intravenous formulations contain the solubility enhancer sulfobutyl ether beta-cyclodextrin sodium (SBECD), which is renally cleared. Accumulation of SBECD in patients with renal impairment may result in liver and renal toxicities. Consider preferential use of the lyophilized powder formulation in patients with renal impairment if available, as it contains less SBECD. Remdesivir may have little or no effect on acute kidney injury compared with placebo; however, the certainty of evidence is low.[883] Transaminase elevations have been reported. Monitor liver function before starting treatment and during treatment as clinically appropriate. Consider discontinuing treatment if alanine aminotransferase (ALT) levels increase to ≥10 times the upper limit of normal. Discontinue treatment if ALT elevation is accompanied by signs or symptoms of liver inflammation. Monitor prothrombin time before starting treatment and during treatment as clinically appropriate as increases in prothrombin time have been reported.
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported. Administer in a setting where severe hypersensitivity reactions can be managed. Monitor patients during the infusion and observe for at least 1 hour after infusion.
Evidence for this indication is emerging. Remdesivir probably reduces hospital admission (moderate-certainty evidence), and may have little or no impact on mortality (low-certainty evidence). The effect on mechanical ventilation and time to symptom resolution is very uncertain. The balance between benefits and potential harms favors treatment, but only in the highest risk group.[769][770][771] A randomized, double-blind, placebo-controlled trial of 562 patients found that a 3-day course of remdesivir resulted in an 87% lower risk of hospitalization or death among nonhospitalized patients who were at high risk for disease progression compared with placebo. The most common coexisting conditions were diabetes, obesity, and hypertension.[783]
Logistical or supply constraints may make patient triage for antiviral treatment necessary. Therapy should be prioritized for patients who are at the highest risk of progressing to severe disease.
Oral antiviral agents (e.g., molnupiravir, nirmatrelvir/ritonavir) are also available and may be recommended. The World Health Organization states that nirmaltrelvir/ritonavir may represent a superior choice to remdesivir (and monoclonal antibodies).[769][770][771] See the Emerging section for more information on oral antiviral agents.
Admit patients with suspected or confirmed severe disease to an appropriate healthcare facility under the guidance of a specialist team as these patients are at risk of rapid clinical deterioration.
Severe disease in adults is defined as having clinical signs of pneumonia plus at least one of the following: respiratory rate >30 breaths/minute, severe respiratory distress, or SpO₂ <90% on room air. Severe disease in children is defined as having clinical signs of pneumonia plus at least one of the following: central cyanosis or SpO₂ <90%, severe respiratory distress, general danger signs (inability to breastfeed or drink, lethargy or unconsciousness, or convulsions), or fast breathing (<2 months: ≥60 breaths per minute; 2-11 months: ≥50 breaths per minute; 1-5 years: ≥40 breaths per minute).[79]
Pregnant women should be managed by a multidisciplinary team, including obstetric, perinatal, neonatal, and intensive care specialists, as well as midwifery and mental health and psychosocial support. A woman-centered, respectful, skilled approach to care is recommended.[79] The multidisciplinary team should be organized as soon as possible after maternal hypoxemia occurs in order to assess fetal maturity, disease progression, and the best options for delivery.[873]
Implement local infection prevention and control procedures when managing patients with COVID-19.
Use the Clinical Frailty Scale (CFS) to assess baseline health and inform discussions on treatment expectations when appropriate and within an individualized assessment of frailty. Clinical Frailty Scale Opens in new window Do not use the CFS for younger people, people with stable long-term disabilities (e.g., cerebral palsy), learning disabilities, or autism. Make an individualized assessment of frailty in these people, using clinical assessment and alternative scoring methods.[537] Hospitalized frail patients are at higher risk of all-cause mortality compared with non-frail hospitalized patients, regardless of the frailty score/assessment tool used.[786] A meta-analysis found that an increase in CFS was associated with an increase in mortality (each 1-point increase in CFS was associated with a 12% increase in mortality).[787] Patients with a score between 4-9 had significantly increased mortality compared with those with a score of 1-3.[788] However, one systematic review and meta-analysis found that there was no difference in short-term mortality between frail and nonfrail patients.[789] Some studies suggest that a more nuanced understanding of frailty and outcomes is needed, and you should exercise caution in placing too much emphasis on the influence of frailty alone when discussing prognosis in older people.[790]
Guidance on when to stop isolation varies widely across locations. Isolation periods may depend on various factors including vaccination status, circulating SARS-CoV-2 variants, and patient factors (e.g., immunocompetent/immunocompromised, asymptomatic/symptomatic, disease severity). The World Health Organization recommends discontinuing transmission-based precautions (including isolation) and releasing patients from the care pathway 10 days after symptom onset plus at least 3 days without fever and respiratory symptoms.[79] However, this guidance varies and you should consult your local public health guidance for more information.
Treatment recommended for ALL patients in selected patient group
Start supplemental oxygen therapy immediately in any patient with emergency signs (i.e., obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma and/or convulsions), or any patient without emergency signs and SpO₂ <90%.[79][479]
Target SpO₂ to ≥94% during resuscitation in adults and children with emergency signs who require emergency airway management and oxygen therapy. Once the patient is stable, a target SpO₂ >90% in children and nonpregnant adults, and ≥92% to 95% in pregnant women, is recommended. Nasal prongs or a nasal cannula are preferred in young children.[79] Some guidelines recommend that SpO₂ should be maintained no higher than 96%.[792]
Some centers may recommend different SpO₂ targets in order to support prioritization of oxygen flow for the most severely ill patients in hospital.
Consider positioning techniques (e.g., high supported sitting), and airway clearance management to optimize oxygenation and assist with secretion clearance in adults. Consider awake prone positioning (for 8-12 hours/day, broken into shorter periods over the day) in severely ill patients who require supplemental oxygen.[79][479] Awake prone positioning of nonintubated patients was associated with improvement in oxygen variables (PaO₂/FiO₂, PaO₂, and SpO₂), respiratory rate, rate of intubation, and mortality. However, evidence is limited.[793][794][795][796] However, one small nonrandomized controlled trial found that prone positioning offered no clinical benefit among patients with hypoxemia who are not on mechanical ventilation, with evidence of worsening clinical outcomes at day 5.[797]
Monitor patients closely for signs of progressive acute hypoxemic respiratory failure.[79][479]
The World Health Organization recommends high-flow oxygen (HFNO), continuous positive airway pressure [CPAP], or noninvasive ventilation (helmet or face mask interface) in hospitalized patients with severe disease and acute hypoxemic respiratory failure not needing emergent intubation, rather than standard oxygen therapy.[79] Choice depends on factors such as availability of devices and the supply of oxygen, personal comfort and experience, and patient-specific considerations (e.g., claustrophobia with CPAP or noninvasive ventilation masks, nasal discomfort with HFNO).
