History

• Incubation period is typically within 14 days of exposure, and within 5 days in most patients. Incubation for more than 14 days occurs in a small percentage of patients ^r16r17
  • Patients may or may not report close contact with an infected person; the high transmissibility of the Omicron variant contributes to the number of cases with unknown exposure history
• In symptomatic patients, illness may evolve over the course of a week or longer, beginning with mild symptoms that progress in some cases to the point of respiratory distress and shock ^r18
  • Median time from symptom onset to pneumonia is 5 days; time to severe hypoxemia is 7 to 12 days ^r3
• The most common complaints in unvaccinated people are fever/chills and cough, which may or may not be productive ^r18r19r20
  • Fever is often not present at presentation, even in hospitalized patients, and may be very mild (less than 38 °C) ^r18
  • Myalgia, headache, and fatigue are common; fatigue may be profound ^r18r19
  • Upper respiratory tract symptoms (eg, rhinorrhea, sneezing, sore throat) may be present in up to 20% of symptomatic infections ^r19
  • Gastrointestinal symptoms (eg, abdominal pain, nausea, vomiting, diarrhea) are present in 10% to 20% of symptomatic infections ^r18r19
  • Alteration in smell and/or taste is less common but highly suggestive ^r19r21r22
• When COVID-19 is acquired after vaccination, a shift in the most common symptoms has been reported: headache, rhinorrhea, sneezing, sore throat, and loss of smell are most prominent, whereas cough and fever are less common than in unvaccinated people ^r23
• Patients with moderate to severe disease often complain of dyspnea;^r18 however, it has been recognized that many patients with severe hypoxemia due to COVID-19 do not perceive dyspnea^r24r25r19
  • Hemoptysis has been reported in a small percentage of patients ^r18
  • Pleuritic chest pain has been reported ^r17
• Patients with severe or critical disease most commonly have pulmonary disease; however, cardiac, vascular, and neurologic manifestations may accompany pulmonary disease ^c1c2c3c4
  • The most common symptoms among severe or critically ill patients are fever, cough, dyspnea, chest tightness, and fatigue ^r26
    • These symptoms may not have shifted significantly with vaccination, because among populations with access to vaccination, the large majority of people who progress to severe or critical illness are unvaccinated ^r27

Physical examination

• Physical findings may include systemic, neurologic, dermatologic, gastrointestinal, or more, but clinicians should be particularly attuned to pulmonary and hemodynamic indicators of critical illness
  • Patients with severe disease may appear quite ill, with tachypnea and labored respirations ^c5c6
  • Patients in apparent distress require immediate assessment of airway, breathing, and circulation (eg, pulses, blood pressure)
  • Clinicians should be aware of the COVID-19–related phenomenon of silent (or "happy") hypoxemia: absence of signs of respiratory distress may be misleading ^r24r25c7
  • Oxygenation should be assessed promptly by peripheral saturation (eg, pulse oximetry^r6); be aware that pulse oximetry may be less accurate in dark-skinned persons, in whom the readings may be falsely high (ie, higher than concurrently measured arterial blood oxygen levels)^r1
  • Tachyarrhythmias may be noted on auscultation or cardiac monitor ^r28c8
• Fever is typical, often exceeding 39 °C, but may be low-grade or absent in early disease, especially in vaccinated people. Patients in the extremes of age or with immunodeficiency may not develop fever ^r18r23c9
• Conjunctival secretions, injection, and chemosis have been reported ^r29
• Signs of arterial or deep venous thrombosis may be detected
  • Large-vessel stroke with associated neurologic deficit has been described as the presenting clinical event ^r30c10c11
• Other reported neurologic findings in severe disease include hyperactive deep tendon reflexes, ankle clonus, and positive Babinski sign ^r31c12c13c14
• Patients may be agitated, confused, or poorly responsive ^r31c15c16
• A variety of skin changes have been described, including purpura^r33 and petechiae^r34; vesicular^r35 and nonspecific erythematous exanthems^r36 typical of viral infections; and acral lesions^r37r38r39 resembling chilblains or Janeway lesions, particularly in young patients. Typical viral eruptions generally occur early in the disease, but remnants may be apparent in patients presenting with severe disease ^r32c17c18c19
• Hypotension, tachycardia, and cool/clammy extremities suggest shock ^c20c21c22
  • In children, shock manifests as hypotension plus 2 or more of the following criteria: ^r6
    • Altered mental status ^c23
    • Tachycardia (heart rate more than 160 beats per minute in infants or 150 in older children) or bradycardia (heart rate less than 90 in infants or 70 in older children) ^c24
    • Prolonged capillary refill (more than 2 seconds) or warm vasodilation and bounding pulses ^c25
    • Tachypnea ^c26
    • Mottled skin, petechiae, or purpura ^c27c28c29
    • Oliguria ^c30
    • Hyperthermia or hypothermia ^c31c32

