History

• In symptomatic patients, illness may evolve over the course of a week or longer, beginning with mild symptoms; syndrome is usually dominated by respiratory complaints, but it may include alterations in taste and smell, gastrointestinal symptoms, myalgias, and fatigue (often profound) ^{r15c1c2c3c4c5c6c7c8c9c10}
  • Median time from symptom onset to pneumonia is 5 days; time to severe hypoxemia is 7 to 12 days ^r10
• In patients with progression to severe disease, deterioration is typically rapid and characterized by progressive hypoxemia which may or may not be associated with symptoms of dyspnea^r16r17c11
  • Clinicians should be aware that lack of dyspnea may be misleading, as it has been recognized that many patients with severe hypoxemia due to COVID-19 do not perceive dyspnea
• Cardiac, vascular, and neurologic manifestations may accompany pulmonary disease, resulting in localized symptoms (eg, pain, including headache) and alterations in cognition and level of consciousness ^c12c13c14c15

Physical examination

• Reported case series have not fully detailed physical findings, 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 ^c16c17
  • 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 ^c18
  • Oxygenation should be assessed promptly by peripheral saturation (eg, pulse oximetry^r8); 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
• Fever is typical, often exceeding 39 °C. Patients in the extremes of age or with immunodeficiency may not develop fever ^r15c19
• Patients with severe disease may appear quite ill, with tachypnea and labored respirations
• Tachyarrhythmias may be noted on auscultation or cardiac monitor ^r18c20
• Signs of arterial or deep venous thrombosis may be detected
  • Large-vessel stroke and associated neurologic deficit has been described as the presenting clinical event ^r19c21c22
• Other reported neurologic findings in severe disease include hyperactive deep tendon reflexes, ankle clonus, and positive Babinski sign ^r20c23c24c25
• Patients may be agitated, confused, or poorly responsive ^r20c26c27
• A variety of skin changes have been described, including purpura^r21 and petechiae^r22 as well as the vesicular^r23 and nonspecific erythematous exanthems^r24 typical of viral infections. Typical viral eruptions generally occur early in the disease, but remnants may be apparent in patients presenting with severe disease ^c28c29c30
• Hypotension, tachycardia, and cool/clammy extremities suggest shock ^c31c32c33
  • In children, hypotension plus 2 or more of the following criteria: ^r8
    • Altered mental status ^c34
    • 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) ^c35
    • Prolonged capillary refill (more than 2 seconds) or warm vasodilation and bounding pulses ^c36
    • Tachypnea ^c37
    • Mottled skin, petechiae, or purpura ^c38c39c40
    • Oliguria ^c41
    • Hyperthermia or hypothermia ^c42c43

Causes

• Infection due to SARS-CoV-2 (2019 novel coronavirus) ^c44
• Person-to-person transmission has been documented^r25 and occurs with close contact,^r26 probably largely via respiratory droplets and perhaps in some cases by aerosolization^r26
• Additional means of transmission are possible but not established (eg, contact with infected environmental surfaces, fomites, fecal-oral route) ^c45c46c47

