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.[120]
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.[120][568] 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.[819] 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.[120]
Advise patients and household members to follow appropriate infection prevention and control measures:
Discontinue transmission-based precautions (including isolation) and release patients from the care pathway: 10 days after positive test (asymptomatic patients); 10 days after symptom onset plus at least 3 days without fever and respiratory symptoms (symptomatic patients).[120] The Centers for Disease Control and Prevention (CDC) recommends discontinuing isolation once at least 10 days (not moderately to severely immunocompromised) or up to 20 days (moderately to severely immunocompromised) have passed since symptoms first appeared, and at least 24 hours have passed since last fever without the use of antipyretics, and symptoms have improved, if a symptom-based strategy is used. In asymptomatic people, the CDC recommends discontinuing isolation once at least 10 days (not moderately to severely immunocompromised) or up to 20 days (moderately to severely immunocompromised) have passed since the date of a positive test. Moderately to severely immunocompromised patients may produce replication-competent virus beyond 20 days and require additional testing and consultation with infectious diseases specialists and infection control experts before discontinuing isolation. Alternatively, the CDC recommends at least two negative reverse-transcription polymerase chain reaction (RT-PCR) tests on respiratory specimens collected 24 hours apart before ending isolation if a test-based strategy is used. A symptom-based strategy is preferred; however, a test-based strategy can be considered in moderately to severely immunocompromised patients.[821] Guidance on when to stop isolation depends on local recommendations and may differ between countries. For example, in the UK the isolation period is 10 days in patients with milder disease who are managed in the community.[822]
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).[120][568]
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.[120]
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.[600] 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.[830]
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.[120][600]
Advise patients to improve air circulation by opening a window or door.[600]
Provide basic mental health and psychosocial support for all patients, and manage any symptoms of insomnia, depression, or anxiety as appropriate.[120]
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.[831]
Most children with mild disease can be managed with supportive care alone.[568]
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.[120][600] There is no evidence at present of severe adverse events in COVID-19 patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, or of effects as a result of the use of NSAIDs on acute healthcare utilization, long-term survival, or quality of life in patients with COVID-19.[823][824][825][826][827][828][829]
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
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.[568]
Monoclonal antibody treatment may be recommended in certain patients; however, international guidelines vary in their recommendations.
See the Emerging section for more information.
Isolate patients with suspected or confirmed moderate disease (i.e., clinical signs of pneumonia but no signs of severe pneumonia) to contain virus transmission.[120]
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.[120][568]
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:
Discontinue transmission-based precautions (including isolation) and release patients from the care pathway 10 days after symptom onset plus at least 3 days without fever and respiratory symptoms.[120] The Centers for Disease Control and Prevention (CDC) recommends discontinuing isolation once at least 10 days (not moderately to severely immunocompromised) or up to 20 days (moderately to severely immunocompromised) have passed since symptoms first appeared, and at least 24 hours have passed since last fever without the use of antipyretics, and symptoms have improved, if a symptom-based strategy is used. In asymptomatic people, the CDC recommends discontinuing isolation once at least 10 days (not moderately to severely immunocompromised) or up to 20 days (moderately to severely immunocompromised) have passed since the date of a positive test. Moderately to severely immunocompromised patients may produce replication-competent virus beyond 20 days and require additional testing and consultation with infectious diseases specialists and infection control experts before discontinuing isolation. Alternatively, the CDC recommends at least two negative reverse-transcription polymerase chain reaction (RT-PCR) tests on respiratory specimens collected 24 hours apart before ending isolation if a test-based strategy is used. A symptom-based strategy is preferred; however, a test-based strategy can be considered in moderately to severely immunocompromised patients.[821] Guidance on when to stop isolation depends on local recommendations and may differ between countries. For example, in the UK the isolation period is 14 days from a positive test in hospitalized patients, and 10 days in patients with milder disease who are managed in the community. Immunocompetent patients who tested positive on RT-PCR and have completed their 14-day isolation period are exempt from testing prior to hospital discharge if they are within 90 days from their initial illness onset or test, unless they develop new symptoms.[822]
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).[120][568] 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.[120] 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.[120]
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.[600] 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.[830]
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.[120][600]
Advise patients to improve air circulation by opening a window or door.[600]
Provide basic mental health and psychosocial support for all patients, and manage any symptoms of insomnia, depression, or anxiety as appropriate.[120]
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.[831]
Most children with moderate disease can be managed with supportive care alone.[568]
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.[120][568][600] 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.[120]
Do not offer an antibiotic for preventing secondary bacterial pneumonia in people with COVID-19.[600]
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.[600]
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.[120][600] There is no evidence at present of severe adverse events in COVID-19 patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, or of effects as a result of the use of NSAIDs on acute healthcare utilization, long-term survival, or quality of life in patients with COVID-19.[823][824][825][826][827][828][829]
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
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.[568]
Monoclonal antibody treatment may be recommended in certain patients; however, international guidelines vary in their recommendations.