Causes

• Infection due to SARS-CoV-2 ^c33
  • Person to person transmission has been documented^r17 and occurs through exposure to infectious respiratory fluids (droplet and aerosols of various sizes) through inhalation, direct contact of fluids with mucous membranes (splashes or sprays, such as being coughed on), or touching mucous membranes with hands contaminated by respiratory fluids ^r40
    • Highest risk of exposure appears to be contact within 6 feet, but well-documented transmission at farther than 6 feet has occurred in indoor locations, primarily with poor ventilation, prolonged contact, and/or increased exhalation of the infectious person (such as from singing or exercise) ^r40
    • Infection through contact with infected surfaces and fomites is possible but is not the primary mode of transmission ^r41
      • Routine cleaning, routine hand hygiene, and disinfecting after people with known or suspected COVID-19 have been present in an indoor space all lower the risk of transmission through surfaces and fomites
  • Many animals (eg, pets, livestock, wildlife) may acquire SARS-CoV-2 from humans or from one another, and cases of animal to human transmission have been reported. The extent to which humans may acquire infection from animals is low, to date ^r42c34
  • There is currently no evidence for transmission via food or water

Risk factors and/or associations

Primary diagnostic tools

• Most patients who are critically ill with COVID-19 will already be diagnosed with COVID-19 via a positive result on a polymerase chain reaction test or antigen test
• In cases where COVID-19 is suspected in a critically ill patient (eg, requiring mechanical ventilation) without a confirmed diagnosis, lower respiratory samples should be sent if upper respiratory samples are negative
  • NIH treatment guidelines recommend endotracheal aspirates over bronchial wash or bronchoalveolar lavage samples ^r15
  • Upper respiratory samples include nasopharyngeal, nasal midturbinate, anterior nasal, nasopharyngeal wash or aspirate, oropharyngeal, or saliva specimens
  • Lower respiratory samples include bronchoalveolar lavage fluid, tracheal aspirate, pleural fluid, lung biopsy specimen, and sputum
  • Care must be taken to minimize risks associated with aerosolization during specimen collection. Clinicians should not attempt to induce sputum, because the process may increase aerosolization and risk of transmission ^r49
  • CDC provides instructions for collection and handling of specimens. Commercial, institutional, and public health laboratories may have different requirements and should be consulted for questions about collection site, swabs, transport media, or handling ^r49
• Serologic testing is not recommended for routine use in diagnosis, but it may be useful in the diagnosis of MIS-C or MIS-A (ie, multisystem inflammatory syndrome in children or adults, respectively) because patients might present as critically ill with no prior diagnosis of COVID-19 ^r15
• Other testing should be performed concurrently, if indicated, to identify alternative pathogens (eg, influenza, respiratory syncytial, and other viruses; bacterial pathogens); such tests should not delay arrangements for SARS-CoV-2 testing ^{r6d2d2d2d2d2d2d2d2}
  • Coinfections have been reported, but the frequency is unknown ^r50r51
  • Circulation of common respiratory viruses has been altered by public health measures to prevent COVID-19; be alert for off-season circulation and for increases in transmission when COVID-19 mitigation measures are relaxed ^r52
  • Influenza may be clinically indistinguishable from COVID-19; additionally, coinfection can occur. Therefore, when influenza and SARS-CoV-2 are both circulating in the community, testing for both viruses is recommended for all patients hospitalized with acute respiratory infection. In patients who present with acute respiratory illness but who do not require hospitalization, influenza testing is recommended in addition to testing for SARS-CoV-2, if influenza test results would alter management ^r15r53
    • CDC recommends nucleic acid detection over antigen testing for both pathogens, by either multiplex or individual assay
• Chest imaging may be indicated to assess severity; plain radiography, CT, and ultrasonography have been used ^r20
  • Recommendations for COVID-19–specific diagnostic use differ regionally, according to availability of testing, prevalence of disease, and public policy
    • During the initial outbreak in Wuhan, China, CT scan was considered a surrogate diagnostic modality, based on the following factors: greater sensitivity compared with chest radiographs; the observation that CT may find characteristic abnormalities even in the absence of a positive molecular test result; the high prevalence of COVID-19 in that geographic area at the time; and the public health goal of detecting and isolating all infected persons ^r54
    • CDC recommends against using chest radiograph or CT as a specific diagnostic measure for COVID-19; American College of Radiology cautions that findings are not specific to that disease and overlap with other viral pneumonias ^r55c36c37c38
  • In patients with moderate to severe disease, chest imaging is essential to document extent and severity of lung involvement and to serve as a baseline against which to compare should respiratory status worsen ^r20r54c39c40
    • In patients with severe disease, CT may offer an advantage over plain radiographs in distinguishing progression of infection from heart failure due to myocarditis or from pulmonary embolism (both commonly associated with COVID-19) ^r54
• Routine blood work should be ordered as appropriate for clinical management based on disease severity (eg, CBC, coagulation studies, chemistry panel including tests of hepatic and renal function and—if sepsis is suspected—lactate level and blood cultures) ^{r6d3d3d3d3d3d3d3d3}
• Public health reporting requirements vary by jurisdiction; clinicians should consult local authorities. In some regions, public health authorities may be able to facilitate testing and undertake contact tracing and monitoring