Risk factors and/or associations

Primary diagnostic tools

• Polymerase chain reaction tests are the standard for diagnosis; antigen testing^r34 has also received emergency use authorization in the United States. Specific test methods and availability vary; public health authorities may assist in arranging diagnostic testing in some areas. Attempts to culture the virus are not recommended. Serologic tests^r35 are not recommended for diagnostic purposes in most circumstances ^{r31r32r33c75c76}
• WHO^r36r37r8 and CDC^r32 have slightly different criteria for whom to test, and the rapid evolution of the pandemic and variable availability of testing render actual practice very fluid. Both organizations support testing in hospitalized patients with a clinically compatible illness
• Collection of specimens from upper respiratory tract or lower respiratory tract is recommended for viral testing.^r32 Care must be taken to minimize risks associated with aerosolization during specimen collection
  • CDC provides specific instructions for collection and handling of specimens submitted for testing at CDC laboratories (commercial and institutional laboratories and public health laboratories in other jurisdictions may have different requirements) ^r38
    • Upper respiratory tract
      • Nasopharyngeal, deep nasal (midturbinate), anterior nare, oropharyngeal, or saliva specimens may be submitted. Only synthetic fiber (eg, polyester) swabs with plastic or wire shafts are acceptable. Flocked swabs are recommended for obtaining deep nasal specimens. If more than one swab is collected, they may be placed in the same container. Note that not all tests are designed for use on all specimens
        • For nasopharyngeal specimen, insert swab into nostril parallel to palate. Leave swab in place for a few seconds to absorb secretions, then remove while gently rotating. It is not necessary to repeat on the other side if the first effort produces a good specimen (ie, swab is saturated)
        • For deep nasal specimen, insert a flocked swab about 2 cm and rotate; repeat on opposite side, using the same swab
        • For anterior nares, insert a flocked swab about 1 cm, rotate in contact with mucus membrane, and leave in place for 10 to 15 seconds; repeat on opposite side, using same swab
        • For oropharyngeal specimen, swab the posterior pharynx, avoiding tongue and tonsils
        • For tests designed for use on saliva, supervised self-collection of 1 to 5 mL is recommended
      • Nasopharyngeal wash (or aspirate) or nasal aspirate specimens (using 1 to 1.5 mL nonbacteriostatic saline) are also acceptable in some cases
      • Because testing methods vary, it is advisable to check with the laboratory to determine which specimens are suitable for the available test
    • Lower respiratory tract
      • Bronchoalveolar lavage or tracheal aspirate are suitable lower respiratory tract specimens ^c77c78
      • A deep cough sputum specimen (collected after mouth rinse) is also acceptable ^c79
        • WHO and CDC advise against attempts to induce sputum, because the process may increase aerosolization and risk of transmission
  • Infectious Diseases Society of America guidelines provide additional guidance and an algorithm, including indications for repeated testing when suspicion for disease is high but initial test result is negative ^r39
    • Favor nasopharyngeal, nasal, or midturbinate specimens, saliva specimen, or combined anterior nasal/oropharyngeal swab over oropharyngeal swab alone for SARS-CoV-2 RNA testing ^c80c81
    • For patients with high likelihood of disease but negative initial result, repeated testing is recommended; in patients with lower respiratory tract symptoms, sputum or other lower respiratory tract specimen is recommended for repeated testing
  • A systematic review and meta-analysis compared frequency with which SARS-CoV-2 RNA was detected in sputum, nasopharyngeal swabs, and oropharyngeal swabs in patients with documented COVID-19. Overall positivity was 71% for sputum, 54% for nasopharyngeal swabs, and 43% for oropharyngeal swabs. Earlier testing resulted in higher positivity rates in all specimens ^r40
• Serologic testing is not recommended for routine use in diagnosis, but it may be useful under some circumstances (eg, high suspicion for disease with persistently negative results on viral RNA tests; in the diagnosis of multisystem inflammatory syndrome in children; in other situations in which retrospective confirmation of disease is indicated) ^r35c82