Treatment recommended for ALL patients in selected patient group
Fluids and electrolytes: use cautious fluid management in adults and children without tissue hypoperfusion and fluid responsiveness as aggressive fluid resuscitation may worsen oxygenation.[79] Correct any electrolyte or metabolic abnormalities, such as hyperglycemia or metabolic acidosis, according to local protocols.[798]
Breathlessness and cough: keep the room cool, and encourage relaxation, breathing techniques, and changing body positions. Identify and treat any reversible causes of breathlessness (e.g., pulmonary edema, pulmonary embolism, COPD, asthma). Consider a trial of oxygen, if available.[537] Short-term use of a cough suppressant may be considered in select patients (e.g., if the cough is distressing to the patient) provided there are no contraindications.[537]
Anxiety, delirium, and agitation: identify and treat any underlying or reversible causes (e.g., offer reassurance, treat hypoxia, correct metabolic or endocrine abnormalities, address coinfections, minimize use of drugs that may cause or worsen delirium, treat substance withdrawal, maintain normal sleep cycles, treat pain or breathlessness).[79][537] Low doses of haloperidol (or another suitable antipsychotic) can be considered for agitation.[79] Nonpharmacologic interventions are the mainstay for the management of delirium when possible, and prevention is key.[799]
Mouth care: an important part of overall patient care in hospitalized patients who are ventilated or nonventilated and those undergoing step-down or end-of-life care.[800]
Mental health symptoms: provide basic mental health and psychosocial support for all patients, and manage any symptoms of insomnia or depression as appropriate.[79]
Treatment recommended for ALL patients in selected patient group
Primary options
enoxaparin: consult specialist for guidance on dose
OR
dalteparin: consult specialist for guidance on dose
Secondary options
fondaparinux: consult specialist for guidance on dose
OR
heparin: consult specialist for guidance on dose
Assess the risk of bleeding as soon as possible after admission, or by the time of the first consultant review, using a suitable risk assessment tool.[537]
Start venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized adults and adolescents, provided there are no contraindications.[79][479][801][802] In the UK, the National Institute for Health and Care Excellence (NICE) recommends starting as soon as possible (within 14 hours of admission), in young people and adults who need low-flow oxygen and who do not have an increased bleeding risk, and continuing for a minimum of 7 days including after discharge.[537] In children, the indications for venous thromboembolism prophylaxis should be the same as those for children without COVID-19.[479]
Low molecular weight heparin, unfractionated heparin, or fondaparinux are the recommended options for standard thromboprophylaxis.[79] In the UK, NICE recommends low molecular weight heparin first-line, with fondaparinux or unfractionated heparin reserved for patients who cannot have low molecular weight heparin.[537] In the US, the National Institutes of Health guidelines panel recommends parenteral over oral anticoagulants and, when heparin is used, low molecular weight heparin is preferred over unfractionated heparin. The panel recommends against the use of therapeutic-dose oral anticoagulants, except in the context of a clinical trial.[479] Unfractionated heparin is contraindicated in patients with severe thrombocytopenia and patients with a history of heparin-induced thrombocytopenia. Fondaparinux is recommended in patients with a history of heparin-induced thrombocytopenia. Mechanical thromboprophylaxis (e.g., intermittent pneumatic compression devices) is recommended if anticoagulation is contraindicated or not available.[802][803]
The optimal dose is yet to be determined. Standard prophylaxis doses are generally recommended over intermediate- or full treatment-dose regimens in patients without an established indication for higher-dose anticoagulation across most guidelines.[806] However, this recommendation varies and you should consult your local guidelines. The World Health Organization recommends standard thromboprophylaxis dosing of anticoagulation rather than therapeutic or intermediate dosing in patients without an established indication for higher-dose anticoagulation.[79] In the UK, NICE recommends a prophylactic dose of a low molecular weight heparin for a minimum of 7 days (including after discharge) in young people and adults who need low-flow oxygen and who do not have an increased bleeding risk. A treatment dose of a low molecular weight heparin for 14 days or until discharge (whichever is sooner) may be considered in young people and adults who need low-flow oxygen and who do not have an increased bleeding risk; however, this is a conditional recommendation only. The decision should be carefully considered, and choice of the most appropriate dose regimen should be guided by bleeding risk, clinical judgment, and local protocols. For those who do not need supplemental oxygen, follow standard VTE prophylaxis guidelines.[537] In the US, the National Institutes of Health guidelines panel recommends therapeutic-dose heparin for patients who have a D-dimer level above the upper limit of normal, require low-flow oxygen, and have no increased bleeding risk, unless a contraindication exists. Treatment should continue for 14 days or until hospital discharge, whichever comes first. The panel recommends using prophylactic-dose heparin for patients who are not administered therapeutic heparin, unless a contraindication exists.[479] Dose adjustments may be required in patients with extremes of body weight or renal impairment.[537]
For patients who are already on an anticoagulant for another underlying condition, continue the patient’s current medication and therapeutic dose unless contraindicated by a change in clinical circumstances.[479][537] Consider switching to low molecular weight heparin as the preferred option for venous thromboembolism prophylaxis if the patient’s clinical condition is deteriorating and the patient is not currently on low molecular weight heparin.[537]
Evidence supports the use of lower-dose anticoagulant regimens. A Cochrane review found that higher-dose regimens resulted in little to no difference in all-cause mortality compared with lower-dose regimens in hospitalized patients; however, higher-dose regimens were associated with an increased risk of minor bleeding up to 30 days (high-certainty evidence). Higher-dose anticoagulants probably reduce pulmonary embolism and slightly increase major bleeding compared with lower-dose regimens up to 30 days (moderate-certainty evidence). Higher-dose anticoagulants may result in little or no difference in deep vein thrombosis, stroke, major adverse limb events, myocardial infarction, atrial fibrillation, or thrombocytopenia compared with lower-dose regimens up to 30 days (low-certainty evidence). Anticoagulants may reduce all‐cause mortality compared with no anticoagulants, but the evidence is very uncertain.[807]
Monitor patients for signs and symptoms suggestive of thromboembolism and proceed with appropriate diagnostic and management pathways if clinically suspected.[79] If the patient’s clinical condition changes, assess the risk of VTE, reassess the bleeding risk, and review VTE prophylaxis.[537]
Continue until hospital discharge.[79] Routine post-discharge VTE prophylaxis is not generally recommended, except in certain high-risk patients, in the context of a clinical trial, or if another indication for VTE prophylaxis exists.[479][801][802] Ensure patients who require VTE prophylaxis after discharge are able to use it correctly or have arrangements made for someone to help them.[537]
There is currently insufficient evidence to determine the risks and benefits of prophylactic anticoagulation in hospitalized patients with COVID-19.[812] A systematic review and meta-analysis found that the pooled odds of mortality between anticoagulated and nonanticoagulated hospitalized patients were similar, but lower in the standard prophylactic-dose group. Prophylactic-dose anticoagulation significantly decreased the odds of in-hospital death by 17% compared with no anticoagulation. Mortality increased in the intermediate- to therapeutic-dose group with an increased risk of major bleeding.[813] Clinicians should rely on pre-COVID-19 evidence-based principles of anticoagulation management combined with rational approaches to address clinical challenges.[801]
Treatment recommended for ALL patients in selected patient group
Monitor patients closely for signs of clinical deterioration, and respond immediately with appropriate supportive care interventions.[79]
Treatment recommended for SOME patients in selected patient group
Consider empiric antibiotics if there is clinical suspicion of secondary bacterial infection. Give within 1 hour of initial assessment for patients with suspected sepsis or if the patient meets high-risk criteria (or within 4 hours of establishing a diagnosis of secondary bacterial pneumonia); do not wait for microbiology results. Base the regimen on the clinical diagnosis (e.g., community-acquired pneumonia, hospital-acquired pneumonia, sepsis), local epidemiology and susceptibility data, and local treatment guidelines.[79][479][537]
Do not offer antibiotics for preventing or treating pneumonia if SARS-CoV-2, another virus, or a fungal infection is likely to be the cause.[537] Guidelines recommend against empiric broad-spectrum antibiotics in the absence of a proven or suspected bacterial infection.[479]
Consider seeking specialist advice for people who: are immunocompromised; have a history of infection with resistant organisms; have a history of repeated infective exacerbations of lung disease; are pregnant; or are receiving advanced respiratory or organ support.[537] Seek specialist advice if there is a suspicion that the person has an infection with multidrug-resistant bacteria and may need a different antibiotic, or there is clinical or microbiologic evidence of infection and the person's condition does not improve as expected after 48 to 72 hours of antibiotic treatment.[537]
Reassess antibiotic use daily. De-escalate empiric therapy on the basis of microbiology results and clinical judgment. Regularly review the possibility of switching from intravenous to oral therapy. Duration of treatment should be as short as possible (e.g., 5 to 7 days). Antibiotic stewardship programs should be in place.[79]
Treatment recommended for SOME patients in selected patient group
Primary options
dexamethasone: children: consult specialist for guidance on dose; adults: 6 mg orally/intravenously once daily for 7-10 days
OR
hydrocortisone: children: consult specialist for guidance on dose; adults: 50 mg orally/intravenously every 8 hours for 7-10 days
Secondary options
prednisone: children: consult specialist for guidance on dose; adults: 40 mg/day orally given in 1-2 divided doses for 7-10 days
OR
methylprednisolone: children: consult specialist for guidance on dose; adults: 32 mg/day orally/intravenously given in 1-2 divided doses for 7-10 days
Consider a systemic corticosteroid. Guideline recommendations vary.
