Coronavirus disease 2019 (COVID-19)

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

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

ACUTE

mild to moderate (nonsevere) disease

1st line – consider home management or hospital admission

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1st line –

consider home management or hospital admission

Consider isolating patients with suspected or confirmed asymptomatic or mild to moderate disease.[85][644][657] For disease severity definitions, see Criteria.

Manage patients in a healthcare facility, in a community facility, or at home, according to guidance from your local public health authority. Home management can be considered in most patients, with telemedicine or remote visits as appropriate. Manage patients at high risk of deterioration in a healthcare facility.

Implement local infection prevention and control procedures when managing patients. Advise patients in home isolation and household members to follow appropriate infection prevention and control measures:

WHO: home care for patients with suspected or confirmed COVID-19 and management of their contacts Opens in new window

Guidance on when to stop isolation varies widely across locations. Isolation periods, if applicable, may depend on various factors including circulating SARS-CoV-2 variants and patient factors (e.g., immunocompetent/immunocompromised, asymptomatic/symptomatic, disease severity). The World Health Organization recommends 10 days of isolation for symptomatic patients, and 5 days of isolation for asymptomatic patients (based on very low-certainty evidence). Rapid antigen testing may be used to reduce the period of isolation.[85] Some countries now recommend isolation periods as short as 5 days to 7 days, and some no longer recommend isolation periods at all. Consult your local public health guidance for more information.

Plus – monitoring

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Plus –

monitoring

Treatment recommended for ALL patients in selected patient group

Closely monitor patients (particularly those with risk factors for severe illness) for signs and symptoms of disease progression. Counsel patients about signs and symptoms of deterioration or complications that require prompt urgent care (e.g., difficulty breathing, chest pain).[85][644]

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.[85]

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.[85]

Plus – symptom management and supportive care

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Plus –

symptom management and supportive care

Treatment recommended for ALL patients in selected patient group

For the management of cough, advise patients to avoid lying on their back as this makes coughing ineffective, and follow your local guidelines for treating acute cough.[397]

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.[85][397]

Advise patients to improve air circulation by opening a window or door.[397]

Provide basic mental health and psychosocial support for all patients, and manage any symptoms of insomnia, depression, or anxiety as appropriate.[85]

Consider treatment for olfactory dysfunction (e.g., olfactory training, intranasal corticosteroids) if it persists beyond 2 weeks.[660][661] A Cochrane review found there is very limited evidence regarding the efficacy and harms of different interventions for preventing or treating persistent olfactory dysfunction following infection. The only evidence available is for intranasal corticosteroids (for prevention), and this is of very low certainty, so no conclusions could be drawn.[662][663] A systematic review and meta-analysis found that there were no significant differences in the improvement of olfactory scores with either intranasal or oral corticosteroids plus olfactory training compared with olfactory training alone. Olfactory function was significantly improved after olfactory training.[664]

Most children with mild or moderate disease can be managed with supportive care alone (unless considered high risk for progression to severe disease).[644]

Consider – antipyretic/analgesic

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Consider –

antipyretic/analgesic

Treatment recommended for SOME patients in selected patient group

Acetaminophen or ibuprofen are recommended.[85][397]

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).

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

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

Consider – antimicrobials

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Consider –

antimicrobials

Treatment recommended for SOME patients in selected patient group

Consider empiric antibiotics in patients with moderate disease 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.[85][397][644] The regimen should be based on the clinical diagnosis, local epidemiology and susceptibility data, and local treatment guidelines.

Do not offer an antibiotic for preventing secondary bacterial pneumonia in people with COVID-19.[397]

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.[397]

Consider – antiviral

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Consider –

antiviral

Treatment recommended for SOME patients in selected patient group

Consider an antiviral agent. Options include nirmatrelvir/ritonavir, molnupiravir, and remdesivir. Guideline recommendations vary.

The World Health Organization strongly recommends nirmatrelvir/ritonavir in patients with nonsevere disease who are at high risk of hospitalization, and conditionally recommends nirmatrelvir/ritonavir in patients with nonsevere disease who are at moderate risk of hospitalization. It suggests the use of molnupiravir or remdesivir in patients with nonsevere disease who are at high risk of hospitalization if nirmatrelvir/ritonavir is not available, but suggests against the use of these agents in patients who are at moderate risk of hospitalization. Antiviral therapy is not recommended in patients who are at low risk of hospitalization (most patients). For risk definitions, see "World Health Organization: hospitalization risk for patients with nonsevere disease" in Criteria. Nirmatrelvir/ritonavir is a superior choice to other treatments for nonsevere disease because it may have greater efficacy in preventing hospitalization compared with the alternatives, has fewer concerns with respect to harms than does molnupiravir, and is easier to administer than intravenous remdesivir. However, it does have significant and complex drug-drug interactions.[398][665][666]

In the UK, the National Institute for Health and Care Excellence (NICE) recommends nirmatrelvir/ritonavir or molnupiravir for patients who do not need supplemental oxygen, and are thought to be at high risk of progression to severe disease. In addition to this, nirmatrelvir/ritonavir is also recommended in the following: people ≥70 years of age; people with a BMI ≥35 kg/m²; patients with diabetes or heart failure.[397][667]

In the US, the National Institutes of Health guidelines panel recommends nirmatrelvir/ritonavir and remdesivir as preferred treatments, and molnupiravir as an alternative treatment (i.e., when preferred therapies are not available, feasible to use, or clinically appropriate), for nonhospitalized patients with mild to moderate disease who are at high risk of clinical progression.[644] The Infectious Diseases Society of America supports the use of antivirals in these patients, but only recommends molnupiravir in patients who have no other treatment options.[465]

Treatment should be initiated as soon as possible after diagnosis, ideally within 5 days of symptom onset for nirmatrelvir/ritonavir or molnupiravir, or within 7 days of symptom onset for remdesivir.[397][398][644] Longer and/or additional courses of nirmatrelvir/ritonavir or remdesivir may be required in immunocompromised patients who have prolonged symptomatic disease with evidence of ongoing viral replication, despite receiving an initial course of antiviral therapy. If a patient requires hospitalization after starting treatment, the full treatment course can be completed at the healthcare provider’s discretion. 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. Logistical constraints may make it difficult to administer remdesivir in some outpatient settings as it requires administration via intravenous infusion.