• 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 ^r8d2
  • Coinfections have been reported, but the frequency is unknown ^r41r42r43
  • 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 ^r4r44c83
    • CDC recommends nucleic acid detection over antigen testing for both pathogens, either by multiplex or individual assay
• 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;^r46 plain radiography, CT, and ultrasonography have been used ^r45c84c85
  • Recommendations for COVID-19–specific diagnostic use differ regionally, according to availability of testing, prevalence of disease, and public policy
    • During the peak of the 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; and the public health goal of detecting and isolating all infected persons ^r46
    • 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 ^r47c86c87c88
  • 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) ^r46
• Routine blood work should be ordered initially and repeated 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). Troponin and B-type natriuretic peptide levels may be helpful in assessing the possibility of myocardial involvement ^{r8r10r48c89c90c91c92c93c94c95c96c97c98d3}
• 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
  • Clinical performance characteristics of these tests are not well defined. Although high sensitivity and specificity can be achieved in test development, data on accuracy in clinical usage are lacking ^r10r39
  • 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 ^r10r39
• 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 equivalent and may be as high as 100%; therefore, false-positive results are uncommon, but 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 ^r34
  • A Cochrane review noted wide-ranging sensitivity and specificity of antigen tests (average sensitivity, 56.2%; average specificity, 99.5%), but it concluded that existing published evaluation of these tests has been based largely on application to remnant laboratory samples and thus may not reflect performance in clinical use
• A Cochrane review^r49 notes that antibody tests are most likely to be clinically useful 15 days or more into the course of infection and that data are scarce regarding antibody tests beyond 35 days. For instances when clinicians judge that antibody testing is indicated, Infectious Diseases Society of America^r35 makes the following recommendations:
  • Testing 3 to 4 weeks after symptom onset maximizes sensitivity
    • Sensitivity at 1 week ranges from 0.23 to 0.63; at 2 weeks, from 0.68 to 0.96
  • Test should measure anti-SARS-CoV-2 IgG or total antibody; a high-specificity test should be used
    • Unlike the usual pattern of antibody production, IgM antibody response to SARS-CoV-2 is somewhat delayed, occurring almost simultaneously with IgG production, so there is no advantage to testing selectively for the IgM fraction
• Routine blood work is not diagnostic, but a pattern of typical abnormalities has emerged, particularly in patients with severe illness:
  • Leukopenia may be observed and relative lymphopenia is common, especially in patients with more severe illness ^r15r25r45
  • Anemia was noted in about half of patients in one series ^r45
  • Both elevated and low platelet counts have been seen ^r15r25r45
  • Prolonged prothrombin time has been reported ^r50
  • Levels of D-dimer and fibrinogen may be elevated ^{r15r25c99c100}
  • Elevated levels of lactate dehydrogenase and liver enzymes (ALT and AST) are common ^r15r45c101
  • Serum procalcitonin levels are usually within reference range; elevated levels have been seen in patients with secondary infection ^r15
  • Serum levels of some other acute phase reactants (eg, C-reactive protein, ferritin) are elevated in most patients, as is the erythrocyte sedimentation rate ^{r45c102c103c104}
  • 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 ^r51
    • Some experts caution against measuring these biomarkers in the absence of suggestive clinical findings,^r51 whereas others note the possibility that elevations suggest noncoronary myocardial involvement that may benefit from early use of vasopressors and inotropes^r10
• Lactate level of 2 mmol/L or higher suggests presence of septic shock ^r8