See the Emerging section for more information.
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).[120]
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.[120] 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.[894]
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 individualised assessment of frailty. Clinical Frailty Scale external link opens in a 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.[600] 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).[832] However, 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.[834]
Discontinue transmission-based precautions (including isolation) and release patients from the care pathway 10 days after symptom onset plus at least 3 days without fever and respiratory symptoms.[120] The Centers for Disease Control and Prevention (CDC) recommends discontinuing isolation once at least 10 days and up to 20 days have passed since symptoms first appeared, and at least 24 hours have passed since last fever without the use of antipyretics, and symptoms have improved, if a symptom-based strategy is used. Consider consultation with infection control experts before discontinuing isolation. Moderately to severely immunocompromised patients may produce replication-competent virus beyond 20 days and require additional testing and consultation with infectious diseases specialists and infection control experts before discontinuing isolation. Alternatively, the CDC recommends at least two negative reverse-transcription polymerase chain reaction (RT-PCR) tests on respiratory specimens collected 24 hours apart before ending isolation if a test-based strategy is used. A symptom-based strategy is preferred; however, a test-based strategy can be considered in moderately to severely immunocompromised patients.[821] Guidance on when to stop isolation depends on local recommendations and may differ between countries. For example, in the UK the isolation period is 14 days from a positive test in hospitalized patients. Immunocompetent patients who tested positive on RT-PCR and have completed their 14-day isolation period are exempt from testing prior to hospital discharge if they are within 90 days from their initial illness onset or test, unless they develop new symptoms.[822]
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%.[120][568]
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.[120] Some guidelines recommend that SpO₂ should be maintained no higher than 96%.[836]
Some centers may recommend different SpO₂ targets in order to support prioritization of oxygen flow for the most severely ill patients in hospital. NHS England recommends a target of 92% to 96% (or 90% to 94% if clinically appropriate), for example.[837]
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.[120][568] Awake prone positioning of nonintubated patients was associated with improvement in oxygen variables (PaO₂/FiO₂, PaO₂, and SpO₂), respiratory rate, and mortality, but no significant difference was noted in the rate of intubation. However, evidence is limited.[838][839]
Monitor patients closely for signs of progressive acute hypoxemic respiratory failure.[120][568]
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.[120] Correct any electrolyte or metabolic abnormalities, such as hyperglycemia or metabolic acidosis, according to local protocols.[840]
Cough: 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. 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.[600] 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.[830]
Breathlessness: 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.[600]
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).[120][600] Low doses of haloperidol (or another suitable antipsychotic) can be considered for agitation.[120] Nonpharmacologic interventions are the mainstay for the management of delirium when possible, and prevention is key.[841]
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.[842]
Mental health symptoms: provide basic mental health and psychosocial support for all patients, and manage any symptoms of insomnia or depression as appropriate.[120]
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.[600]
Start venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized adults and adolescents, provided there are no contraindications.[120][568][843][844] The UK 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.[600] For hospitalized children, indications for VTE prophylaxis should be the same as those for children without COVID-19.[568]
Low molecular weight heparin, unfractionated heparin, or fondaparinux are the recommended options for standard thromboprophylaxis.[120] NICE recommends low molecular weight heparin first-line, with fondaparinux or unfractionated heparin reserved for patients who cannot have low molecular weight heparin.[600] Unfractionated heparin is contraindicated in patients with severe 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.[844][846]
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.[848] 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.[120] 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.[600] The National Institutes of Health guidelines panel recommends prophylactic-dose anticoagulation, and states that there are insufficient data to recommend increased anticoagulant doses for VTE prophylaxis in COVID-19 patients outside the setting of a clinical trial.[568]
Dose adjustments may be required in patients with extremes of body weight or renal impairment.[600]
For patients who are already on an anticoagulant for another condition, continue the patient’s current therapeutic dose unless contraindicated by a change in clinical circumstances. 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.[600]
Monitor patients for signs and symptoms suggestive of thromboembolism and proceed with appropriate diagnostic and management pathways if clinically suspected.[120] If the patient’s clinical condition changes, assess the risk of VTE, reassess the bleeding risk, and review VTE prophylaxis.[600]
Continue until hospital discharge.[120] Routine post-discharge VTE prophylaxis is not generally recommended, except in certain high-risk patients.[568][843][844] Ensure patients who require VTE prophylaxis after discharge are able to use it correctly or have arrangements made for someone to help them.[600]
There is currently insufficient evidence to determine the risks and benefits of prophylactic anticoagulation in hospitalized patients with COVID-19.[852] 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.[853] Clinicians should rely on pre-COVID-19 evidence-based principles of anticoagulation management combined with rational approaches to address clinical challenges.[843]
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.[120]
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.[120][568][600]
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.[600] There is insufficient evidence to recommend empiric broad-spectrum antibiotics in the absence of another indication.[568]
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.[600] 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.[600]
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.[120]
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.[807][808][809][855][856]
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.[600]
In the US, the National Institutes of Health guidelines panel recommends dexamethasone, either alone or in combination with remdesivir (see the Emerging section for information on 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.[568] The Infectious Diseases Society of America supports the use of dexamethasone in hospitalized patients with severe disease.[857]
Monitor patients for adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, reactivation of latent infections) and assess for drug-drug interactions.[568]
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.[807][808][809] This recommendation is based on data from the UK RECOVERY and REMAP-CAP trials.[858][859]
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).[600] Tocilizumab has not been granted a conditional marketing authorization for this indication in the UK as yet.