Evidence for the use of antivirals in patients with nonsevere disease is limited. Nirmatrelvir/ritonavir was found to reduce the risk of hospitalization or death by 89% (within 3 days of symptom onset) and 88% (within 5 days of symptom onset) compared with placebo in nonhospitalized high-risk adults in the phase 2/3 EPIC-HR trial.[669] However, the phase 2/3 EPIC-SR trial found that time to sustained alleviation of all signs and symptoms did not differ significantly between nirmatrelvir/ritonavir and placebo, regardless of vaccination status, in patients who were symptomatic (nonhospitalized) and at standard or high risk for severe disease.[670] Meta-analyses have found that nirmatrelvir/ritonavir reduced the risk of emergency department visits, hospitalization, intensive care unit admission, oxygen requirement, and mortality. However, large-scale randomized controlled trials are required to confirm these findings.[671][672] One systematic review found that nirmatrelvir/ritonavir reduced the risk of mortality and hospitalization in older patients (moderate-certainty evidence), but did not improve the outcomes of mortality and hospitalization in patients <65 years of age (low-certainty evidence).[673] A Cochrane review found that nirmatrelvir/ritonavir may reduce the risk of all-cause mortality and hospital admission or death within 28 days in unvaccinated outpatients with previous infection who were at high risk with symptom onset within 5 days and infected with the Delta variant (low-certainty evidence from one trial). Very low-certainty evidence exists regarding the effects on all-cause mortality and viral clearance in unvaccinated inpatients with mild to moderate infection caused by the Omicron variant.[674] Molnupiravir was found to reduce the risk of hospitalization or death by 31% (absolute risk reduction from 9.7% to 6.8%) in the 29 days after use compared with placebo in nonhospitalized, unvaccinated, at-risk adults in the phase 3 MOVe-OUT trial.[675] However, the PANORAMIC trial found that molnupiravir did not reduce the risk of hospitalization or death among high-risk vaccinated adults in the community compared with placebo, although it did reduce time to recovery.[676] Meta-analyses are conflicting. Some meta-analyses show no significant effect on reducing mortality or hospitalization with molnupiravir.[677][678] However, others show that molnupiravir has a significant impact on reducing mortality and hospitalization.[679][680] Emerging evidence suggests that use of molnupiravir may be contributing to the evolution of the SARS-CoV-2 virus, but further research is required.[681] Remdesivir was found to reduce the risk of hospitalization or death by 87% compared with placebo in nonhospitalized high-risk adults in a randomized, double-blind, placebo-controlled trial.[682] When comparing nirmatrelvir/ritonavir and molnupiravir, nirmatrelvir/ritonavir demonstrated superiority to molnupiravir in terms of all-cause mortality and hospitalization rate in one systematic review and meta-analysis. The incidence of adverse events was higher with nirmatrelvir/ritonavir, but no significant difference was observed between the two drugs in terms of adverse events that led to treatment discontinuation.[683] There are limited data available on the use of antiviral therapy in immunocompromised patients.[644]

Remdesivir and nirmatrelvir/ritonavir may be offered to pregnant women, if indicated. However, molnupiravir is not recommended for pregnant or breastfeeding women.[398][644] A pregnancy test should be performed prior to initiation of molnupiravir because animal studies have shown reproductive toxicity and it may affect bone and cartilage growth. Contraception is recommended during molnupiravir treatment and for 4 days after the last dose in women of childbearing potential, and for at least 3 months after the last dose in men of reproductive potential who are sexually active with women of childbearing potential. The World Health Organization recommends that pregnant or breastfeeding women may be offered nirmatrelvir/ritonavir as part of a fully informed shared decision-making process given the possible benefit and residual uncertainty regarding potential adverse effects.[398] In the US, the National Institutes of Health guidelines panel also recommends that nirmatrelvir/ritonavir may be offered to pregnant women.[644] A case series of 47 pregnant women treated with nirmatrelvir/ritonavir found that treatment was well tolerated, although there was an unexpectedly high rate of cesarean deliveries. Further larger studies are needed to evaluate for complications in pregnant women and neonates.[771]

Remdesivir is associated with nephrotoxicity, hepatotoxicity, and hypersensitivity reactions. Remdesivir may have little or no effect on acute kidney injury compared with placebo; however, the certainty of evidence is low.[772] 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. 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. Bradycardia has been reported during the infusion and may persist past the initial infusion.[773][774]

Adverse effects with nirmatrelvir/ritonavir and molnupiravir are generally considered to be mild. However, there are limited safety data on these new medications, and all suspected adverse effects must be reported to your local pharmacovigilance program. Common adverse effects of nirmatrelvir/ritonavir include diarrhea, dysgeusia, hypertension, and myalgia. Cases of abdominal pain, anaphylaxis, hypersensitivity reactions, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported in postmarketing surveillance.[775] Use caution in patients with preexisting liver diseases (ritonavir has been associated with elevated liver enzymes, hepatitis, and jaundice). Common adverse effects of molnupiravir include diarrhea, nausea, headache, and dizziness. Cases of virologic rebound (i.e., recurrent positive polymerase chain reaction result) and the recurrence of symptoms have been reported after antiviral treatment. However, it appears to be mild and self-limited. Virologic rebound was more common in patients taking nirmtarelvir/ritonavir compared with untreated patients, but was also reported in patients taking molnupiravir.[668]

Nirmatrelvir/ritonavir has significant and complex drug-drug interactions, primarily due to the ritonavir component of the combination. Carefully review the patient’s medication history before starting treatment. Patients already on ritonavir-containing regimen for HIV or hepatitis C virus infection do not need to adjust the dose of their current antiviral regimen, and the dose of nirmatrelvir/ritonavir is unchanged for these patients (unless a dose adjustment is required based on the patient's renal function). Recommendations for managing drug-drug interactions may differ for patients on extended courses of nirmatrelvir/ritonavir. IDSA: management of drug interactions with nirmatrelvir/ritonavir Opens in new window