The World Health Organization strongly recommends systemic corticosteroid therapy (low-dose intravenous or oral dexamethasone or hydrocortisone) for 7 to 10 days in adults with severe disease. This recommendation is based on two meta-analyses that pooled data from eight randomized trials (over 7000 patients), including the UK RECOVERY trial. Moderate-quality evidence suggests that systemic corticosteroids probably reduce 28-day mortality in patients with severe disease. There is no evidence directly comparing dexamethasone and hydrocortisone. The harms of treatment in this context are considered to be minor. It is unclear whether these recommendations can be applied to children or those who are immunocompromised.[769][770][771][816][817]
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In the UK, the National Institute for Health and Care Excellence recommends offering dexamethasone (or an alternative such as hydrocortisone or prednisone when dexamethasone cannot be used or is unavailable) to people who need supplemental oxygen to meet their prescribed oxygen saturation levels, or who have a level of hypoxia that needs supplemental oxygen but who are unable to have or tolerate it. Treatment is for up to 10 days unless there is a clear indication to stop early.[537]
In the US, the National Institutes of Health guidelines panel recommends dexamethasone, either alone or in combination with remdesivir, in hospitalized adults who require supplemental oxygen. Alternative corticosteroids may be used in situations where dexamethasone is not available. It is not routinely recommended for pediatric patients who require only low levels of oxygen support (i.e., via a nasal cannula only). Use of dexamethasone for the treatment of severe disease in children who are profoundly immunocompromised has not been evaluated, may be harmful, and therefore should be considered only on a case-by-case basis.[479] The Infectious Diseases Society of America supports the use of dexamethasone in hospitalized patients with severe disease.[480]
Moderate- and low-certainty evidence supports the use of corticosteroids in hospitalized patients. A Cochrane review found that systemic corticosteroids probably slightly reduce all-cause mortality in hospitalized patients with symptomatic disease. Most participants in the studies were treated with noninvasive or invasive mechanical ventilation. Low-certainty evidence suggests that there may also be a reduction in ventilator-free days; however, the current evidence remains uncertain due to methodological limitations. Evidence of an increased risk of mortality in symptomatic hospitalized patients without any need for additional oxygen was limited by a lack of statistical significance. It is unknown which systemic corticosteroid is most effective.[818]
Monitor patients for adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, reactivation of latent infections) and assess for drug-drug interactions.[479]
Treatment recommended for SOME patients in selected patient group
Primary options
remdesivir: children ≥12 years of age and ≥40 kg and adults: 200 mg intravenously as a loading dose on day 1, followed by 100 mg every 24 hours for 5-10 days
Consider the antiviral agent remdesivir. Guideline recommendations vary, and there are conflicting recommendations across international guidelines.
In the UK, the National Institute for Health and Care Excellence recommends considering remdesivir in hospitalized adults and children ≥12 years of age (weighing ≥40 kg) who require low-flow supplemental oxygen. Limited evidence suggests that remdesivir probably reduces the risk of death in hospitalized patients who need low-flow supplemental oxygen (moderate certainty). This is likely because it is being given early in the disease course.[537]
In the US, the National Institutes of Health guidelines panel recommends remdesivir in hospitalized adults who require supplemental oxygen. It may be given alone (e.g., for patients who require minimal supplemental oxygen) or in combination with dexamethasone (e.g., for patients who require increasing amounts of supplemental oxygen). The panel recommends remdesivir in hospitalized children ages ≥12 years who have risk factors for severe disease and have an emergent or increasing need for supplemental oxygen. The panel recommends remdesivir in hospitalized children ages ≥16 years who have an emergent or increasing need for supplemental oxygen, regardless of whether they have risk factors for severe disease. The panel recommends considering remdesivir in hospitalized children of all ages who have an emergent or increasing need for supplemental oxygen, in consultation with a pediatric infectious disease specialist.[479] Remdesivir is approved in pediatric patients ≥28 days of age (weighing at least 7 lbs [3 kg]) in the US.[782]
The Infectious Diseases Society of America supports the use of remdesivir in hospitalized patients with severe disease who require oxygen.[480]
The World Health Organization recommends against the use of remdesivir in hospitalized patients in addition to standard care, regardless of disease severity. This weak or conditional recommendation is based on a systematic review and network meta-analysis of four randomized trials with 7333 hospitalized patients, and included the ACTT-1 trial and preliminary results from the WHO Solidarity trial. At the time of publication, there was no evidence that remdesivir improved patient outcomes such as time to clinical improvement, the need for mechanical ventilation, or mortality. However, the meta-analysis did not prove that remdesivir had no benefit. Updated results from the WHO Solidarity trial published in May 2022 found that remdesivir may have a small effect against death and/or progression to ventilation. Overall, 14.5% of patients receiving remdesivir died compared with 15.6% in the control group. However, remdesivir had no significant effect on patients who were already being ventilated. In patients who were already ventilated, 42.1% of patients receiving remdesivir died compared with 38.5% in the control group. In patients who were not already ventilated, 11.9% of patients receiving remdesivir died compared with 13.5% in the control group, while 14.1% versus 15.7% progressed to ventilation.[820] This recommendation is currently being reviewed, with an updated recommendation expected soon.[769][770][771][819]
Moderate-certainty evidence does not support the use of remdesivir in hospitalized patients. A Cochrane review found that remdesivir probably has little or no effect on 28-day all-cause mortality in hospitalized patients compared with placebo or usual care (moderate certainty). Effects on clinical improvement or worsening were uncertain. There were insufficient data available to examine the effect of remdesivir on mortality across subgroups defined by respiratory support at baseline.[821]
The recommended treatment course for this indication is 5 days or until hospital discharge, whichever comes first.[479] Evidence does not suggest any greater benefit with a 10-day course of remdesivir compared with a 5-day course, but suggests an increased risk of harm.[537] However, some experts may recommend a 10-day course in patients who have not shown substantial clinical improvement by day 5.[479] There may be no benefit in completing the full course of remdesivir if the patient progresses.[537] However, US guidelines recommend completing the full treatment course if the patient progresses to requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation.[479]
Adverse effects include nephrotoxicity and hepatotoxicity. Remdesivir is not recommended in patients with an estimated glomerular filtration rate <30 mL/minute. Monitor renal function before starting treatment and during treatment as clinically appropriate. Intravenous formulations contain the solubility enhancer sulfobutyl ether beta-cyclodextrin sodium (SBECD), which is renally cleared. Accumulation of SBECD in patients with renal impairment may result in liver and renal toxicities. Consider preferential use of the lyophilized powder formulation in patients with renal impairment if available, as it contains less SBECD. Remdesivir may have little or no effect on acute kidney injury compared with placebo; however, the certainty of evidence is low.[883] Transaminase elevations have been reported. Monitor liver function before starting treatment and during treatment as clinically appropriate. Consider discontinuing treatment if alanine aminotransferase (ALT) levels increase to ≥10 times the upper limit of normal. Discontinue treatment if ALT elevation is accompanied by signs or symptoms of liver inflammation. Monitor prothrombin time before starting treatment and during treatment as clinically appropriate as increases in prothrombin time have been reported.
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported. Administer in a setting where severe hypersensitivity reactions can be managed. Monitor patients during the infusion and observe for at least 1 hour after infusion.
Treatment recommended for SOME patients in selected patient group
Primary options
tocilizumab: children: consult specialist for guidance on dose; adults: 8 mg/kg intravenously as a single dose, maximum 800 mg/dose
MoreOR
sarilumab: children: consult specialist for guidance on dose; adults: 400 mg intravenously as a single dose
MoreConsider an IL-6 inhibitor. Guideline recommendations vary.