In the US, 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.[857] Tocilizumab has been granted an emergency-use authorization in the US for the treatment of hospitalized adults and pediatric patients 2 years of age and older who are receiving systemic corticosteroids and require supplemental oxygen.[860]
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.[807]
These drugs should be avoided in patients who are significantly immunocompromised.[568]
Treatment recommended for SOME patients in selected patient group
Treat laboratory-confirmed coinfections (e.g., malaria, tuberculosis, influenza) as appropriate according to local protocols.[120] 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.[568]
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.[120][600] There is no evidence at present of severe adverse events in COVID-19 patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, or of effects as a result of the use of NSAIDs on acute healthcare utilization, long-term survival, or quality of life in patients with COVID-19.[823][824][825][826][827][828][829]
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
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.[568]
Monoclonal antibody treatment may be recommended in certain patients; however, international guidelines vary in their recommendations.
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.[120]
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.[120] Follow local palliative care guidelines.
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.[865]
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.[120]
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.[600]
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.[120] 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.[894]
Discontinue transmission-based precautions (including isolation) and release patients from the care pathway 10 days after symptom onset plus at least 3 days without fever and respiratory symptoms.[120] The Centers for Disease Control and Prevention (CDC) recommends discontinuing isolation once at least 10 days and up to 20 days have passed since symptoms first appeared, and at least 24 hours have passed since last fever without the use of antipyretics, and symptoms have improved, if a symptom-based strategy is used. Consider consultation with infection control experts before discontinuing isolation. Moderately to severely immunocompromised patients may produce replication-competent virus beyond 20 days and require additional testing and consultation with infectious diseases specialists and infection control experts before discontinuing isolation. Alternatively, the CDC recommends at least two negative reverse-transcription polymerase chain reaction (RT-PCR) tests on respiratory specimens collected 24 hours apart before ending isolation if a test-based strategy is used. A symptom-based strategy is preferred; however, a test-based strategy can be considered in moderately to severely immunocompromised patients.[821] Guidance on when to stop isolation depends on local recommendations and may differ between countries. For example, in the UK the isolation period is 14 days from a positive test in hospitalized patients. Immunocompetent patients who tested positive on RT-PCR and have completed their 14-day isolation period are exempt from testing prior to hospital discharge if they are within 90 days from their initial illness onset or test, unless they develop new symptoms.[822]
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.[568]
Implement standard interventions to prevent complications associated with critical illness.[120]
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.[120][568][843][844]
Unfractionated heparin is preferred over fondaparinux in critically ill patients if low molecular weight heparin, as the preferred option for venous thromboembolism prophylaxis, cannot be used.[844]
The UK National Institute for Health and Care Excellence (NICE) 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.[600]
Some guidelines recommend that escalated doses can be considered in critically ill patients.[843][611]
Dose adjustments may be required in patients with extremes of body weight or renal impairment.[600]
Evidence is limited in patients with critical disease.
A multicenter randomized controlled trial found that intermediate-dose prophylactic anticoagulation did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or 30-day mortality compared with standard-dose prophylactic anticoagulation among patients admitted to the intensive care unit. These results do not support the routine empiric use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the intensive care unit.[891]
An open-label, multiplatform randomized controlled trial found that an initial strategy of therapeutic-dose heparin did not result in a greater probability of survival to hospital discharge or a greater number of organ support-free days in critically ill patients compared with usual-care thromboprophylaxis.[892]
See Severe COVID-19 above for more detailed information on VTE prophylaxis.