Primary options

nirmatrelvir and ritonavir: children ≥12 years of age and ≥40 kg body weight and adults with eGFR ≥60 mL/minute: 300 mg (nirmatrelvir)/100 mg (ritonavir) orally twice daily for 5 days; children ≥12 years of age and ≥40 kg body weight and adults with eGFR 30 to 59 mL/minute: 150 mg (nirmatrelvir)/100 mg (ritonavir) orally twice daily for 5 days

Secondary 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

Remdesivir may be approved for use in children <12 years of age in some countries. Consult your local drug information source for more information. However, there is insufficient evidence to routinely recommend its use in children <12 years of age (treatment may be considered based on age and risk factors). No dose adjustment is required in patients with any degree of hepatic or renal impairment (including patients on dialysis).

molnupiravir: adults: 800 mg orally twice daily for 5 days

Consider – monoclonal antibody

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Consider –

monoclonal antibody

Treatment recommended for SOME patients in selected patient group

Consider a monoclonal antibody in patients who are at high risk of clinical progression. Guideline recommendations vary.

The World Health Organization strongly recommends against the use of sotrovimab and casirivimab/imdevimab for patients with nonsevere disease, as there is evidence of a reduction in effectiveness against currently circulating variants of SARS-CoV-2 and their subvariants. The agency makes no recommendations for other monoclonal antibodies.[398][665][666]

In the UK, the National Institute for Health and Care Excellence recommends offering sotrovimab as an option for treating patients ≥12 years of age and ≥40 kg body weight who do not need supplemental oxygen, who have an increased risk for progression to severe disease, and for whom nirmatrelvir/ritonavir is contraindicated or unsuitable.[397][667] Tixagevimab/cilgavimab is not recommended.[684]

In the US, the National Institutes of Health guidelines panel recommends against bebtelovimab for the treatment of nonhospitalized patients with mild to moderate disease who are at high risk of progressing to severe disease. This is because SARS-CoV-2 Omicron subvariants that are anticipated to be resistant to bebtelovimab have been rapidly increasing in the US. The panel makes no recommendations for other monoclonal antibodies.[644] Bebtelovimab is not currently authorized for use in any US region.[685]

Choice of monoclonal antibody depends on availability, as well as clinical and contextual factors including information about efficacy with different SARS-CoV-2 variants and subvariants.[397][398][644] Options may include bebtelovimab, tixagevimab/cilgavimab, casirivimab/imdevimab, sotrovimab, bamlanivimab/etesevimab, and regdanvimab, depending on your location. Check your local guidance for information about whether a particular monoclonal antibody is effective against current circulating SARS-CoV-2 variants and subvariants. 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.

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. Casirivimab/imdevimab decreases the risk of infection and development of clinical symptoms (high-certainty evidence). Bamlanivimab decreases the risk of infection (moderate-certainty evidence). These findings only apply to unvaccinated people, and are only applicable to variants prevailing during the study.[686] A systematic review and meta-analysis of 27 randomized controlled trials found that monoclonal antibodies had limited effects on most of the outcomes in nonhospitalized patients with the certainty of evidence ranging from very low to moderate for most outcomes. Monoclonal antibodies reduced hospitalization, but there were no effects on mortality.[687]

Monoclonal antibodies are generally administered by intravenous infusion. Outpatient administration in specialized clinics is required, which may limit their feasibility.[398] Treatment should be started as soon as possible and within 7 days of symptom onset.[397][398][644]

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.

severe disease

1st line – hospital admission

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1st line –

hospital admission

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. For disease severity definitions, see Criteria.

Implement local infection prevention and control procedures.

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.[397] 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.[397] Evidence for the use of the CFS in COVID-19 is evolving despite limitations in the reporting on its application in practice.[693] Patients with a score between 4-9 had significantly increased mortality compared with those with a score of 1-3 in one systematic review and meta-analysis.[694] Each 1-point increase in score was associated with a 12% increase in mortality.[695] However, another systematic review and meta-analysis found that there was no difference in short-term mortality between frail and nonfrail patients.[696] A more nuanced understanding of frailty and outcomes is needed, and caution is required in placing too much emphasis on the influence of frailty on the prognosis of older people.[697]

Guidance on when to stop isolation varies widely across locations. The World Health Organization recommends 10 days of isolation for symptomatic patients, and 5 days of isolation for asymptomatic patients (based on very low-certainty evidence). Rapid antigen testing may be used to reduce the period of isolation.[85] This guidance varies and you should consult your local public health guidance for more information.

Consider – oxygen therapy

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Consider –

oxygen therapy

Treatment recommended for SOME 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%.[85][644]

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.[85] Some guidelines recommend that SpO₂ should be maintained no higher than 96%.[699]

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.[85][644] Awake prone positioning reduced the risk of endotracheal intubation compared with usual care. However, it did not significantly reduce mortality, ventilator-free days, length of stay in the intensive care unit or hospital, or escalation of oxygen modality. Adverse events were uncommon.[700]

Monitor patients closely for signs of progressive acute hypoxemic respiratory failure.[85][644]

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.[85] 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).

Plus – symptom management and supportive care

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Plus –

symptom management and supportive care

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.[85]

Fluids and electrolytes: use cautious fluid management in adults and children without tissue hypoperfusion and fluid responsiveness as aggressive fluid resuscitation may worsen oxygenation.[85] Correct any electrolyte or metabolic abnormalities, such as hyperglycemia or metabolic acidosis, according to local protocols.[701]

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.[397] For the management of cough, advise patients to avoid lying on their back as this makes coughing ineffective, and follow your local guidelines for treating acute cough.[397]

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).[85][397] Low doses of haloperidol (or another suitable antipsychotic) can be considered for agitation.[85] Nonpharmacologic interventions are the mainstay for the management of delirium when possible, and prevention is key.[702]

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.[703]

Mental health symptoms: provide basic mental health and psychosocial support for all patients, and manage any symptoms of insomnia or depression as appropriate.[85]

Plus – venous thromboembolism (VTE) prophylaxis

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Plus –

venous thromboembolism (VTE) prophylaxis

Treatment recommended for ALL patients in selected patient group

Assess the patient’s risk of bleeding as soon as possible after admission, or by the time of the first attending physician review, using a suitable risk assessment tool.[397]