Laboratory

• Positive identification of SARS-CoV-2 RNA by a polymerase chain reaction test is considered confirmation of diagnosis
  • Laboratory-based polymerase chain reaction testing has high sensitivity and high specificity and is thus the reference standard. Point of care polymerase chain reaction testing has moderate sensitivity and high specificity ^r3r56
  • False-negative results have been reported and may be due to a variety of factors, including inadequate sensitivity, poor or unrepresentative specimen, or time course of disease. Repeated sampling should be considered if suspicion for COVID-19 is high and initial result is negative; in patients with severe pulmonary involvement, lower respiratory tract specimens may provide a higher yield ^r3r57
• Antigen tests are also available for use in diagnosis, and they have the advantage of rapid turnaround
  • In general, these tests are less sensitive than polymerase chain reaction, although specificity is nearly equivalent ^r58
    • False-positive results are uncommon but do occur; they are more likely in a low-prevalence setting
    • False-negative results are common, depending on the test. A negative result may warrant retesting (preferably within 2 days) with polymerase chain reaction if there is a high suspicion for infection based on clinical or epidemiologic indicators
    • Additional guidance on antigen testing, including when confirmatory testing is indicated (based on symptoms, exposure, vaccination status, and setting) is available from CDC ^r58
  • A Cochrane review noted wide-ranging performance of antigen tests; summary sensitivities ranged from 34.1% to 88.1%, but average specificity was 99.6% ^r59
    • Sensitivity is higher in symptomatic versus asymptomatic cases, in the first week after symptom onset versus later, and in those with Ct values (cycle threshold) on polymerase chain reaction test of 25 or less versus higher; all of these correlations reflect improved sensitivity with higher viral loads
    • Performance varies across brands. Antigen tests with sufficient sensitivity and specificity may be considered as a replacement for polymerase chain reaction tests when rapid decisions about patient care must be made and when timely polymerase chain reaction test is unavailable, with confirmatory polymerase chain reaction test advised in lower-prevalence settings
• For patients with severe or critical illness, antibody testing is most likely to be useful in the diagnosis of MIS-C or MIS-A (ie, multisystem inflammatory syndrome in children or adults, respectively); antibody testing is not indicated for routine diagnosis of COVID-19
• Routine blood work is not diagnostic, but a pattern of typical abnormalities has emerged
  • In reports of patients with varying severity of illness: ^r17r18r20
    • Abnormalities of blood cell counts are common: leukopenia, relative lymphopenia, anemia, thrombocytopenia, and thrombocytosis ^r17r18r20
    • Laboratory indicators of inflammation/acute phase reactants are frequently elevated: C-reactive protein, erythrocyte sedimentation rate, ferritin, fibrinogen
    • COVID-19–induced abnormal coagulability may be reflected in prolonged prothrombin time, elevated D-dimer level, or elevated fibrinogen level ^r17r18r20r60
    • Elevated levels of lactate dehydrogenase and liver enzymes (ALT and AST) are common ^c41
    • Serum procalcitonin levels are usually within reference range; elevated levels have been seen in patients with secondary infection ^r18
    • Troponin level is commonly elevated, but it does not necessarily signify myocardial infarction in the absence of other indicators (eg, ECG changes); similarly, B-type natriuretic peptide level may be elevated without necessarily indicating presence of heart failure ^r61
      • Some experts caution against measuring these biomarkers in the absence of suggestive clinical findings,^r61 whereas others note the possibility that elevations suggest noncoronary myocardial involvement that may benefit from early use of vasopressors and inotropes^r3
  • Information from patients with severe or critical illness similarly shows common patterns ^r26
    • Most such patients have had elevated C-reactive protein and D-dimer levels (83.5% and 73.3%, respectively)
    • Many such patients had WBC count abnormalities; most common were lymphopenia (70.3%), leukocytosis (21.7%), and leukopenia (18.2%), but 56.9% had normal WBC counts
    • Other common findings were liver function test abnormalities (39.8%), elevated procalcitonin level (36.6%), and thrombocytopenia (19.0%)
      • Elevated levels of procalcitonin were associated with significantly higher risk of severe infection ^r62
    • Lactate level of 2 mmol/L or higher suggests presence of septic shock ^r6

Imaging

• Chest imaging (eg, plain radiography, CT, ultrasonography) has been found to be sensitive but not highly specific to COVID-19 ^r63
• Chest imaging (eg, plain radiography, CT, ultrasonography) has shown abnormalities in most reported patients; it usually shows bilateral involvement, varying from consolidation in more severely ill patients to ground-glass opacities in less severe and recovering pneumonia ^{r8r17r18r20r64c42}
• CT appears to be more sensitive^r63r65r54 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19^r66
  • Certain chest CT findings may suggest more severe disease: bronchial wall thickening, crazy paving (thickened interlobular septa and intralobular lines superimposed on diffuse ground-glass changes), linear opacity (typical of interstitial lung disease), and ground-glass opacity (hazy increased lung opacity which is less opaque than consolidation), as well as bilateral involvement compared with unilateral ^r67
• Bedside ultrasonography is widely used to monitor progression of pulmonary infiltrates, and to assess cardiac function and fluid status; it may also be used to detect deep vein thrombosis or vascular catheter thrombosis, which appear to be common in patients with COVID-19 ^r3r68