The World Health Organization strongly recommends an IL-6 inhibitor (tocilizumab or sarilumab), in combination with a systemic corticosteroid and initiated at the same time, in patients with severe disease. This recommendation is based on high-certainty evidence that shows IL-6 inhibitors reduce mortality and the need for mechanical ventilation, and low-certainty evidence that suggests that IL-6 inhibitors may also reduce the duration of mechanical ventilation and hospitalization. The evidence regarding the risk of severe adverse events is uncertain. The applicability of this recommendation to children is currently uncertain.[769][770][771] This recommendation is based on data from the UK RECOVERY and REMAP-CAP trials.[822][823]
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In the UK, the National Institute for Health and Care Excellence recommends a single dose of tocilizumab in hospitalized adults if all of the following conditions apply: they are having or have completed a course of corticosteroids such as dexamethasone (unless they cannot have corticosteroids); they have not had another IL-6 inhibitor during this admission; there is no evidence of a bacterial or viral infection (other than SARS-CoV-2) that might be worsened by tocilizumab; AND they either need supplemental oxygen and have a C-reactive protein level of ≥75 mg/L, OR they are within 48 hours of starting high-flow nasal oxygen, continuous positive airway pressure, noninvasive ventilation, or invasive mechanical ventilation. Consider tocilizumab for children and young people who have severe disease or pediatric inflammatory multisystem syndrome only if they are ages 1 year and over, and only in the context of a clinical trial. Sarilumab may be considered an alternative option in adults only if tocilizumab cannot be used or is unavailable (use the same eligibility criteria as those for tocilizumab).[537]
In the US, the National Institutes of Health guidelines panel recommends tocilizumab (or sarilumab if tocilizumab is not available or not feasible to use) for patients on a corticosteroid with rapidly increasing oxygen needs and systemic inflammation.[479] The Infectious Diseases Society of America recommends considering tocilizumab in hospitalized adults with progressive severe disease who have elevated markers of systemic inflammation, in addition to standard of care (i.e., corticosteroids), rather than standard of care alone. Sarilumab may be used if tocilizumab is not available.[480]
IL-6 inhibitors and Janus kinase inhibitors (see table below) are viewed as alternatives to each other and should not be administered together. There is potential for an additive risk of infection.
Patients on IL-6 inhibitors are at increased risk of infection including active tuberculosis, invasive fungal infections, and opportunistic pathogens.
Routine blood work including neutrophil count, platelets, transaminases, and total bilirubin should be checked prior to initiation of therapy. All patients should be monitored for signs and symptoms of infection given the increased risk of immunosuppression in addition to systemic corticosteroids.[769]
These drugs should be avoided in patients who are significantly immunocompromised.[479]
Treatment recommended for SOME patients in selected patient group
Primary options
baricitinib: children: consult specialist for guidance on dose; adults: 4 mg orally once daily for 14 days
Secondary options
tofacitinib: children and adults: consult specialist for guidance on dose
OR
ruxolitinib: children and adults: consult specialist for guidance on dose
Consider a JAK inhibitor. Guideline recommendations vary.
The World Health Organization strongly recommends a JAK inhibitor (baricitinib), in combination with a systemic corticosteroid and initiated at the same time, in patients with severe disease. This recommendation is based on moderate-certainty evidence that baricitinib probably reduces mortality and duration of mechanical ventilation, and high-certainty evidence that baricitinib reduces length of hospital stay. The applicability of this recommendation to children is currently uncertain.[769][770][771]
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In the UK, the National Institute for Health and Care Excellence recommends baricitinib in hospitalized adults who: need supplemental oxygen, and are having or have completed a course of corticosteroids (unless contraindicated), and have no evidence of infection (other than SARS-CoV-2) that might be worsened by baricitinib. Baricitinib may also be considered in children ≥2 years of age provided they meet the same criteria.[537]
In the US, the National Institutes of Health guidelines panel recommends baricitinib in patients on a corticosteroid with rapidly increasing oxygen needs and systemic inflammation.[479] The Infectious Diseases Society of America suggests baricitinib (in combination with a corticosteroid) in hospitalized adults with severe disease. It suggests baricitinib with remdesivir, rather than remdesivir alone, in patients who cannot receive a corticosteroid because of a contraindication.[480]
Other drugs in this class include tofacitinib and ruxolitinib. The World Health Organization recommends against using these drugs unless baricitinib or IL-6 inhibitors are not available. The effects of tofacitinib or ruxolitinib on mortality, need for mechanical ventilation, and hospital length of stay remain uncertain and more trial evidence is needed.[769][770][771] In the US, the National Institutes of Health guidelines panel recommends tofacitinib only if baricitinib is not available or it is not feasible to use it.[479] The Infectious Diseases Society of America suggests tofacitinib in hospitalized adults with severe disease who are not on noninvasive or invasive mechanical ventilation.[480]
JAK inhibitors and IL-6 inhibitors (see table above) are viewed as alternatives to each other and should not be administered together. There is potential for an additive risk of infection.
Patients are at increased risk of infection including active tuberculosis, invasive fungal infections, and opportunistic pathogens.[769] Avoid use in patients with known active tuberculosis. All patients should be monitored for signs and symptoms of infection given the increased risk of immunosuppression in addition to systemic corticosteroids. Monitor complete blood count with differential before and during treatment.
Baricitinib is not recommended in patients with severe renal or hepatic impairment.[769] Baricitinib is not recommended in adults with an estimated glomerular filtration rate ≤15 mL/minute (≤30 mL/minute in children <9 years of age), or in patients on dialysis or renal replacement therapy. A dose reduction is recommended in patients with an estimated glomerular filtration rate ≤60 mL/minute. Baricitinib has not been studied in patients with severe hepatic impairment and it is unknown whether a dose adjustment is required in these patients. It should only be used if the potential benefits outweigh the potential risks. Use caution with tofacitinib and ruxolitinib in patients with moderate to severe renal impairment (including those on dialysis); a dose adjustment may be required. Monitor renal and hepatic function before and during treatment.
Adverse effects include leukopenia, lymphopenia, thrombocytosis, anemia, blood clotting abnormalities, hepatic impairment, and secondary infection.[769] Other serious adverse effects include venous thrombosis and severe infections. The US Food and Drug Administration has issued a warning about increased risk of serious heart-related events, cancer, blood clots, and death with JAK inhibitors.[884]
Treatment recommended for SOME patients in selected patient group
Treat laboratory-confirmed coinfections (e.g., malaria, tuberculosis, influenza) as appropriate according to local protocols.[79] The treatment of influenza is the same in all patients regardless of SARS-CoV-2 coinfection. Start empiric treatment with oseltamivir in hospitalized patients who are suspected of having either or both infections as soon as possible without waiting for influenza test results. Antiviral therapy can be stopped once influenza has been ruled out.[479]
Treatment recommended for SOME patients in selected patient group
Primary options
acetaminophen: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 325-1000 mg orally (immediate-release) every 4-6 hours when required, maximum 4000 mg/day
OR
ibuprofen: children 6 months to 11 years of age: 5-10 mg/kg orally every 6-8 hours when required, maximum 40 mg/kg/day; children ≥12 years of age and adults: 200-400 mg orally every 4-6 hours when required, maximum 2400 mg/day
Acetaminophen or ibuprofen are recommended.[79][537]
Ibuprofen should only be taken at the lowest effective dose for the shortest period needed to control symptoms. It is not recommended in pregnant women (especially in the third trimester) or children <6 months of age (age cut-offs vary by country).
Treatment recommended for SOME patients in selected patient group
Primary options
sotrovimab: children ≥12 years of age and adults: consult specialist for guidance on dose
Secondary options
casirivimab and imdevimab: children ≥12 years of age and adults: consult specialist for guidance on dose
OR
bamlanivimab: children and adults: consult specialist for guidance on dose (administered with etesevimab)
Consider a monoclonal antibody. Options may include sotrovimab, casirivimab/imdevimab, and bamlanivimab/etesevimab, depending on your location. Guideline recommendations vary.
The World Health Organization recommends casirivimab/imdevimab (but not sotrovimab) for patients with severe disease with a seronegative status (i.e., no detectable SARS-CoV-2 antibodies). Casirivimab/imdevimab should only be used where viral genotyping can confirm a susceptible SARS-CoV-2 variant (i.e., excluding Omicron). Casirivimab/imdevimab probably reduces mortality and possibly reduces the need for mechanical ventilation in patients who are seronegative based on moderate- and low-certainty evidence, respectively. Sotrovimab did not demonstrate efficacy in seronegative patients with severe/critical disease in one randomized controlled trial. Treatment is in addition to the current standard of care. The applicability of this recommendation to children is currently uncertain.[769][770][771]
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In the UK, the National Institute for Health and Care Excellence recommends casirivimab/imdevimab in hospitalized patients ≥12 years of age who are seronegative, provided they meet all of the eligibility criteria and none of the exclusion criteria (see guidance for more information).[537] Do not offer casirivimab/imdevimab to patients who are known or suspected to have infection caused by an Omicron variant. Only offer casirivimab/imdevimab to patients when the infection is known to be caused by a variant susceptible to casirivimab/imdevimab.