If the patient is already on anticoagulation for another underlying condition, continue the current treatment dose of the anticoagulant, unless contraindicated or there is a change in clinical circumstances (e.g., bleeding develops or risk of bleeding increases).[397][644][688] Consider switching to low molecular weight heparin if the patient’s clinical condition is deteriorating and the patient is not currently on low molecular weight heparin.[397] A systematic review and meta-analysis found that the use of oral anticoagulation prior to hospital admission was not associated with a reduced risk of intensive care unit admission and mortality. However, the review acknowledged that further trials are needed.[704]

Start VTE prophylaxis in all hospitalized patients, provided that there are no contraindications.[85][397][644][688] US guidelines recommend prophylactic anticoagulation for children ≥12 years of age unless it is contraindicated.[644] Start as soon as possible (within 14 hours of admission).[397] A Cochrane review found that anticoagulants may reduce all‐cause mortality compared with no anticoagulants, but the evidence is very uncertain.[705] 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.[706]

Low molecular weight heparin, unfractionated heparin, or fondaparinux are the recommended options. Low molecular weight heparin is preferred over unfractionated heparin and fondaparinux, unless contraindicated.[85][397][644] Fondaparinux is the recommended option in patients with a history of heparin-induced thrombocytopenia.[707] A meta-analysis found that low molecular weight heparin was associated with decreased intensive care unit admission, mechanical ventilation, hospital stay, and mortality compared with unfractionated heparin in hospitalized patients, and there was no difference in the incidence of bleeding.[708] Oral anticoagulants (including direct oral anticoagulants) are generally not recommended, except in the context of a clinical trial.[644][688] Mechanical thromboprophylaxis (e.g., intermittent pneumatic compression device) is recommended if anticoagulants are contraindicated or not available.[707] Consult a specialist for guidance on the choice of anticoagulant in special patient populations (e.g., children, pregnant and breastfeeding women, hepatic or renal impairment, active cancer).

Standard prophylaxis doses are generally recommended over intermediate or therapeutic doses in patients without an established indication for higher-dose anticoagulation.[85][688] However, recommendations vary and you should consult your local guidance. In the UK, the National Institute for Health and Care Excellence recommends prophylaxis doses of low molecular weight heparin. However it also makes a conditional recommendation to consider treatment doses of low molecular weight heparin in those who may benefit. 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.[397] In the US, the National Institutes of Health guidelines panel recommends therapeutic doses of 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. The panel recommends using standard prophylaxis doses of heparin for patients who are not administered therapeutic doses, unless a contraindication exists.[644] 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).[705] Consult a specialist for guidance on the dose of anticoagulant in special patient populations (e.g., children, pregnant and breastfeeding women, hepatic or renal impairment, active cancer). Dose adjustments may be required in patients with extremes of body weight or renal impairment.[397]

Anticoagulation is generally continued until hospital discharge. Routine post-discharge VTE prophylaxis is generally not recommended, except in certain high-risk patients, in the context of a clinical trial, or if another indication for VTE prophylaxis exists.[85][644][688] However, in the UK, the National Institute for Health and Care Excellence recommends treatment for a minimum of 7 days, including after discharge, if standard prophylaxis doses of heparin are used.[397] If therapeutic doses of heparin are used, the recommended treatment duration is 14 days or until hospital discharge (or transfer to intensive care unit), whichever is sooner.[397][644] A systematic review and meta-analysis found that extended thromboprophylaxis (with either a direct oral anticoagulant or low molecular weight heparin at prophylaxis doses) administered for <35 days was significantly associated with a reduced risk of thrombosis and all-cause mortality in patients post-discharge who were at high risk of thromboembolism, without increasing the risk of major bleeding.[709]

Monitor patients for signs and symptoms suggestive of thromboembolism and proceed with appropriate diagnostic and management pathways if clinically suspected.[85] See Complications.

If the patient’s clinical condition changes, assess the risk of VTE, reassess the bleeding risk, and review VTE prophylaxis.[397] Monitoring of clinical parameters during thromboprophylaxis depends on the anticoagulant and dose used. Consult your local protocols for more information.

Primary options

enoxaparin: consult specialist for guidance on dose

dalteparin: consult specialist for guidance on dose

Secondary options

fondaparinux: consult specialist for guidance on dose

heparin: consult specialist for guidance on dose

Consider – antimicrobials

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Consider –

antimicrobials

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.[85][397][644]

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.[397] Guidelines recommend against empiric broad-spectrum antibiotics in the absence of a proven or suspected bacterial infection.[644]

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.[397] 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.[397]

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.[85] A meta-analysis found that the prevalence of antibiotic prescribing in patients with COVID-19 was 75%, which is significantly higher than the estimated prevalence of bacterial coinfection. Therefore, unnecessary antibiotic use is likely to be high in these patients.[710]

Treat laboratory-confirmed coinfections (e.g., malaria, tuberculosis, influenza) as appropriate according to local protocols.[85]

Consider – corticosteroid

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Consider –

corticosteroid

Treatment recommended for SOME patients in selected patient group

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 moderate-quality evidence that suggests 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.[398][665][666]

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 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.[397]

In the US, the National Institutes of Health guidelines panel and the Infectious Diseases Society of America recommend dexamethasone (or an alternative corticosteroid if dexamethasone is not available) for up to 10 days or until hospital discharge, in hospitalized adults who require supplemental oxygen. It may be given alone or in combination with remdesivir. Corticosteroids are not routinely recommended for children 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.[465][644]

Evidence supports the use of corticosteroids in hospitalized patients. A Cochrane review found that systemic corticosteroids probably slightly reduce all-cause mortality up to 30 days in hospitalized patients with symptomatic disease (moderate-certainty evidence), although the evidence is very uncertain about the effect on all-cause mortality up to 120 days. Evidence related to the most effective type, dose, or timing of corticosteroid is uncertain.[711] A living systematic review and network meta-analysis found that corticosteroids probably reduce mortality compared with standard care.[712][713] Evidence suggests that higher doses may be superior to lower doses in reducing mortality in patients with severe or critical disease.[714] However, the RECOVERY trial found that higher-dose corticosteroids significantly increased the risk of death compared with usual care (which included low-dose corticosteroids) in hospitalized patients who required either no oxygen or simple oxygen only.[715] Evidence also suggests that shorter treatment courses may optimize the mortality benefit in hospitalized patients. An optimal duration of treatment was <7 days in one meta-analysis, with no additional survival benefit reported with ≥7 days of treatment.[716]