Most common

• Influenza ^{c43d4d4d4d4d4d4d4d4}
  • Presentation includes fever, coryza, sore throat, dry cough, and myalgias; unlike COVID-19, influenza usually has fairly sudden onset
  • Most cases are self-limited, but older adults (eg, those aged 65 years or older) or those with significant comorbidities often require hospitalization
  • Usually occurs in winter months in temperate climates but is less seasonal in equatorial regions
    • Mitigation measures for COVID-19 may alter the timing and amount of circulating respiratory viruses, including influenza virus ^r52
  • Patients with severe disease may have abnormal chest radiographic findings suggesting influenzal pneumonia or secondary bacterial pneumonia
  • Positive result on rapid influenza diagnostic test confirms influenza diagnosis with high specificity during typical season; negative result does not rule out influenza
  • Influenza may be clinically indistinguishable from COVID-19; additionally, coinfection can occur. Therefore, when influenza and SARS-CoV-2 are both circulating in the community, testing for both viruses is recommended for all patients hospitalized with acute respiratory infection ^r15r53
    • CDC recommends nucleic acid detection over antigen testing for both pathogens, by either multiplex or individual assay
• Other viral pneumonias ^{c44d2d2d2d2d2d2d2d2}
  • Presentations include fever, dry cough, and dyspnea
  • Physical examination may find scattered rales
  • Chest radiography usually shows diffuse patchy infiltrates
  • Diagnosis is usually clinical. Testing for specific viral causes may be done; multiplex panels can test simultaneously for various common viral respiratory pathogens (eg, respiratory syncytial virus, adenoviruses, others)
  • As with influenza virus, timing and amount of circulating respiratory viruses may be altered by COVID-19 mitigation measures ^r52
• Bacterial pneumonia ^{c45d2d2d2d2d2d2d2d2}
  • Presentation includes fever, cough, and dyspnea; pleuritic pain occurs in some cases
  • Physical examination may find signs of consolidation (eg, dullness to percussion, auscultatory rales, tubular breath sounds)
  • Chest radiography usually shows lobar consolidation or localized patchy infiltrate
  • Sputum examination may find abundant polymorphonuclear leukocytes and a predominant bacterial organism
  • Pneumococcal or legionella antigens may be detectable in urine; sputum culture may find those or other pathogens

Admission criteria

Recommendations for specialist referral

• All patients should be managed according to local public health guidance
• Consult infectious disease specialist to coordinate diagnosis and management as needed
• Consult pulmonologist to aid in obtaining deep specimens for diagnosis and managing mechanical ventilation if necessary
• Consult critical care specialist to manage fluids, mechanical ventilation, and hemodynamic support as needed