In the US, the National Institutes of Health guidelines panel states that casirivimab/imdevimab and sotrivimab and bamlanivimab/etesevimab are not currently authorized for use in hospitalized patients with severe disease, but they may be available through expanded access programs for patients who are hospitalized with severe disease who have not developed an antibody response or who are not expected to mount an effective immune response (e.g., immunocompromised patients).[479]
Choice of monoclonal antibody depends on availability, as well as clinical and contextual factors including emerging information about efficacy with different variants. Preclinical evidence has emerged suggesting that casirivimab/imdevimab and bamlanivimab/etesevimab lack neutralization activity against the Omicron variant in vitro. Sotrovimab appears to retain activity against Omicron; however, sotrovimab is not active against the Omicron BA.2 subvariant. Consult local guidance for details regarding specific variants and resistance. Logistical or supply constraints may make patient triage necessary. Treatment should be prioritized for patients who are at the highest risk of progressing to severe disease.[479][537][769]
Evidence for the use of monoclonal antibodies in hospitalized patients is uncertain. A Cochrane review found that casirivimab/imdevimab probably has no effect on mortality, progression to invasive mechanical ventilation, and 30-day hospital discharge in hospitalized patients (moderate-certainty evidence). Bamlanivimab may have little to no effect on efficacy outcomes when compared with placebo, but it may increase the occurrence of severe symptoms and adverse events (low-certainty evidence).[781] The UK RECOVERY trial found that casirivimab/imdevimab reduced 28-day mortality in hospitalized patients who were seronegative at baseline, but not in those who were seropositive at baseline.[830]
Monoclonal antibodies are administered by intravenous infusion. Casirivimab/imdevimab is also available in a subcutaneous formulation, but intravenous administration is recommended. However, if intravenous infusions are not feasible or would cause a delay in treatment, subcutaneous administration may be considered.[479] Dose varies across guidelines; consult local protocols.
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported. Administer in a setting where severe hypersensitivity reactions can be managed. Monitor patients during the infusion and observe for at least 1 hour after infusion.
Treatment recommended for SOME patients in selected patient group
Consider any appropriate experimental or emerging therapies.
Antiviral therapies will have a greater effect early in the course of the disease, whereas immunosuppressive/anti-inflammatory therapies are likely to have a greater effect later in the course of the disease.[479]
See the Emerging section for more information.
Treatment recommended for SOME patients in selected patient group
Routinely assess older patients for mobility, functional swallow, cognitive impairment, and mental health concerns. Based on that assessment determine whether the patient is ready for discharge, and whether the patient has any rehabilitation and follow-up requirements.[79]
Treatment recommended for SOME patients in selected patient group
Palliative care interventions should be made accessible at each institution that provides care for patients with COVID-19. Identify whether the patient has an advance care plan and respect the patient’s priorities and preferences when formulating the patient’s care plan.[79] Follow local palliative care guidelines.
There are a lack of data on palliative care in patients with COVID-19. A rapid systematic review of pharmacologic strategies used for palliative care in these patients, the first international review of its kind, found that a higher proportion of patients required continuous subcutaneous infusions for medication delivery than is typically seen in the palliative care population. Modest doses of commonly used end-of-life medications were required for symptom control. However, these findings should be interpreted with caution due to the lack of data available.[831]
Admit or transfer patients with critical disease (i.e., presence of acute respiratory distress syndrome, sepsis, or septic shock) to an intensive/critical care unit under the guidance of a specialist team.[79]
Discuss the risks, benefits, and potential outcomes of treatment options with patients and their families, and allow them to express preferences about their management. Take their wishes and expectations into account when considering the ceiling of treatment. Use decision support tools if available. Put treatment escalation plans in place, and discuss any existing advance care plans or advance decisions to refuse treatment with patients who have preexisting advanced comorbidities.[537]
Implement local infection prevention and control procedures when managing patients with COVID-19.
Pregnant women should be managed by a multidisciplinary team, including obstetric, perinatal, neonatal, and intensive care specialists, as well as midwifery and mental health and psychosocial support. A woman-centered, respectful, skilled approach to care is recommended.[79] The multidisciplinary team should be organized as soon as possible after maternal hypoxemia occurs in order to assess fetal maturity, disease progression, and the best options for delivery.[873]
Guidance on when to stop isolation varies widely across locations. Isolation periods may depend on various factors including vaccination status, circulating SARS-CoV-2 variants, and patient factors (e.g., immunocompetent/immunocompromised, asymptomatic/symptomatic, disease severity). The World Health Organization recommends discontinuing transmission-based precautions (including isolation) and releasing patients from the care pathway 10 days after symptom onset plus at least 3 days without fever and respiratory symptoms.[79] However, this guidance varies and you should consult your local public health guidance for more information.
Treatment recommended for ALL patients in selected patient group
Consider fluid and electrolyte management, antimicrobial treatment, and symptom management as appropriate. See Severe COVID-19 above for more detailed information.
Follow local guidelines for the management of pain, sedation, and delirium.[479]
Implement standard interventions to prevent complications associated with critical illness.[79]
Treatment recommended for ALL patients in selected patient group
Primary options
enoxaparin: consult specialist for guidance on dose
OR
dalteparin: consult specialist for guidance on dose
Secondary options
heparin: consult specialist for guidance on dose
OR
fondaparinux: consult specialist for guidance on dose
Start venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized adults and adolescents, provided there are no contraindications.[79][479][801][802]
Recommendations for patients with critical disease may differ from those for severe disease (see above). Consult your local guidelines.
In the UK, the National Institute for Health and Care Excellence recommends a prophylactic dose of a low molecular weight heparin to young people and adults who need high-flow nasal oxygen, continuous positive airway pressure, noninvasive ventilation, or invasive mechanical ventilation, and who do not have an increased bleeding risk. An intermediate or treatment dose of a low molecular weight heparin is only recommended in these patients as part of a clinical trial.[537]
In the US, the National Institutes of Health guidelines panel recommends prophylactic-dose heparin (low molecular weight heparin preferred over unfractionated heparin) for patients who are receiving intensive care unit level of care (including patients receiving high-flow oxygen), unless there is a contraindication. The panel recommends against the use of intermediate-dose and therapeutic-dose anticoagulation in these patients, except in the context of a clinical trial. Patients who start on therapeutic-dose heparin while in a non-intensive care unit setting and then transfer to the intensive care unit should be switched from therapeutic to prophylactic-dose heparin unless venous thromboembolism is confirmed.[479]
Some guidelines recommend that escalated doses can be considered in critically ill patients.[801][869]
Dose adjustments may be required in patients with extremes of body weight or renal impairment.[537]
Evidence is limited in patients with critical disease. A systematic review and meta-analysis of nearly 28,000 hospitalized patients found that both intermediate-dose and therapeutic-dose anticoagulation decreased the risk of thrombotic events in critically ill patients in the intensive care unit compared with prophylactic-dose anticoagulation, but these regimens were associated with an increased bleeding risk and unchanged in-hospital mortality.[870]
See Severe COVID-19 above for more detailed information on VTE prophylaxis.