Monitor patients for adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, reactivation of latent infections) and assess for drug-drug interactions. Patients who are already receiving corticosteroid treatment for an underlying condition should continue treatment.[644]

Primary options

dexamethasone: children: consult specialist for guidance on dose; adults: 6 mg orally/intravenously once daily for 7-10 days

hydrocortisone sodium succinate: children: consult specialist for guidance on dose; adults: 50 mg 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

methylprednisolone: children: consult specialist for guidance on dose; adults: 32 mg/day orally/intravenously given in 2-4 divided doses for 7-10 days

Consider – antiviral

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Consider –

antiviral

Treatment recommended for SOME patients in selected patient group

Consider the antiviral agent remdesivir. Guideline recommendations vary.

The World Health Organization conditionally recommends the intravenous antiviral remdesivir in adults with severe disease. This recommendation is based on low-certainty evidence that suggests remdesivir possibly reduces mortality, and moderate-certainty evidence that suggests it probably reduces the need for mechanical ventilation. Moderate-certainty evidence suggests that remdesivir probably has little or no impact on time to symptom improvement. There is insufficient evidence to make a recommendation around use in children.[398][665][666]

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In the UK, the National Institute for Health and Care Excellence recommends remdesivir as an option in hospitals in adults at high risk of serious illness, and children (ages 4 weeks to 17 years and weight ≥3 kg) who have pneumonia and need supplemental oxygen or who weigh ≥40 kg and have a high risk of serious illness.[397][684]

In the US, the National Institutes of Health guidelines panel and the Infectious Diseases Society of America recommend remdesivir in hospitalized children and 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 also recommends remdesivir alone in hospitalized children ages 12 to 17 years who have risk factors for severe disease but do not require supplemental oxygen.[465][644]

Remdesivir should be administered as soon as possible after onset of symptoms. The recommended treatment course for this indication is 5 to 10 days or until hospital discharge, whichever comes first.[397][398][644] 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.[397] However, some experts may recommend a 10-day course in patients who have not shown substantial clinical improvement by day 5.[644] There may be no benefit in completing the full course of remdesivir if the patient progresses.[397] 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.[644] Longer and/or additional courses may be required in immunocompromised patients who have prolonged, symptomatic disease with evidence of ongoing viral replication despite receiving an initial course of therapy.[644]

Despite guidelines recommending the use of remdesivir in patients with severe disease, evidence for its use is conflicting. A Cochrane review found that remdesivir probably has little or no effect on all-cause mortality (up to 150 days) in hospitalized patients with moderate to severe disease compared with placebo or usual care (moderate-certainty evidence). Remdesivir probably increases the chance of clinical improvement up to day 28 slightly, and decreases the risk of clinical worsening within 28 days (moderate-certainty evidence).[717] A 1-year follow-up of hospitalized patients in a randomized controlled trial found no long-term benefits (quality-of-life or symptom outcomes) for remdesivir compared with standard of care.[718]

Adverse effects include nephrotoxicity and hepatotoxicity. Remdesivir may have little or no effect on acute kidney injury compared with placebo; however, the certainty of evidence is low.[772] 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.

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 – interleukin-6 (IL-6) inhibitor

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Consider –

interleukin-6 (IL-6) inhibitor

Treatment recommended for SOME patients in selected patient group

Consider an IL-6 inhibitor. Guideline recommendations vary.

The World Health Organization strongly recommends a single dose of an IL-6 inhibitor (tocilizumab or sarilumab) in adults with severe disease. IL-6 inhibitors may be administered in combination with corticosteroids and Janus kinase inhibitors, and should be initiated at the same time as systemic corticosteroids. 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.[398][665][666]

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In the UK, the National Institute for Health and Care Excellence recommends a single dose of tocilizumab in hospitalized adults who are having systemic corticosteroids and need supplemental oxygen.[397][667]

In the US, the National Institutes of Health guidelines panel and the Infectious Diseases Society of America recommend a single dose of tocilizumab in hospitalized adults on a corticosteroid with rapidly increasing oxygen needs and systemic inflammation.[465][644]

Evidence supports the use of IL-6 inhibitors. A Cochrane review found that tocilizumab reduced all-cause mortality at day 28 (high-certainty evidence) compared with standard care alone or placebo. The evidence suggests uncertainty around the effect of tociluzumab on mortality after day 60. Evidence for an effect on these outcomes for sarilumab is very uncertain. Tocilizumab and sarilumab probably result in little or no increase in clinical improvement at day 28 (i.e., hospital discharge or improvement measured by trialist-defined scales) (moderate-certainty evidence). The evidence for clinical improvement after day 60 is very uncertain for both drugs.[720] [ ] A living systematic review and network meta-analysis found that IL-6 inhibitors (with corticosteroids) probably reduce mortality (moderate-certainty evidence), are likely to reduce the need for mechanical ventilation (moderate-certainty evidence), and may reduce the duration of hospitalization (moderate-certainty evidence) compared with standard care.[712][713] IL-6 inhibitors may not be beneficial when used alone (without corticosteroids).[721]

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.[398]

These drugs should be avoided in patients who are significantly immunocompromised.[644]

Primary options

tocilizumab: children: consult specialist for guidance on dose; adults: 8 mg/kg intravenously as a single dose, maximum 800 mg/dose

sarilumab: children: consult specialist for guidance on dose; adults: 400 mg intravenously as a single dose

Consider – Janus kinase (JAK) inhibitor

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Consider –

Janus kinase (JAK) inhibitor

Treatment recommended for SOME patients in selected patient group

Consider a JAK inhibitor. Guideline recommendations vary.