Drug therapy

• Antiviral agent
  • Remdesivir ^r91r93c46
    • For patients NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO):
      • Remdesivir Solution for injection; Neonates weighing 3.5 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
      • Remdesivir Solution for injection; Infants and Children 1 to 11 years weighing at least 3.5 kg NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
      • Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing less than 40 kg NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
      • Remdesivir Solution for injection; Children and Adolescents weighing 40 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
      • Remdesivir Solution for injection; Adults NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement. The NIH recommends treatment for 5 days or until hospital discharge.
    • For patients REQUIRING invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO):
      • Remdesivir Solution for injection; Neonates weighing 3.5 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 9 days.
      • Remdesivir Solution for injection; Infants and Children 1 to 11 years weighing at least 3.5 kg requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 9 days.
      • Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing less than 40 kg requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 9 days.
      • Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing 40 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days. The NIH recommends against starting remdesivir; but, treatment may be continued (in combination with dexamethasone) in patients who progress to mechanical ventilation or ECMO.
      • Remdesivir Solution for injection; Adults requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days. The NIH recommends against starting remdesivir; but, treatment may be continued (in combination with dexamethasone) in patients who progress to mechanical ventilation or ECMO.
• Immunomodulators
  • Baricitinib ^c47
    • Baricitinib Oral tablet; Children 2 to less than 9 years: 2 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines state there are insufficient data to recommend either for or against use in pediatric patients.
    • Baricitinib Oral tablet; Children and Adolescents 9 years of age and older: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines state there are insufficient data to recommend either for or against use in pediatric patients.
    • Baricitinib Oral tablet; Adults: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines recommend use with dexamethasone (with or without remdesivir) IF on supplemental oxygen, including noninvasive ventilation or high-flow oxygen, AND there is evidence of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone.
  • Tocilizumab ^c48
    • Tocilizumab Solution for injection; Adults: 8 mg/kg (max: 800 mg) IV infusion once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first. The EUA requires concurrent use with a systemic corticosteroid. The NIH COVID-19 treatment guidelines recommend a single 8 mg/kg (actual body weight, up to 800 mg) IV dose given with dexamethasone (with or without remdesivir) for hospitalized patients on supplemental oxygen, including high-flow oxygen and noninvasive ventilation, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, NIH recommends use with dexamethasone for patients on mechanical ventilation or ECMO IF admitted to an ICU within the prior 24 hours.
  • Sarilumab ^c49
    • Sarilumab Solution for injection; Adults: The NIH COVID-19 treatment guidelines recommend a single 400 mg IV dose given with dexamethasone (with or without remdesivir) to treat hospitalized adults on supplemental oxygen, including high-flow oxygen and noninvasive ventilation, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, may be given with dexamethasone for patients on mechanical ventilation or ECMO IF admitted to an ICU within the prior 24 hours. Sarilumab is an alternative if tocilizumab is not available or cannot be used.
  • Tofacitinib
    • Tofacitinib Oral tablet; Adults: The NIH COVID-19 treatment guidelines recommend 10 mg PO twice daily for up to 14 days or until hospital discharge (whichever comes first) to treat hospitalized adults on supplemental oxygen, including noninvasive ventilation and high-flow oxygen, with rapidly increasing oxygen needs and systemic inflammation. MUST be given with dexamethasone (with or without remdesivir). Tofacitinib is an alternative if baricitinib is not available or cannot be used.
• Vasopressors
  • Norepinephrine ^c50
    • Norepinephrine Bitartrate Solution for injection; Neonates†: 0.1 to 0.5 mcg/kg/minute continuous IV infusion; titrate every 30 minutes to clinical response (Usual Max: 2 mcg/kg/minute).
    • Norepinephrine Bitartrate Solution for injection; Infants†, Children†, and Adolescents†: 0.1 mcg/kg/minute continuous IV infusion; titrate to clinical response (Usual Max: 2 mcg/kg/minute).
    • Norepinephrine Bitartrate Solution for injection; Adults: 0.1 mcg/kg/minute (weight-based) or 8 to 12 mcg/minute (flat-dose) continuous IV infusion, initially. Titrate by 0.02 mcg/kg/minute (or more in emergency cases) to clinical response. Usual dosage range: 0.05 to 0.4 mcg/kg/minute (weight-based) or 2 to 4 mcg/minute (flat-dose). Infusion rates up to 3.3 mcg/kg/minute have been used.
  • Epinephrine ^c51
    • Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate to clinical response.
    • Epinephrine Hydrochloride Solution for injection; Adults: 0.01 to 2 mcg/kg/minute continuous IV infusion. Titrate by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes to clinical response.
  • Vasopressin ^c52
    • Vasopressin Solution for injection; Adults: 0.01 unit/minute continuous IV infusion; titrate by 0.005 unit/minute every 10 to 15 minutes to clinical response. Max: 0.07 unit/minute.
• Inotrope
  • Dobutamine ^c53
    • Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion; titrate to clinical response. Usual dosage range: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
• Corticosteroid
  • For treatment of severe COVID-19 in patients requiring supplemental oxygen
    • Dexamethasone ^c54
      • Dexamethasone Sodium Phosphate Solution for injection; Children and Adolescents: The NIH guidelines recommend 0.15 mg/kg/dose (maximum dose of 6 mg) IV once daily for up to 10 days for pediatric patients requiring high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO. Not routinely recommended for pediatric patients requiring only low oxygen support. Use in pediatric patients who are profoundly immunocompromised should be considered on a case-by-case basis
      • Dexamethasone Sodium Phosphate Solution for injection; Children and Adolescents: The NIH guidelines recommend 0.15 mg/kg/dose (maximum dose of 6 mg) IV once daily for up to 10 days for pediatric patients requiring high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO. Not routinely recommended for pediatric patients requiring only low oxygen support. Use in pediatric patients who are profoundly immunocompromised should be considered on a case-by-case basis
      • Dexamethasone Sodium Phosphate Solution for injection; Adults: 6 mg IV once daily for up to 10 days or until hospital discharge (whichever comes first) is recommended by the NIH guidelines for use in hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The WHO strongly recommends systemic corticosteroids for 7 to 10 days in patients with severe or critical COVID-19. Before starting therapy, review the patient's medical history and assess the potential risks and benefits.
    • Methylprednisolone ^c55