Treatment recommended for ALL patients in selected patient group
The World Health Organization recommends high-flow nasal oxygen (HFNO), continuous positive airway pressure (CPAP), or noninvasive ventilation (helmet or face mask interface) in hospitalized patients with severe or critical disease and acute hypoxemic respiratory failure not needing emergent intubation, rather than standard oxygen therapy. Choice depends on factors such as availability of devices and the supply of oxygen, personal comfort and experience, and patient-specific considerations (e.g., claustrophobia with CPAP or noninvasive ventilation masks, nasal discomfort with HFNO).[79]
In the UK, the National Institute for Health and Care Excellence recommends CPAP in patients with hypoxemia that is not responding to supplemental oxygen with a fraction of inspired oxygen of ≥0.4 (40%), and escalation to invasive mechanical ventilation would be an option but it is not immediately needed or it is agreed that respiratory support should not be escalated beyond CPAP. Ensure there is access to critical care providers for advice, regular review, and prompt escalation of treatment if needed, and regular assessment and management of symptoms alongside noninvasive respiratory support. Consider using HFNO for people when: they cannot tolerate CPAP but need humidified oxygen at high flow rates; maximal conventional oxygen is not maintaining their target oxygen saturations and they do not need immediate invasive mechanical ventilation or escalation to invasive mechanical ventilation is not suitable, and CPAP is not suitable; or they need a break from CPAP (e.g., mealtimes, skin pressure relief, mouth care), need humidified oxygen or nebulizers (or both), or need weaning from CPAP. Do not routinely offer HFNO as the main form of respiratory support for people with respiratory failure in whom escalation to invasive mechanical ventilation would be appropriate.[537]
In the US, the National Institutes of Health guidelines panel recommends HFNO over noninvasive ventilation in adults with acute hypoxemic respiratory failure despite conventional oxygen therapy. The panel recommends a closely monitored trial of noninvasive ventilation in adults if HFNO is not available. A time-limited trial of either noninvasive ventilation or HFNO is recommended in infants and children with persistent respiratory failure despite conventional oxygen therapy who have no indicators for endotracheal intubation.[479]
Airborne precautions are recommended for these interventions (including bubble CPAP) due to uncertainty about the potential for aerosolization.[79] Despite the trend to avoid HFNO, it has been shown to have a similar risk of aerosol generation to standard oxygen masks.[885]
Consider awake prone positioning (for 8-12 hours/day, broken into shorter periods over the day) in severely ill patients who require HFNO or noninvasive ventilation.[79] In the UK, the National Institute for Health and Care Excellence recommends considering awake prone positioning for hospitalized patients who are not intubated and have higher oxygen needs.[537] In the US, the National Institutes of Health guidelines panel recommends a trial of awake prone positioning in adults with persistent hypoxemia who require HFNO and for whom endotracheal intubation is not otherwise indicated. There is insufficient evidence to recommend either for or against a trial of awake prone positioning in children. The panel recommends against using awake prone positioning as a rescue therapy for refractory hypoxemia to avoid intubation in patients who otherwise meet the indications for intubation and invasive mechanical ventilation.[479] Awake prone positioning of nonintubated patients was associated with improvement in oxygen variables (PaO₂/FiO₂, PaO₂, and SpO₂), respiratory rate, rate of intubation (particularly among those who required advanced respiratory support and those in intensive care unit settings), and mortality. However, evidence is limited.[793][794][795][796]
Monitor patients closely for acute deterioration. If patients do not improve after a short trial of these interventions, they require urgent endotracheal intubation.[79][792]
Limited evidence suggests that noninvasive ventilation reduces the need for intubation, improves resource utilization, may be associated with better outcomes, and is safe.[841] There is no certain evidence that noninvasive respiratory support increases or decreases mortality in patients with COVID-19 acute respiratory failure.[840] Indirect and low-certainty evidence suggests that noninvasive ventilation probably reduces mortality in patients with COVID-19, similar to invasive mechanical ventilation, but may increase the risk of viral transmission. HFNO may reduce mortality compared with no HFNO.[842] HFNO was superior to noninvasive ventilation for acute respiratory failure in terms of decreasing mortality. However, there was no significant difference in intubation rates and length of hospital stay between the two groups.[844][845] The RECOVERY-RS trial (an open-label, multicenter, adaptive randomized controlled trial) found that CPAP reduced the need for invasive mechanical ventilation in adults admitted to hospital with acute respiratory failure. Neither CPAP nor HFNO reduced mortality when compared with conventional oxygen therapy.[846]
Treatment recommended for ALL patients in selected patient group
Consider endotracheal intubation and mechanical ventilation in patients who are acutely deteriorating despite advanced oxygen/noninvasive ventilatory support measures.[79][479]
Use of mechanical ventilation in COVID-19 patients carries a high risk of mortality. Mortality is highly variable across studies, ranging between 21% and 100%. An overall in-hospital mortality risk ratio of 0.70 has been reported based on random-effect pooled estimates. However, it is important to note that outcomes appear to have improved as the pandemic has progressed.[849] Early intubation may be associated with lower all-cause mortality compared with patients undergoing late intubation.[850]
Endotracheal intubation should be performed by an experienced provider using airborne precautions.[79] Intubation by video laryngoscopy is recommended if possible.[479] Young children, or adults who are obese or pregnant, may desaturate quickly during intubation and therefore require preoxygenation with 100% fraction of inspired oxygen (FiO₂) for 5 minutes.[79] Cuffed endotracheal tubes are preferred over uncuffed endotracheal tubes in children.[479]
Mechanically ventilated patients with acute respiratory distress syndrome (ARDS) should receive a lung-protective, low tidal volume/low inspiratory pressure ventilation strategy (lower targets are recommended in children). A higher positive end-expiratory pressure (PEEP) strategy is preferred over a lower PEEP strategy in moderate to severe ARDS. However, individualization of PEEP, where the patient is monitored for beneficial or harmful effects and driving pressure during titration with consideration of the risks and benefits of PEEP titration, is recommended.[79][479][792]
Although some patients with COVID-19 pneumonia meet the criteria for ARDS, there is some discussion about whether COVID-19 pneumonia is its own specific disease with atypical phenotypes. Anecdotal evidence suggests that the main characteristic of the atypical presentation is the dissociation between well-preserved lung mechanics and the severity of hypoxemia.[851][852][853][854][855][856] However, this approach has been criticized.[857][858] Results from three large observational cohort studies with data from critically ill patients with acute respiratory failure found that COVID-19-related ARDS had no consistent respiratory subphenotype at baseline (start of invasive ventilation). However, time-dependent analysis showed that two subphenotypes developed during the first 4 days of mechanical ventilation. Patients with an upward trajectory of ventilatory ratio had a higher risk of venous thrombotic events, more frequently developed acute kidney injury, required longer invasive mechanical ventilation, and had higher mortality.[859] It has been argued that an evidence-based approach extrapolating data from ARDS not related to COVID-19 is the most reasonable approach for intensive care of COVID-19 patients.[860] As a consequence of this, some clinicians have warned that protocol-driven ventilator use may be causing lung injury in some patients, and that ventilator settings should be based on physiologic findings rather than using standard protocols. High PEEP may have a detrimental effect on patients with normal compliance.[851] PEEP should always be carefully titrated.[861]
Consider prone ventilation in patients with severe ARDS for 12 to 16 hours per day. Pregnant women in the third trimester may benefit from being placed in the lateral decubitus position. Caution is required in children.[79][479][792] Longer durations may be feasible in some patients.[862]
Lung recruitment maneuvers are suggested, but staircase recruitment maneuvers are not recommended.[479][792]
Treatment recommended for SOME patients in selected patient group
Consider a trial of an inhaled pulmonary vasodilator in adults and children who have severe acute respiratory distress syndrome and refractory hypoxemia despite optimizing ventilation. Taper off if there is no rapid improvement in oxygenation.[479][792]
Treatment recommended for SOME patients in selected patient group
Consider extracorporeal membrane oxygenation (ECMO) according to availability and expertise if the above methods fail.[79][792][863]
There is insufficient evidence to recommend either for or against the routine use of ECMO.[479]
A systematic review and meta-analysis found that in-hospital mortality in adults receiving ECMO was 39%, and the risk of mortality was higher when compared with influenza patients on ECMO (44% versus 38%).[864]
Another systematic review and meta-analysis found that the pooled mortality rate was 48.8%, and the rate increased as the pandemic progressed.[865]
A registry-based cohort study found that ECMO was associated with a 7.1% reduction in mortality in selected adults (i.e., PaO₂/FiO₂ <80 mmHg) with COVID-19-associated respiratory failure, compared with conventional mechanical ventilation without ECMO. It was most effective in patients ages <65 years and those with a PaO₂/FiO₂ <80 mmHg or with driving pressures >15 cm H₂O during the first 10 days of mechanical ventilation.[866]
Single-access, dual-stage venovenous ECMO with early extubation appears to be safe and effective in patients with COVID-19 respiratory failure.[867]
There is a risk of neurologic complications (e.g., intracranial hemorrhage, ischemic stroke, and hypoxic ischemic brain injury) in patients on ECMO.[868]
Treatment recommended for SOME patients in selected patient group
The management of sepsis and septic shock in patients with COVID-19 is beyond the scope of this topic. See the Complications section.