The World Health Organization strongly recommends an oral JAK inhibitor (baricitinib) for 14 days or until hospital discharge (whichever is first) in adults with severe disease. Baricitinib may be administered in combination with corticosteroids and IL-6 inhibitors, and should be initiated at the same time as systemic corticosteroids. This recommendation is based on high-certainty evidence that baricitinib reduces mortality, and moderate-certainty evidence that baricitinib probably reduces the duration of mechanical ventilation and the length of hospital stay. The applicability of this recommendation to children is currently uncertain.[398][665][666]

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 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. It may also be considered in children ≥2 years of age provided they meet the same criteria.[397]

In the US, the National Institutes of Health guidelines panel and the Infectious Diseases Society of America recommend baricitinib in patients on a corticosteroid with rapidly increasing oxygen needs and systemic inflammation.[465][644]

Other drugs in this class include tofacitinib and ruxolitinib. The World Health Organization recommends against using other drugs in this class 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.[398][665][666]

Evidence supports the use of JAK inhibitors. A Cochrane review found that JAK inhibitors probably reduced all-cause mortality up to day 28 (moderate-certainty evidence) and up to day 60 (high-certainty evidence). They probably make little or no difference in improvement in clinical status or the rate of adverse events (moderate-certainty evidence). Baricitinib was the most often evaluated JAK inhibitor.[722] A living systematic review and network meta-analysis found that JAK inhibitors probably reduce mortality (high-certainty evidence), reduce the duration of mechanical ventilation (high-certainty evidence), and reduce length of hospital stay (high-certainty evidence) compared with standard care.[712][713]

Patients are at increased risk of infection including active tuberculosis, invasive fungal infections, and opportunistic pathogens.[398] 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.[398] 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.[398] Other serious adverse effects include venous thrombosis and severe infections.

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

ruxolitinib: children and adults: consult specialist for guidance on dose

Consider – antipyretic/analgesic

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Consider –

antipyretic/analgesic

Treatment recommended for SOME patients in selected patient group

Acetaminophen or ibuprofen are recommended.[85][397]

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

Consider – plan for discharge and rehabilitation

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Consider –

plan for discharge and rehabilitation

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.[85]

Consider – palliative care

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Consider –

palliative care

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.[85] Follow local palliative care guidelines.

There is a lack of data on palliative care in patients with COVID-19. A Cochrane review found very low-certainty evidence for the efficacy of pharmacologic interventions for palliative symptom relief, and no evidence on the safety of pharmacologic interventions or safety and efficacy of nonpharmacologic interventions for palliative symptom control. More evidence is needed to guide end-of-life management.[768] 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.[723]

critical disease

1st line – intensive/critical care unit admission

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1st line –

intensive/critical care unit admission

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.[85] For disease severity definitions, see Criteria.

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.[397]

Implement local infection prevention and control procedures.

Plus – symptom management and supportive care

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Plus –

symptom management and supportive care

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.

Implement standard interventions to prevent complications associated with critical illness.[85] The management of sepsis and septic shock in patients with COVID-19 is beyond the scope of this topic. See Complications.

Treat laboratory-confirmed coinfections (e.g., malaria, tuberculosis, influenza) as appropriate according to local protocols.[85]

Plus – venous thromboembolism (VTE) prophylaxis

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Plus –

venous thromboembolism (VTE) prophylaxis

Treatment recommended for ALL patients in selected patient group

If not already started, start VTE prophylaxis in all hospitalized patients, provided there are no contraindications.[85][644][688][776]

See Severe COVID-19 above for more detailed information on VTE prophylaxis. However, recommendations for patients with critical disease may differ from those for severe disease. 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.[397]

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 therapeutic-dose anticoagulation in these patients, except in the context of a clinical trial. There is insufficient evidence to recommend either for or against the use of an intermediate dose in these patients. 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.[644]

Evidence for VTE prophylaxis 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.[766] Another smaller systematic review and meta-analysis found no difference between escalated doses and standard prophylaxis dosing in terms of impact on mortality in critically ill patients. However, there was a reduced risk of pulmonary embolism in the escalated dose group.[767]

Primary options

enoxaparin: consult specialist for guidance on dose

dalteparin: consult specialist for guidance on dose

Secondary options

heparin: consult specialist for guidance on dose

fondaparinux: consult specialist for guidance on dose

Consider – high-flow nasal oxygen or noninvasive ventilation

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Consider –

high-flow nasal oxygen or noninvasive ventilation

Treatment recommended for SOME 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).[85]

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.[397]

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.[644]

Airborne precautions are recommended for these interventions (including bubble CPAP) due to uncertainty about the potential for aerosolization.[85] However, CPAP and HFNO do not appear to be associated with significant additional air or surface viral contamination compared with supplemental oxygen.[737] Despite the trend to avoid HFNO, it has been shown to have a similar risk of aerosol generation to standard oxygen masks.[738] A systematic review and meta-analysis found no association between HFNO and noninvasive ventilation and aerosol generation-increased airborne pathogen detection.[739]

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.[85] 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.[397] 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.[644] Awake prone positioning reduced the risk of endotracheal intubation compared with usual care. However, it did not significantly reduce mortality, ventilator-free days, length of stay in the intensive care unit or hospital, or escalation of oxygen modality. Adverse events were uncommon.[700]

Monitor patients closely for acute deterioration. If patients do not improve after a short trial of these interventions, they require urgent endotracheal intubation.[85][699]

Limited evidence suggests that noninvasive ventilation reduces the need for intubation, improves resource utilization, may be associated with better outcomes, and is safe.[727] There is no certain evidence that noninvasive respiratory support increases or decreases mortality in patients with COVID-19 acute respiratory failure.[726] 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.[728] 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.[730][731] HFNO may reduce intubation rate and 28-day intensive care unit mortality, and may improve 28-day ventilator-free days compared with conventional oxygen therapy in patients with acute respiratory failure. However, large-scale randomized controlled trials are necessary.[732] 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.[733] The HELMET-COVID trial (a multicenter randomized clinical trial) found that helmet noninvasive ventilation did not significantly reduce 28-day mortality compared with usual respiratory support (alternate use of mask noninvasive ventilation, HFNO, or standard oxygen according to clinical response) among patients with acute hypoxemic respiratory failure. However, there were several important limitations to the study, and interpretation of the findings is limited by imprecision in the effect size estimate.[734] The SOHO-COVID trial (a randomized clinical trial) found that HFNO did not significantly reduce 28-day mortality compared with standard oxygen therapy among patients with respiratory failure.[735] However, another randomized controlled trial found that treatment with HFNO reduced the likelihood of invasive mechanical ventilation and decreased the time to clinical recovery compared with conventional low-flow oxygen therapy in patients with severe disease.[736]