      • Methylprednisolone Sodium Succinate Solution for injection; Adults: 8 mg IV every 6 hours or 16 mg IV every 12 hours for 7 to 10 days. The WHO strongly recommends systemic corticosteroids in patients with severe or critical COVID-19. The NIH recommends methylprednisolone as an alternative corticosteroid for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The NIH recommends 32 mg IV once daily (or in 2 divided doses) for up to 10 days or until hospital discharge (whichever comes first). Before starting therapy, review the patient's medical history and assess the potential risks and benefits.
    • Prednisone ^c56
      • Prednisone Oral solution; Adults: 40 mg PO daily for 7 to 10 days. The WHO strongly recommends systemic corticosteroids in patients with severe or critical COVID-19. The NIH recommends prednisone as an alternative corticosteroid for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The NIH recommends 40 mg PO once daily (or in 2 divided doses) for up to 10 days or until hospital discharge (whichever comes first). Before starting therapy, review the patient's medical history and assess the potential risks and benefits.
  • For treatment of COVID-19–related septic shock refractory to vasopressors and fluids
    • Hydrocortisone ^c57
      • Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 mg IV every 6 hours or 200 mg/day continuous IV infusion.
• Anticoagulants (prophylactic intensity)
  • Enoxaparin ^c58
    • Enoxaparin Sodium (Porcine) Solution for injection; Neonates and Infants younger than 2 months†: 0.75 mg/kg subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
    • Enoxaparin Sodium (Porcine) Solution for injection; Infants, Children, and Adolescents 2 months to 17 years†: 0.5 mg/kg subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
    • Enoxaparin Sodium (Porcine) Solution for injection; General medical Adult patients with risk factors for DVT due to restrictive mobility during acute illness (e.g., moderate to severe congestive heart failure, severe respiratory disease, or patients who are confined to bed and have 1 or more of the following risk factors: active cancer, history of VTE, sepsis, acute neurological disease, and inflammatory bowel disease): 40 mg subcutaneously once daily for 14 days or less.
  • Dalteparin
    • Dalteparin Sodium (Porcine) Solution for injection; Infants†, Children, and Adolescents: 92 International Units/kg subcutaneously once daily; adjust dose to maintain an anti-factor Xa level of 0.1 to 0.3 International Units/mL.
    • Dalteparin Sodium (Porcine) Solution for injection; General medical adult patients with risk factors for DVT due to restrictive mobility during acute illness (e.g., moderate to severe congestive heart failure, severe lung disease, or patients who are confined to bed and have 1 or more of the following risk factors: active cancer, history of VTE, sepsis, acute neurological disease, and/or inflammatory bowel disease): 5,000 International Units subcutaneously once daily for up to 14 days.
• Anticoagulants (therapeutic intensity for those with suspected or proven thromboembolism)
  • Enoxaparin
    • Enoxaparin Sodium (Porcine) Solution for injection; Infants 1 to 2 months†: 1.5 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.8 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours post-dose or 0.5 to 0.8 units/mL 2 to 6 hours post-dose.
    • Enoxaparin Sodium (Porcine) Solution for injection; Infants 3 to 11 months†: 1 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.5 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
    • Enoxaparin Sodium (Porcine) Solution for injection; Children 1 to 5 years†: 1 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.2 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
    • Enoxaparin Sodium (Porcine) Solution for injection; Children and Adolescents 6 to 17 years†: 1 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
    • Enoxaparin Sodium (Porcine) Solution for injection; Adults: 1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose subcutaneously every 24 hours. Start warfarin therapy when appropriate, as early as day 1 and usually within 72 hours of initiation of enoxaparin. Continue enoxaparin for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved.
  • Dalteparin
    • Dalteparin Sodium (Porcine) Solution for injection; Infants, Children, Adolescents: 129 International Units/kg/dose subcutaneously once daily; adjust dose to maintain anti-Xa concentration of 0.5 to 1 International Unit/mL drawn 4 hours after injection. Give 5 to 10 days until target INR is reached; or give for duration of treatment (6 months or longer for idiopathic DVT or until risk factor is resolved and 3 months or longer for secondary DVT). If VTE is CVL-related, remove CVL if possible. If not, give prophylactic doses after treatment until CVL is removed.
    • Dalteparin Sodium (Porcine) Solution for injection; Adults: 200 International Units/kg/dose (Max: 18,000 International Units/dose) subcutaneously once daily or 100 International Units/kg/dose subcutaneously every 12 hours with warfarin on day 1. Stop dalteparin after at least 5 days of combined therapy once the INR is therapeutic.
• Sedatives (for mechanically ventilated patients)
  • Dexmedetomidine ^c59
    • Dexmedetomidine Hydrochloride Solution for injection; Term Neonates†: 0.05 to 0.5 mcg/kg IV, then 0.05 to 0.6 mcg/kg/hour continuous IV infusion, initially. Titrate until target level of sedation is attained. Loading doses are often bypassed. Max: 2.5 mcg/kg/hour.
    • Dexmedetomidine Hydrochloride Solution for injection; Infants†: 0.5 to 1 mcg/kg IV, then 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.
    • Dexmedetomidine Hydrochloride Solution for injection; Children† and Adolescents†: 0.5 to 1 mcg/kg IV, then 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.
    • Dexmedetomidine Hydrochloride Solution for injection; Adults: 1 mcg/kg IV, then 0.2 to 0.7 mcg/kg/hour continuous IV infusion, initially. Titrate until target level of sedation is attained. Loading doses are often bypassed. Max: 1.5 mcg/kg/hour.
  • Propofol ^c60
    • Propofol Emulsion for injection; Adolescents 17 years: 5 mcg/kg/minute continuous IV infusion, initially; titrate by 5 to 10 mcg/kg/minute every 5 to 10 minutes to clinical response. Usual dose: 5 to 50 mcg/kg/minute. Do not exceed 4 mg/kg/hour unless the benefits outweigh the risks. May use 10 to 20 mg IV bolus if needed to rapidly increase sedation depth in patients where hypotension is unlikely to occur.
    • Propofol Emulsion for injection; Adults: 5 mcg/kg/minute continuous IV infusion, initially; titrate by 5 to 10 mcg/kg/minute every 5 to 10 minutes to clinical response. Usual dose: 5 to 50 mcg/kg/minute. Do not exceed 4 mg/kg/hour unless the benefits outweigh the risks. May use 10 to 20 mg IV bolus if needed to rapidly increase sedation depth in patients where hypotension is unlikely to occur.
• Neuromuscular blockers (for mechanically ventilated patients)
  • Rocuronium ^c61
    • Intermittent IV dosage
      • Rocuronium Bromide Solution for injection; Neonates: 0.45 to 0.6 mg/kg IV once, followed by 0.075 to 0.6 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Rocuronium Bromide Solution for injection; Infants, Children, and Adolescents: 0.45 to 0.6 mg/kg IV once, followed by 0.075 to 0.6 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Rocuronium Bromide Solution for injection; Adults: 0.6 to 1 mg/kg IV once, followed by 0.1 to 1 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Continuous infusion IV dosage
      • Rocuronium Bromide Solution for injection; Neonates: 0.6 mg/kg IV bolus, followed by 5 to 10 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Rocuronium Bromide Solution for injection; Infants, Children, and Adolescents: 0.6 mg/kg IV bolus, followed by 5 to 10 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Rocuronium Bromide Solution for injection; Adults: 0.6 to 1 mg/kg IV bolus, followed by 8 to 12 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Usual dosage range: 4 to 16 mcg/kg/minute. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Nondrug and supportive care