Treatment recommended for SOME patients in selected patient group
Primary options
dexamethasone: children: consult specialist for guidance on dose; adults: 6 mg orally/intravenously once daily for 7-10 days
OR
hydrocortisone: children: consult specialist for guidance on dose; adults: 50 mg orally/intravenously every 8 hours for 7-10 days
Secondary options
prednisone: children: consult specialist for guidance on dose; adults: 40 mg/day orally given in 1-2 divided doses for 7-10 days
OR
methylprednisolone: children: consult specialist for guidance on dose; adults: 32 mg/day orally/intravenously given in 1-2 divided doses for 7-10 days
Consider a systemic corticosteroid. Guideline recommendations vary.
The World Health Organization (WHO) strongly recommends systemic corticosteroid therapy (low-dose intravenous or oral dexamethasone or hydrocortisone) for 7 to 10 days in adults with critical disease. This recommendation is based on two meta-analyses that pooled data from eight randomized trials (over 7000 patients), including the UK RECOVERY trial. Moderate-quality evidence suggests that systemic corticosteroids probably reduce 28-day mortality in patients with critical disease. They also probably reduce the need for invasive ventilation. There is no evidence directly comparing dexamethasone and hydrocortisone. The harms of treatment in this context are considered to be minor. It is unclear whether these recommendations can be applied to children or those who are immunocompromised.[769][770][771][816][817] There is also evidence that corticosteroids probably increase ventilator-free days (moderate certainty).[825][826]
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In the UK, the National Institute for Health and Care Excellence recommends offering dexamethasone (or an alternative such as hydrocortisone or prednisone when dexamethasone cannot be used or is unavailable) to people who need supplemental oxygen to meet their prescribed oxygen saturation levels, or who have a level of hypoxia that needs supplemental oxygen but who are unable to have or tolerate it. Treatment is for up to 10 days unless there is a clear indication to stop early.[537]
In the US, the National Institutes of Health guidelines panel recommends using dexamethasone, either alone or in combination with remdesivir, in hospitalized patients who require high-flow oxygen or noninvasive ventilation. In patients who are on mechanical ventilation or extracorporeal membrane oxygenation, the panel recommends dexamethasone alone or in combination with tocilizumab for patients who are within 24 hours of admission to the intensive care unit. Alternative corticosteroids may be used in situations where dexamethasone is not available. The panel recommends using dexamethasone in hospitalized children who require high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation.[479]
Moderate- and low-certainty evidence supports the use of corticosteroids in hospitalized patients. A Cochrane review found that systemic corticosteroids probably slightly reduce all-cause mortality in hospitalized patients with symptomatic disease. Most participants in the studies were treated with noninvasive or invasive mechanical ventilation. Low-certainty evidence suggests that there may also be a reduction in ventilator-free days; however, the current evidence remains uncertain due to methodological limitations. Evidence of an increased risk of mortality in symptomatic hospitalized patients without any need for additional oxygen was limited by a lack of statistical significance. It is unknown which systemic corticosteroid is most effective.[818]
Monitor patients for adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, reactivation of latent infections) and assess for drug-drug interactions.[479]
A meta-analysis found an increased risk of venous thromboembolism with corticosteroid administration in patients with critical disease. However, no definite findings were available due to the differing corticosteroid regimens and the heterogeneity of the studies.[871]
Treatment recommended for SOME patients in selected patient group
Primary options
remdesivir: children ≥12 years of age and ≥40 kg and adults: 200 mg intravenously as a loading dose on day 1, followed by 100 mg every 24 hours for 5-10 days
Consider the antiviral agent remdesivir. Guideline recommendations vary, and there are conflicting recommendations across international guidelines. Remdesivir may increase the risk of death in critically ill patients, and currently only US guidelines recommend its use in select patients.
In the US, the National Institutes of Health guidelines panel recommends remdesivir, in combination with dexamethasone, in hospitalized patients who require high-flow oxygen or noninvasive ventilation. The panel does not recommend starting remdesivir in patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation. However, the panel does recommend completing the full treatment course of remdesivir if the patient is started on it when they are on supplemental low-flow oxygen (see Severe COVID-19 above) and then progress to requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation.[479] Remdesivir is approved in pediatric patients ≥28 days of age (weighing at least 7 lbs [3 kg]) in the US.[782]
In the UK, the National Institute for Health and Care Excellence recommends against the use of remdesivir in hospitalized patients on high-flow nasal oxygen, continuous positive airway pressure, noninvasive mechanical ventilation, or invasive mechanical ventilation, except as part of a clinical trial. Evidence shows that remdesivir may increase the risk of death in people who are on these interventions (moderate certainty).[537]
The World Health Organization recommends against the use of remdesivir in hospitalized patients in addition to standard care, regardless of disease severity. However, this recommendation is currently being reviewed, with an updated recommendation expected soon.[769][770][771][819]
If used, the recommended treatment course for this indication is 5 days or until hospital discharge, whichever comes first.[479] Evidence does not suggest any greater benefit with a 10-day course of remdesivir compared with a 5-day course, but suggests an increased risk of harm.[537] However, some experts may recommend a 10-day course in patients who have not shown substantial clinical improvement by day 5.[479]
Adverse effects include nephrotoxicity and hepatotoxicity. Remdesivir is not recommended in patients with an estimated glomerular filtration rate <30 mL/minute. Monitor renal function before starting treatment and during treatment as clinically appropriate. Intravenous formulations contain the solubility enhancer sulfobutyl ether beta-cyclodextrin sodium (SBECD), which is renally cleared. Accumulation of SBECD in patients with renal impairment may result in liver and renal toxicities. Consider preferential use of the lyophilized powder formulation in patients with renal impairment if available, as it contains less SBECD. Remdesivir may have little or no effect on acute kidney injury compared with placebo; however, the certainty of evidence is low.[883] Transaminase elevations have been reported. Monitor liver function before starting treatment and during treatment as clinically appropriate. Consider discontinuing treatment if alanine aminotransferase (ALT) levels increase to ≥10 times the upper limit of normal. Discontinue treatment if ALT elevation is accompanied by signs or symptoms of liver inflammation. Monitor prothrombin time before starting treatment and during treatment as clinically appropriate as increases in prothrombin time have been reported.
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported. Administer in a setting where severe hypersensitivity reactions can be managed. Monitor patients during the infusion and observe for at least 1 hour after infusion.
Treatment recommended for SOME patients in selected patient group
Primary options
tocilizumab: children: consult specialist for guidance on dose; adults: 8 mg/kg intravenously as a single dose, maximum 800 mg/dose
MoreOR
sarilumab: children: consult specialist for guidance on dose; adults: 400 mg intravenously as a single dose
MoreConsider an IL-6 inhibitor. Guideline recommendations vary.
The World Health Organization strongly recommends an IL-6 inhibitor (tocilizumab or sarilumab), in combination with a systemic corticosteroid and initiated at the same time, in patients with critical disease. This recommendation is based on high-certainty evidence that shows IL-6 inhibitors reduce mortality and the need for mechanical ventilation, and low-certainty evidence that suggests that IL-6 inhibitors may also reduce the duration of mechanical ventilation and hospitalization. The evidence regarding the risk of severe adverse events is uncertain. The applicability of this recommendation to children is currently uncertain.[769][770][771] This recommendation is based on data from the UK RECOVERY and REMAP-CAP trials.[822][823]
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In the US, the National Institutes of Health guidelines panel recommends adding tocilizumab to dexamethasone (or a suitable alternative corticosteroid) or dexamethasone plus remdesivir in patients who require noninvasive mechanical ventilation or high-flow nasal oxygen and have been recently hospitalized (e.g., within 3 days) with rapidly increasing oxygen needs and systemic inflammation. In patients who are on mechanical ventilation or extracorporeal membrane oxygenation, the panel recommends adding tocilizumab to dexamethasone for patients who are within 24 hours of admission to the intensive care unit. There is insufficient evidence for the panel to recommend either for or against the use of tocilizumab in hospitalized children. Sarilumab may be used as an alternative if tocilizumab is not available or it is not feasible to use it.[479] The Infectious Diseases Society of America recommends considering tocilizumab in hospitalized adults with critical disease who have elevated markers of systemic inflammation, in addition to standard of care (i.e., corticosteroids), rather than standard of care alone. Sarilumab may be used if tocilizumab is not available.[480]
IL-6 inhibitors and Janus kinase inhibitors inhibitors (see table below) are viewed as alternatives to each other and should not be administered together. There is potential for an additive risk of infection.