Imaging

• 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 ^{r12r15r25r45r52c105}
• CT appears to be more sensitive^r46r53 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19^r54
• 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 or vascular catheter thrombosis, which appear to be common in patients with COVID-19 ^r10r55

Most common

• Influenza ^c106d4
  • 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 elderly persons or those with significant comorbidities often require hospitalization
  • Usually occurs in winter months in temperate climates but is less seasonal in equatorial regions
  • 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 ^r4r44
    • CDC recommends nucleic acid detection over antigen testing for both pathogens, either by multiplex or individual assay
• Other viral pneumonias ^c107d2
  • 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 a number of common viral respiratory pathogens such as respiratory syncytial virus, adenovirus, and others
• Bacterial pneumonia ^c108d2
  • 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 in consultation with public health authorities
• Consult infectious disease specialist to coordinate diagnosis and management with public health authorities
• 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 ^r79r80c109
    • 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; 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 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; 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 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.
    • Remdesivir Solution for injection; Children and Adolescents 12 to 17 years 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 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.
    • 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.
• Immunomodulators
  • Baricitinib ^c110
    • 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. Baricitinib is to be taken in combination with remdesivir. According to the NIH COVID-19 guidelines, there are insufficient data to recommend either for or against the use of baricitinib with remdesivir 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. Baricitinib is to be taken in combination with remdesivir. According to the NIH COVID-19 guidelines, there are insufficient data to recommend either for or against the use of baricitinib with remdesivir in pediatric patients.
    • Baricitinib Oral tablet; Adults: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. Baricitinib is to be taken in combination with remdesivir. The NIH COVID-19 guidelines recommend baricitinib plus remdesivir only in rare circumstances where a corticosteroid cannot be used.
  • Tocilizumab ^c111
    • Tocilizumab Solution for injection; Adults: The NIH COVID-19 treatment guidelines recommend a single 8 mg/kg (actual body weight, up to 800 mg) IV dose given with dexamethasone (or equivalent corticosteroid) to treat recently hospitalized adults with rapid respiratory decompensation due to COVID-19 who meet the following criteria:admitted to the ICU within the prior 24 hours and require mechanical ventilation or high-flow nasal canula oxygen (more than 0.4 FiO2/30 L/min) ORnot in the ICU but have rapidly increasing oxygen needs requiring noninvasive mechanical ventilation or high-flow nasal canula AND have significantly increased markers of inflammationSome Panel members also support use of the drug in patients who don't yet require mechanical ventilation or high-flow nasal canula but have rapidly increasing oxygen needs while on dexamethasone AND have a CRP of at least 75 mg/L.
  • Sarilumab ^c112
    • IV dosage
      • Sarilumab Solution for injection; Adults: According to the NIH COVID-19 treatment guidelines, data are insufficient to recommend either for or against the use of sarilumab to treat COVID-19 in patients who are within 24 hours of admission to an intensive care unit (ICU) and require mechanical ventilation (invasive or noninvasive) or high-flow oxygen (greater than 0.4 FiO2/30 L/min); efficacy of sarilumab in these patients has not been determined. For patients not requiring ICU-level care or who are in the ICU but do not meet the above criteria, the NIH guidelines recommend against the use of sarilumab outside clinical trials. 400 mg IV once in combination with antiviral therapy is being evaluated.
    • Subcutaneous dosage
      • Sarilumab Solution for injection; Adults: According to the NIH COVID-19 treatment guidelines, data are insufficient to recommend either for or against the use of sarilumab to treat COVID-19 in patients who are within 24 hours of admission to an intensive care unit (ICU) and require mechanical ventilation (invasive or noninvasive) or high-flow oxygen (greater than 0.4 FiO2/30 L/min); efficacy of sarilumab in these patients has not been determined. For patients not requiring ICU-level care or who are in the ICU but do not meet the above criteria, the NIH guidelines recommend against the use of sarilumab outside clinical trials. 200 or 400 mg subcutaneously once in combination with antiviral therapy is being evaluated.
• Vasopressors
  • Norepinephrine ^c113
    • 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 ^c114
    • Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion; titrate to clinical response. Doses up to 5 mcg/kg/minute may be necessary.
    • Epinephrine Hydrochloride Solution for injection; Adults: 0.05 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 ^c115
    • 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 ^c116
    • 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 ^c117
      • 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 ^c118
      • 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 ^c119
      • 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 ^c120
      • Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 mg IV every 6 hours or 200 mg/day continuous IV infusion. Taper dose once vasopressors are no longer required.
• Anticoagulants
  • Enoxaparin ^c121
    • 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.
• Sedatives (for mechanically ventilated patients)
  • Dexmedetomidine ^c122
    • 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 ^c123
    • 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 ^c124
    • 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 ^c125

WHO,^r8NIH,^r4 and Surviving Sepsis Campaign^r9 provide specific guidance for oxygenation, ventilation, and fluid management in COVID-19