Excellent supportive care remains the mainstay of treatment to date in COVID-19 ^c62

WHO,^r6NIH,^r15 and Surviving Sepsis Campaign^r4 provide specific guidance for oxygenation, ventilation, hemodynamics, fluid management, and prevention of complications in COVID-19

• Oxygenation and ventilation ^c63c64
  • Begin supplemental oxygen therapy when oxygen saturation falls below 90% to 92% ^r4r6
  • Nasal cannula at 5 L/minute or face mask with reservoir bag at 10 to 15 L/minute ^r6c65
    • Titrate to reach SpO₂ of 94% or more initially; Surviving Sepsis recommends that SpO₂ be maintained no higher than 96%
    • Once stable, target SpO₂ of 90% or higher in nonpregnant adults; 92% or higher in pregnant patients
    • In most children the target SpO₂ is 90% or greater; for those who require urgent resuscitation (eg, those with apnea or obstructed breathing, severe respiratory distress, central cyanosis, shock, seizures, or coma), a target SpO₂ of 94% or higher is recommended
  • High-flow nasal cannula is recommended for adults with persistent respiratory failure despite conventional oxygen therapy ^r94c66c67
    • High-flow nasal cannula is recommended over noninvasive positive pressure ventilation by NIH and Surviving Sepsis; there is some evidence that it averts the need for intubation and mechanical ventilation. Noninvasive positive pressure ventilation with close monitoring may be used if high-flow nasal oxygen is not available ^r4r15
  • Noninvasive positive pressure ventilation, such as CPAP and BPAP, may be used in monitored settings with immediate availability of endotracheal intubation if needed; if indications for endotracheal intubation are already present, high-flow nasal cannula or noninvasive positive pressure ventilation should not be used to delay needed mechanical ventilation ^r6
    • Given the potential for noninvasive ventilation techniques to aerosolize the virus, airborne precautions are recommended ^r6
  • For patients with persistent hypoxemia but without other indications for intubation, WHO suggests and NIH recommends a trial of awake prone positioning to improve oxygenation; Surviving Sepsis guideline finds insufficient evidence to make a recommendation ^r15c68
    • NIH recommends against using prone positioning in an attempt to avert the need for mechanical ventilation in patients who otherwise require it (eg, respiratory distress, hemodynamic instability)
  • Mechanical ventilation may become necessary for patients in whom oxygenation targets cannot be met with less invasive measures or who cannot maintain the work of breathing; indications for intubation are the same as for non–COVID-19 conditions (eg, PaO₂/FIO₂ ratio less than 300 mm Hg, coma) ^c69
    • Categorization of degree of acute respiratory distress syndrome in adults, by PaO₂/FIO₂ ratio (mm Hg):
      • Mild: PaO₂/FIO₂ ratio less than 300 but more than 200, with PEEP or CPAP at 5 cm H₂O or more
      • Moderate: PaO₂/FIO₂ ratio of 200 or less but more than 100, with PEEP at 5 cm H₂O or more
      • Severe: PaO₂/FIO₂ ratio of 100 or less, with PEEP at 5 cm H₂O or more
    • Categorization of degree of acute respiratory distress syndrome in children:
      • Indices:
        • Oxygenation index is calculated as FIO₂ multiplied by mean airway pressure (mm Hg), divided by PaO₂ (mm Hg)
        • Oxygen saturation index is a noninvasive surrogate for oxygenation index and is calculated as FIO₂ multiplied by mean airway pressure (mm Hg), divided by the oxygen saturation as measured by pulse oximetry (SpO₂)
      • Mild (invasively ventilated): oxygenation index from 4 to less than 8 or oxygen saturation index from 5 to less than 7.5
      • Moderate (invasively ventilated): oxygenation index from 8 to less than 16 or oxygen saturation index from 7.5 to less than 12.3
      • Severe (invasively ventilated): oxygenation index of 16 or more or oxygen saturation index of 12.3 or more
    • Intubation should be performed by experienced personnel, using video laryngoscopy where available; N95 respirators or comparable, along with eye protection, gown, and gloves, are recommended for use during intubation and other aerosol-generating procedures and when caring for mechanically ventilated patients, to prevent exposure during unexpected ventilator circuit disruptions ^r4r15
      • WHO additionally recommends against disconnection from ventilators, which risks exposing health care workers, and suggests consideration of airway clearance techniques for excessive secretions only with strict infection control practices ^r6
    • Guidelines have a strong recommendation for lower tidal volume of 4 to 8 mL/kg (predicted body weight) over higher tidal volumes and plateau pressures less than 30 cm H₂O for adults ^r4r15r73
    • In children, target tidal volumes of 5 to 8 mL/kg (predicted body weight) for preserved lung compliance and 3 to 6 mL/kg for poor compliance; plateau pressures should be less than 28 cm H₂O ^r6
    • Guidelines suggest a higher PEEP strategy over lower PEEP, with close monitoring for barotrauma and with consideration of risks (eg, overdistention, higher pulmonary vascular resistance) and benefits (eg, improved alveolar recruitment) ^{r4r6r15c70d5d5d5d5d5d5d5d5}
    • For patients with moderate to severe acute respiratory distress syndrome on mechanical ventilation, prone positioning for 12 to 16 hours/day is recommended ^r4r6r15c71
      • Lateral decubitus position may be used for pregnant patients, especially in the third trimester ^r6
    • Sedation with or without neuromuscular blockade may be necessary for comfort and optimal ventilation; the Society of Critical Care Medicine offers guidance on appropriate agents^r95 (eg, propofol, dexmedetomidine) and monitoring; shortages may occur and the American Society of Health-System Pharmacists offers guidance on substitutions^r96
      • Guidelines suggests intermittent neuromuscular blockade as needed (eg, rocuronium) rather than continuous infusion ^{r4r6r15c72c73}
        • Continuous neuromuscular blockade may be needed for patient-ventilator dyssynchrony, prone ventilation, persistently high plateau pressures, or other need for deep sedation; guidelines recommend no more than 48 hours ^r4r15
    • Routine use of inhaled nitric oxide is not recommended by either Surviving Sepsis Campaign or NIH guidelines; both note that a trial may be reasonable as a rescue strategy in patients who remain hypoxemic despite all other measures ^r4r15
    • Similarly, in patients on mechanical ventilation with persistent hypoxemia despite all other measures, recruitment maneuvers (eg, brief high PEEP or CPAP) are suggested except incremental (staircase) PEEP
    • Tracheostomy may be required; it should be performed for indications similar to those in patients without COVID-19 (eg, prolonged mechanical ventilation, secretion management, failed extubation, inability to protect airway)
  • Extracorporeal membrane oxygenation has been used^r18 since the early pandemic in severely ill patients; Surviving Sepsis and WHO suggest using venovenous type, or referral for extracorporeal membrane oxygenation, if all other measures have not alleviated refractory hypoxemia; NIH guideline finds insufficient evidence to recommend for or against use ^r4r6r15c74
    • WHO definition of refractory hypoxemia is: PaO₂/FIO₂ ratio of less than 50 mm Hg for 3 hours, or less than 80 mm Hg for more than 6 hours
• Fluid management
  • Overhydration should be avoided, because it may precipitate or exacerbate acute respiratory distress syndrome
  • An assessment of likely fluid responsiveness may be made by measuring the change in cardiac output (by echocardiography or transpulmonary thermodilution) on passive leg raise; an increase in cardiac output after 1 minute of passive leg raise has been shown to be a reliable predictor of response and helps to avoid overhydration in patients unlikely to respond ^r97
  • In patients with shock:
    • Administration of crystalloids is recommended (preferably buffered/balanced, eg, lactated Ringer solution); WHO^r6 provides the following guidance:
      • Adults: administer 250 to 500 mL over the first 15 to 30 minutes; goal is mean arterial pressure of 60 to 65 mm Hg^r4 (if invasive pressure monitoring is available)
      • Children: 10 to 20 mL/kg bolus over the first 30 to 60 minutes
      • If there is no response to fluid bolus or if signs of fluid overload exist, discontinue or reduce fluid administration
      • For patients who respond to initial bolus and are without evidence of fluid overload, titrate continued fluid to achieve improvement in clinical signs (capillary refill, heart rate, tactile temperature of extremities, palpable pulses), urine output (0.5 mL/kg/hour in adults, 1 mL/kg/hour in children), and hemodynamic parameters (mean arterial pressure more than 65 mm Hg in adults)
    • Administer vasopressors in adults if shock persists after fluid bolus, and in children after 2 fluid boluses or if there are signs of fluid overload
• Management of acute kidney injury
  • NIH guideline recommends continuous renal replacement therapy if available for patients with acute kidney injury who require renal replacement therapy ^r15
    • If continuous renal replacement therapy is not available or not possible owing to limited resources, NIH guideline recommends prolonged intermittent renal replacement therapy rather than intermittent hemodialysis