Consider – invasive mechanical ventilation

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Consider –

invasive mechanical ventilation

Treatment recommended for SOME patients in selected patient group

Consider endotracheal intubation and mechanical ventilation in patients who are acutely deteriorating despite advanced oxygen/noninvasive ventilatory support measures.[85][644]

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. Outcomes appear to have improved as the pandemic has progressed.[740] However, results have not been consistent.[741] Early intubation may be associated with lower all-cause mortality compared with patients undergoing late intubation. However, again, results have not been consistent.[742][743]

Endotracheal intubation should be performed by an experienced provider using airborne precautions.[85] Intubation by video laryngoscopy is recommended if possible.[644] 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.[85] Cuffed endotracheal tubes are preferred over uncuffed endotracheal tubes in children.[644]

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.[85][644][699]

Although some patients with COVID-19 pneumonia meet the criteria for ARDS, there has been some discussion about whether COVID-19 pneumonia is its own specific disease with atypical phenotypes. Anecdotal evidence from early in the pandemic suggested that the main characteristic of the atypical presentation was the dissociation between well-preserved lung mechanics and the severity of hypoxemia.[744][745][746][747][748][749] However, this hypothesis was criticized.[750][751] A systematic review and meta-analysis published in late 2022 found no evidence for distinct respiratory system static compliance-based clinical phenotypes in patients with COVID-19-related ARDS.[752]

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.[753] However, some clinicians have warned that protocol-driven ventilator use may cause 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.[744] Therefore, PEEP should always be carefully titrated.[754]

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.[85][644][699] Longer durations may be feasible in some patients.[755] Lung recruitment maneuvers are suggested, but staircase recruitment maneuvers are not recommended.[644][699] A systematic review and meta-analysis found that there was no significant difference in mortality between prone and supine positioning, and that hospital stay was significantly higher in the prone position group. There was no difference between the two groups in terms of length of stay in the intensive care unit and days of mechanical ventilation.[756]

Consider – inhaled pulmonary vasodilator

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Consider –

inhaled pulmonary vasodilator

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.[644][699]

Evidence is emerging. A systematic review and meta-analysis found that inhaled pulmonary vasodilators may improve oxygenation, but showed no mortality benefit, compared with standard therapy.[757]

Consider – extracorporeal membrane oxygenation (ECMO)

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Consider –

extracorporeal membrane oxygenation (ECMO)

Treatment recommended for SOME patients in selected patient group

Consider ECMO according to availability and expertise if the above methods fail.[85][699]

There is insufficient evidence to recommend either for or against the routine use of ECMO.[644]

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.[758]

Pooled mortality rates in adults receiving ECMO ranged from 39% to 49%.[759][760] The mortality rate in children was 26.6%.[761] Factors associated with an increased risk of mortality included older age, male sex, chronic lung disease, longer duration of symptoms, longer duration of invasive mechanical ventilation, higher driving pressure, and higher partial pressure of arterial carbon dioxide.[762]

There is a high risk of thrombotic and neurologic complications (e.g., circuit thrombosis, major bleeding, intracranial hemorrhage, ischemic stroke, and hypoxic ischemic brain injury) in patients on ECMO.[763][764][765]

Consider – corticosteroid

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Consider –

corticosteroid

Treatment recommended for SOME patients in selected patient group

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 moderate-quality evidence that suggests 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.[398][665][666]

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In the US, the National Institutes of Health guidelines panel recommends using dexamethasone in combination with baricitinib or tocilizumab (or dexamethasone alone if a second immunomodulator cannot be obtained) in hospitalized adults who require high-flow oxygen or noninvasive ventilation. Remdesivir may be added in certain situations. In adults who are on mechanical ventilation or extracorporeal membrane oxygenation, the panel recommends dexamethasone in combination with baricitinib or tocilizumab (or dexamethasone alone if a second immunomodulator cannot be obtained) 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 (with or without remdesivir) in hospitalized children who require high-flow oxygen or noninvasive ventilation, or dexamethasone alone in hospitalized children who require invasive mechanical ventilation or extracorporeal membrane oxygenation.[644]

Evidence supports the use of corticosteroids in hospitalized patients. A Cochrane review found that systemic corticosteroids probably slightly reduce all-cause mortality up to 30 days in hospitalized patients with symptomatic disease, although the evidence is very uncertain about the effect on all-cause mortality up to 120 days. Evidence related to the most effective type, dose, or timing of corticosteroid is uncertain.[711] Evidence suggests that higher doses may be superior to lower doses in reducing mortality in patients with severe or critical disease.[714] However, the RECOVERY trial continues to assess higher doses in hospitalized patients who require noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[715] Evidence also suggests that shorter treatment courses may optimize the mortality benefit in hospitalized patients. An optimal duration of treatment was <7 days in one meta-analysis, with no additional survival benefit reported with ≥7 days of treatment.[716]

Primary options

dexamethasone: children: consult specialist for guidance on dose; adults: 6 mg orally/intravenously once daily for 7-10 days

hydrocortisone sodium succinate: children: consult specialist for guidance on dose; adults: 50 mg 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

methylprednisolone: children: consult specialist for guidance on dose; adults: 32 mg/day orally/intravenously given in 2-4 divided doses for 7-10 days

Consider – antiviral

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Consider –

antiviral

Treatment recommended for SOME patients in selected patient group

Consider the antiviral agent remdesivir. Guideline recommendations vary, and there are conflicting recommendations across international guidelines about the use of remdesivir in patients with critical disease. Remdesivir may increase the risk of death in critically ill patients, and for this reason the World Health Organization and the UK’s National Institute for Health and Care Excellence recommend against the use of remdesivir in patients with critical disease.[397][398]