Patients on IL-6 inhibitors are at increased risk of infection including active tuberculosis, invasive fungal infections, and opportunistic pathogens.
Routine blood work including neutrophil count, platelets, transaminases, and total bilirubin should be checked prior to initiation of therapy. All patients should be monitored for signs and symptoms of infection given the increased risk of immunosuppression in addition to systemic corticosteroids.[769]
These drugs should be avoided in patients who are significantly immunocompromised.[479]
Treatment recommended for SOME patients in selected patient group
Primary options
baricitinib: children: consult specialist for guidance on dose; adults: 4 mg orally once daily for 14 days
Secondary options
tofacitinib: children and adults: consult specialist for guidance on dose
OR
ruxolitinib: children and adults: consult specialist for guidance on dose
Consider a JAK inhibitor. Guideline recommendations vary.
The World Health Organization strongly recommends a JAK inhibitor (baricitinib), in combination with a systemic corticosteroid and initiated at the same time, in patients with critical disease. This recommendation is based on moderate-certainty evidence that baricitinib probably reduces mortality and duration of mechanical ventilation, and high-certainty evidence that baricitinib reduces length of hospital stay. The applicability of this recommendation to children is currently uncertain.[769][770][771]
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In the UK, the National Institute for Health and Care Excellence recommends baricitinib in hospitalized adults who: need supplemental oxygen (or other respiratory support including high-flow nasal oxygen, continuous positive airway pressure, noninvasive ventilation, or mechanical ventilation), and are having or have completed a course of corticosteroids (unless contraindicated), and have no evidence of infection (other than SARS-CoV-2) that might be worsened by baricitinib. Baricitinib may also be considered in children ≥2 years of age provided they meet the same criteria.[537]
In the US, the National Institutes of Health guidelines panel recommends adding baricitinib to dexamethasone (or a suitable alternative corticosteroid) or dexamethasone plus remdesivir in patients who require noninvasive mechanical ventilation or high-flow nasal oxygen and have been recently hospitalized with rapidly increasing oxygen needs and systemic inflammation.[479] The Infectious Diseases Society of America suggests baricitinib in hospitalized adults (in combination with a corticosteroid) with severe disease. It suggests baricitinib with remdesivir, rather than remdesivir alone, in patients who cannot receive a corticosteroid because of a contraindication.[480]
Other drugs in this class include tofacitinib and ruxolitinib. The World Health Organization recommends against using these drugs unless baricitinib or IL-6 inhibitors are not available. The effects of tofacitinib or ruxolitinib on mortality, need for mechanical ventilation, and hospital length of stay remain uncertain and more trial evidence is needed.[769][770][771] In the US, the National Institutes of Health guidelines panel recommends tofacitinib only if baricitinib is not available or it is not feasible to use it.[479] The Infectious Diseases Society of America suggests tofacitinib in hospitalized adults with severe disease who are not on noninvasive or invasive mechanical ventilation.[480]
Evidence to support the use of baricitinib in critically ill patients is emerging. An exploratory, randomized, placebo-controlled trial found that baricitinib (in combination with standard of care, including corticosteroids) reduced 28-day all-cause mortality (19% absolute reduction) and 60-day all-cause mortality (17% absolute reduction) in critically ill hospitalized patients who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation compared with placebo. Further phase 3 trials are needed to confirm these findings as this was a small sample.[872]
JAK inhibitors and IL-6 inhibitors (see table above) are viewed as alternatives to each other and should not be administered together. There is potential for an additive risk of infection.
Patients are at increased risk of infection including active tuberculosis, invasive fungal infections, and opportunistic pathogens.[769] Avoid use in patients with known active tuberculosis. All patients should be monitored for signs and symptoms of infection given the increased risk of immunosuppression in addition to systemic corticosteroids. Monitor complete blood count with differential before and during treatment.
Baricitinib is not recommended in patients with severe renal or hepatic impairment.[769] Baricitinib is not recommended in adults with an estimated glomerular filtration rate ≤15 mL/minute (≤30 mL/minute in children <9 years of age), or in patients on dialysis or renal replacement therapy. A dose reduction is recommended in patients with an estimated glomerular filtration rate ≤60 mL/minute. Baricitinib has not been studied in patients with severe hepatic impairment and it is unknown whether a dose adjustment is required in these patients. It should only be used if the potential benefits outweigh the potential risks. Use caution with tofacitinib and ruxolitinib in patients with moderate to severe renal impairment (including those on dialysis); a dose adjustment may be required. Monitor renal and hepatic function before and during treatment.
Adverse effects include leukopenia, lymphopenia, thrombocytosis, anemia, blood clotting abnormalities, hepatic impairment, and secondary infection.[769] Other serious adverse effects include venous thrombosis and severe infections. The US Food and Drug Administration has issued a warning about increased risk of serious heart-related events, cancer, blood clots, and death with JAK inhibitors.[884]
Treatment recommended for SOME patients in selected patient group
Treat laboratory-confirmed coinfections (e.g., malaria, tuberculosis, influenza) as appropriate according to local protocols.[79] The treatment of influenza is the same in all patients regardless of SARS-CoV-2 coinfection. Start empiric treatment with oseltamivir in hospitalized patients who are suspected of having either or both infections as soon as possible without waiting for influenza test results. Antiviral therapy can be stopped once influenza has been ruled out.[479]
Treatment recommended for SOME patients in selected patient group
Primary options
casirivimab and imdevimab: children ≥12 years of age and adults: consult specialist for guidance on dose
Consider a monoclonal antibody. Guideline recommendations vary.
The World Health Organization recommends casirivimab/imdevimab for patients with critical disease with a seronegative status (i.e., no detectable SARS-CoV-2 antibodies). Casirivimab/imdevimab should only be used where viral genotyping can confirm a susceptible SARS-CoV-2 variant (i.e., excluding Omicron). Casirivimab/imdevimab probably reduces mortality and possibly reduces the need for mechanical ventilation in patients who are seronegative based on moderate- and low-certainty evidence, respectively. Treatment is in addition to the current standard of care. The applicability of this recommendation to children is currently uncertain.[769][770][771]
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Monoclonal antibodies are administered by intravenous infusion. Casirivimab/imdevimab is also available in a subcutaneous formulation, but intravenous administration is recommended. However, if intravenous infusions are not feasible or would cause a delay in treatment, subcutaneous administration may be considered.[479] Dose varies across guidelines; consult local protocols.
Circulating SARS-CoV-2 variants may be associated with resistance to monoclonal antibodies. Data suggests that the efficacy of casirivimab/imdevimab is likely to be compromised against the Omicron variant.[479][537] Consult local guidance for details regarding specific variants and resistance.
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported. Administer in a setting where severe hypersensitivity reactions can be managed. Monitor patients during the infusion and observe for at least 1 hour after infusion.
Logistical or supply constraints may make patient triage for monoclonal antibody treatment necessary.
Treatment recommended for SOME patients in selected patient group
Consider any appropriate experimental or emerging therapies.
Antiviral therapies will have a greater effect early in the course of the disease, whereas immunosuppressive/anti-inflammatory therapies are likely to have a greater effect later in the course of the disease.[479]
See the Emerging section for more information.
Treatment recommended for SOME patients in selected patient group
Routinely assess intensive care patients for mobility, functional swallow, cognitive impairment, and mental health concerns. Based on that assessment determine whether the patient is ready for discharge, and whether the patient has any rehabilitation and follow-up requirements.[79]
Treatment recommended for SOME patients in selected patient group
Palliative care interventions should be made accessible at each institution that provides care for patients with COVID-19. Identify whether the patient has an advance care plan and respect the patient’s priorities and preferences when formulating the patient’s care plan.[79] Follow local palliative care guidelines.
There are a lack of data on palliative care in patients with COVID-19. A rapid systematic review of pharmacologic strategies used for palliative care in these patients, the first international review of its kind, found that a higher proportion of patients required continuous subcutaneous infusions for medication delivery than is typically seen in the palliative care population. Modest doses of commonly used end-of-life medications were required for symptom control. However, these findings should be interpreted with caution due to the lack of data available.[831]
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