Comorbidities

• Severe COVID-19 has been associated with various underlying chronic conditions (eg, diabetes, hypertension) ^r47c76c77

Special populations

• Pregnant patients
  • NIH guideline contains a summary of considerations for pregnant and breastfeeding patients; American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine also have guidance regarding pregnant patients with COVID-19 ^r15r98r99
  • Compared with nonpregnant patients, pregnant patients with COVID-19 have an increased risk of severe disease, including ICU admission, mechanical ventilation, need for extracorporeal membrane oxygenation, and death ^r15r98r99
  • COVID-19 in pregnancy is associated with increased risk for complications such as preterm birth, stillbirth, and hypertensive disorders of pregnancy ^r15r98r99
  • In general, therapeutic management of pregnant patients should be the same as for nonpregnant patients; potentially effective treatments for COVID-19 should not be withheld because of theoretical concerns related to the safety of using those drugs in pregnancy ^r15
• Pediatric patients
  • Evidence to guide treatment in pediatric populations is limited; guidance is generally based on safety and outcomes data in adults ^r15
  • General management of critically ill children is also based on guidance for non-COVID critical illness, such as Surviving Sepsis Campaign septic shock guideline^r100 and Society of Critical Care Medicine guideline on prevention and management of pain, agitation, neuromuscular blockade, and delirium in children^r101