Currently, only US guidelines recommend its use in select patients. The National Institutes of Health guidelines panel recommends remdesivir in certain hospitalized children and adults who require high-flow oxygen or noninvasive ventilation. Examples of those who may benefit the most include: immunocompromised patients; those with evidence of ongoing viral replication; or patients who are ≤10 days from symptom onset. There is insufficient evidence either for or against the use of remdesivir in patients who require mechanical ventilation or ECMO. Some experts may add remdesivir to immunomodulator therapy in patients who have recently been placed on mechanical ventilation or ECMO if they are immunocompromised, have evidence of ongoing viral replication, or are within 10 days from symptom onset.[644]

If used, the recommended treatment course for this indication is 5 days or until hospital discharge, whichever comes first.[644] 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.[397] However, some experts may recommend a 10-day course in patients who have not shown substantial clinical improvement by day 5.[644] Longer and/or additional courses may be required in immunocompromised patients who have prolonged, symptomatic disease with evidence of ongoing viral replication despite receiving an initial course of therapy.[644]

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 – interleukin-6 (IL-6) inhibitor

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Consider –

interleukin-6 (IL-6) inhibitor

Treatment recommended for SOME patients in selected patient group

Consider an IL-6 inhibitor. Guideline recommendations vary.

The World Health Organization strongly recommends a single dose of an IL-6 inhibitor (tocilizumab or sarilumab) in adults with critical disease. IL-6 inhibitors may be administered in combination with corticosteroids and Janus kinase inhibitors, and should be initiated at the same time as systemic corticosteroids. 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.[398][665][666]

BMJ rapid recommendations: a living WHO guideline on drugs for COVID-19 Opens in new window

In the US, the National Institutes of Health guidelines panel and the Infectious Diseases Society of America recommend adding tocilizumab (or sarilumab if tocilizumab is not available or not feasible to use) to dexamethasone (or a suitable alternative corticosteroid) or dexamethasone plus remdesivir in children ≥2 years of age and adults 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. Sarilumab may be used as an alternative if tocilizumab is not available or it is not feasible to use it.[465][644]

Evidence supports the use of IL-6 inhibitors. A Cochrane review found that tocilizumab reduced all-cause mortality at day 28 (high-certainty evidence) compared with standard care alone or placebo. The evidence suggests uncertainty around the effect of tocilizumab on mortality after day 60. Evidence for an effect on these outcomes for sarilumab is very uncertain. Tocilizumab and sarilumab probably result in little or no increase in clinical improvement at day 28 (i.e., hospital discharge or improvement measured by trialist-defined scales) (moderate-certainty evidence). The evidence for clinical improvement after day 60 is very uncertain for both drugs.[720] [ ] A living systematic review and network meta-analysis found that IL-6 inhibitors (with corticosteroids) probably reduce mortality (moderate-certainty evidence), are likely to reduce the need for mechanical ventilation (moderate-certainty evidence), and may reduce the duration of hospitalization (moderate-certainty evidence) compared with standard care.[712][713] IL-6 inhibitors may not be beneficial when used alone (without corticosteroids).[721]

Patients on IL-6 inhibitors are at increased risk of infection including active tuberculosis, invasive fungal infections, and opportunistic pathogens.

These drugs should be avoided in patients who are significantly immunocompromised.[644]

Primary options

tocilizumab: children: consult specialist for guidance on dose; adults: 8 mg/kg intravenously as a single dose, maximum 800 mg/dose

sarilumab: children: consult specialist for guidance on dose; adults: 400 mg intravenously as a single dose

Consider – Janus kinase (JAK) inhibitor

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Consider –

Janus kinase (JAK) inhibitor

Treatment recommended for SOME patients in selected patient group

Consider a JAK inhibitor. Guideline recommendations vary.

The World Health Organization strongly recommends an oral JAK inhibitor (baricitinib) for 14 days or until hospital discharge (whichever is first) in adults with critical disease. Baricitinib may be administered in combination with corticosteroids and IL-6 inhibitors, and should be initiated at the same time as systemic corticosteroids. This recommendation is based on high-certainty evidence that baricitinib reduces mortality, and moderate-certainty evidence that baricitinib probably reduces the duration of mechanical ventilation and the length of hospital stay. The applicability of this recommendation to children is currently uncertain.[398][665][666]

BMJ rapid recommendations: a living WHO guideline on drugs for COVID-19 Opens in new window

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 children ≥2 years of age and adults who require noninvasive mechanical ventilation or high-flow nasal oxygen and have been recently hospitalized with rapidly increasing oxygen needs and systemic inflammation. In patients who are on mechanical ventilation or extracorporeal membrane oxygenation, the panel recommends adding baricitinib to dexamethasone for patients who are within 24 hours of admission to the intensive care unit.[644]

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

ruxolitinib: children and adults: consult specialist for guidance on dose

Consider – plan for discharge and rehabilitation

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Consider –

plan for discharge and rehabilitation

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.[85]

Consider – palliative care

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Consider –

palliative care

Treatment recommended for SOME patients in selected patient group

There is 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.[723]

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Coronavirus disease 2019 (COVID-19)

Treatment algorithm

mild to moderate (nonsevere) disease

consider home management or hospital admission

monitoring

symptom management and supportive care

antipyretic/analgesic

Primary options

antimicrobials

antiviral

Primary options

Secondary options

monoclonal antibody

severe disease

hospital admission

oxygen therapy

symptom management and supportive care

venous thromboembolism (VTE) prophylaxis

Primary options

Secondary options

antimicrobials

corticosteroid

Primary options

Secondary options

antiviral

Primary options

interleukin-6 (IL-6) inhibitor

Primary options

Janus kinase (JAK) inhibitor

Primary options

Secondary options

antipyretic/analgesic

Primary options

plan for discharge and rehabilitation

palliative care

critical disease

intensive/critical care unit admission

symptom management and supportive care

venous thromboembolism (VTE) prophylaxis

Primary options

Secondary options

high-flow nasal oxygen or noninvasive ventilation

invasive mechanical ventilation

inhaled pulmonary vasodilator

extracorporeal membrane oxygenation (ECMO)

corticosteroid

Primary options

Secondary options

antiviral

Primary options

interleukin-6 (IL-6) inhibitor

Primary options

Janus kinase (JAK) inhibitor

Primary options

Secondary options

plan for discharge and rehabilitation

palliative care

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