• Patients with severe respiratory distress, obstructed or absent breathing, central cyanosis, shock, seizures, or coma require aggressive airway management (which may include intubation) and oxygen ^c126d5
  • Assess severity of respiratory distress using the PaO₂/FIO₂ ratio; some guidelines and protocols use this ratio to direct management of oxygenation and ventilation
    • Mild acute respiratory distress syndrome: 300 mm Hg or less, but greater than 200 mm Hg
    • Moderate acute respiratory distress syndrome: 200 mm Hg or less, but greater than 100 mm Hg
    • Severe acute respiratory distress syndrome: 100 mm Hg or less
• Oxygenation and ventilation ^c127c128
  • Begin supplemental oxygen therapy when oxygen saturation falls below 90% to 92% ^r64
  • Nasal cannula at 5 L/minute or face mask with reservoir bag at 10 to 15 L/minute ^r8c129
    • Titrate to reach SpO₂ of 94% or more initially
    • 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 oxygen or noninvasive ventilation has been used to achieve adequate oxygenation in some patients ^r81c130c131
    • High-flow nasal oxygen is recommended by Surviving Sepsis Campaign^r9 and NIH^r4 for patients with COVID-19 who develop hypoxemic respiratory failure despite conventional oxygen therapy; there is some evidence that it averts the need for intubation and mechanical ventilation. Noninvasive positive pressure ventilation may be used if high-flow nasal oxygen is not available
    • However, there is concern that these techniques may result in higher risk of aerosolization of the virus. Additionally, sudden deterioration may require emergent intubation, which is associated with more risk to both patient and provider. Therefore, some authorities reserve these options for settings in which airborne precautions can be taken and close monitoring provided ^r9
  • For patients with persistent hypoxemia but without other indications for intubation, awake prone positioning can be tried as a means to improve oxygenation; it is not recommended as a means of averting the need for mechanical ventilation in patients who otherwise require it (eg, respiratory distress, hemodynamic instability) ^r4c132
  • 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 (eg, PaO₂/FIO₂ ratio of less than 300 mm Hg)^r10c133
    • Recommended settings are tidal volume of 4 to 8 mL/kg (predicted body weight) and inspiratory pressures less than 30 cm H₂O
    • In children, tidal volumes of 5 to 8 mL/kg (predicted body weight) for preserved lung compliance and 3 to 6 mL/kg for poor compliance; inspiratory pressures should be less than 28 cm H₂O
    • Use of PEEP may be necessary in patients with acute respiratory distress syndrome (especially with PaO₂/FIO₂ ratio less than 200 mm Hg).^r10 Optimal regimen is not clearly defined, although guidelines^r8r64 suggest higher pressures (eg, more than 10 cm H₂O) rather than lower pressures. A protocol is available from ARDSNet^r7c134d5
    • 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 ^r4r64
    • For patients with moderate to severe acute respiratory distress syndrome, prone positioning for 12 to 16 hours/day is recommended ^c135
      • Lateral decubitus position for pregnant women
      • 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^r82 (eg, propofol, dexmedetomidine) and monitoring; shortages are occurring and the American Society of Health-System Pharmacists offers guidance on substitutions^r83
        • If neuromuscular blockade (eg, rocuronium) is needed (eg, for ventilator dyssynchrony), Surviving Sepsis Campaign guideline suggests intermittent boluses rather than continuous infusion ^r9c136c137
    • Mechanical ventilation may be required for a prolonged period, necessitating tracheostomy
  • Extracorporeal membrane oxygenation has been used^r15 in severely ill patients, and it can be considered if resources and expertise are available ^c138
• 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 ^r84
  • In patients with shock:
    • Administration of crystalloids is recommended (preferably buffered/balanced; eg, lactated Ringer solution); solutions such as hydroxyethyl starches, gelatins, dextrans, and albumin are not recommended according to the Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19. WHO^r8 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^r64 (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)

Comorbidities

• Severe COVID-19 has been associated with chronic conditions such as diabetes, hypertension, and other cardiovascular conditions; existing published guidance on COVID-19 management does not address issues specific to these comorbidities ^{r15r25c140c141}
• Owing to the role of the ACE2 receptor in the pathogenesis of COVID-19, controversy has arisen over the positive or negative effects that ACE inhibitors and angiotensin receptor blockers may have on the disease. A joint statement by the American College of Cardiology, American Heart Association, and Heart Failure Society of America recommends that persons who are currently taking these medications for appropriate indications should continue to do so ^r85
  • Several analyses of data from large numbers of patients with COVID-19 have shown no association between ACE inhibitors or angiotensin receptor blockers and either acquisition of COVID-19 or severity of infection ^r86r87r88
  • A prospective cohort study based on routinely collected data from more than 8 million persons enrolled in general practices in England identified more than 19,000 persons with COVID-19. Use of ACE inhibitors or angiotensin receptor blockers was associated with reduced risk of COVID-19 disease and was not associated with increased risk of requiring intensive care. The reduction in risk was less for Black people of Caribbean and African descent ^r89

Special populations

• American College of Rheumatology has issued guidance pertaining to children with severe COVID-19 and hyperinflammation. It recommends that immunomodulatory therapy be considered in children with COVID-19 and acute respiratory distress syndrome; shock or cardiac dysfunction; elevated levels of L-lactate dehydrogenase, D-dimer, interleukin-6, interleukin-2 receptor, and/or ferritin; or low albumin level, low platelet count, and/or low lymphocyte count ^r90d6
  • IV immunoglobulin is considered first line therapy; glucocorticoids should be used adjunctively in patients with severe disease. Anakinra may be considered in patients whose condition does not respond to these agents