Treatment recommended for ALL patients in selected patient group
Consider a trial of high-flow nasal oxygen (HFNO) or noninvasive ventilation (e.g., continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]) in selected patients with mild acute respiratory distress syndrome. Patients with hypercapnia, hemodynamic instability, multi-organ failure, or abnormal mental status should generally not receive HFNO, although emerging data suggest that it may be safe in patients with mild to moderate and nonworsening hypercapnia. Patients with hypoxemic respiratory failure and hemodynamic instability, multi-organ failure, or abnormal mental status should not receive these treatments in place of other options such as invasive ventilation.[120]
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 having CPAP when they need a break from CPAP (e.g., mealtimes), need humidified oxygen, 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.[600]
In the US, the National Institutes of Health guidelines panel recommends HFNO over noninvasive ventilation in patients with acute hypoxemic respiratory failure despite conventional oxygen therapy. The panel recommends a closely monitored trial of noninvasive ventilation if HFNO is not available.[568]
Airborne precautions are recommended for these interventions (including bubble CPAP) due to uncertainty about the potential for aerosolization.[120] Despite the trend to avoid HFNO, it has been shown to have a similar risk of aerosol generation to standard oxygen masks.[873]
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.[120] A trial of awake prone positioning is recommended in patients with persistent hypoxemia despite increasing supplemental oxygen requirements in whom endotracheal intubation is not otherwise indicated.[568] Ensure that pharmacologic and nonpharmacologic management strategies, including body positioning, are optimized before escalating treatment to noninvasive respiratory support.[600] Awake prone positioning of nonintubated patients was associated with improvement in oxygen variables (PaO₂/FiO₂, PaO₂, and SpO₂), respiratory rate, and mortality, but no significant difference was noted in the rate of intubation. However, evidence is limited.[838][839]
Monitor patients closely for acute deterioration. If patients do not improve after a short trial of these interventions, they require urgent endotracheal intubation.[120][836]
Evidence is limited. Indirect and low-certainty evidence suggests that noninvasive ventilation probably reduces mortality in patients with COVID-19, similar to mechanical ventilation, but may increase the risk of viral transmission.[866][867] 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. This preprint study has not been published as yet.[868]
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.[120][568]
Endotracheal intubation should be performed by an experienced provider using airborne precautions.[120] Intubation by video laryngoscopy is recommended if possible.[568] 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.[120]
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.[120][568][836] NHS England recommends a low PEEP strategy in patients with normal compliance where recruitment may not be required.[875]
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.[876][877][878][879][880][881] However, this approach has been criticized.[882][883] 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.[884] 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.[876] PEEP should always be carefully titrated.[885]
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.[120][568][836] Longer durations may be feasible in some patients.[886]
Lung recruitment maneuvers are suggested, but staircase recruitment maneuvers are not recommended.[568][836]
Treatment recommended for SOME patients in selected patient group
Consider extracorporeal membrane oxygenation (ECMO) according to availability and expertise if the above methods fail.[120][836][887] ECMO is not suitable for all patients, and only those who meet certain inclusion criteria may be considered for ECMO.[888]
There is insufficient evidence to recommend either for or against the routine use of ECMO.[568]
A systematic review and meta-analysis found that in-hospital mortality in adults receiving ECMO was 37.1% during the first year of the pandemic, similar to those with non-COVID-19-related acute respiratory distress syndrome. Increasing age was a risk factor for death. The duration of treatment appears to be prolonged in COVID-19 patients; however, a prolonged treatment course was not a predictor of mortality.[889]
Single-access, dual-stage venovenous ECMO with early extubation appears to be safe and effective in patients with COVID-19 respiratory failure.[890]
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.[807][808][809][855][856] There is also evidence that corticosteroids probably increase ventilator-free days (moderate certainty).[862][863]
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.[600]
In the US, the National Institutes of Health guidelines panel recommends using dexamethasone, either alone or in combination with remdesivir (see the Emerging section for information on 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.[568]
Monitor patients for adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, reactivation of latent infections) and assess for drug-drug interactions.[568]
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.[893]
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.[807][808][809] This recommendation is based on data from the UK RECOVERY and REMAP-CAP trials.[858][859]
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.[568] 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.[857] Tocilizumab has been granted an emergency-use authorization in the US for the treatment of hospitalized adults and pediatric patients 2 years of age and older who are receiving systemic corticosteroids and require noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation.[860]
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.[807]
These drugs should be avoided in patients who are significantly immunocompromised.[568]
Treatment recommended for SOME patients in selected patient group
Treat laboratory-confirmed coinfections (e.g., malaria, tuberculosis, influenza) as appropriate according to local protocols.[120] 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.[568]
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.[568]
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.[120]
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.[120] Follow local palliative care guidelines.
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.[865]
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