Elsevier Logo

ThisiscontentfromClinicalKey

Want more answers?

Sign up for your free ClinicalKey trial today!  Your first step in getting the right answers when you need them. ClinicalKey is a clinical knowledge solution designed to help healthcare professionals and students find the right answers by providing in-depth, evidence-based knowledge – all from one resource.

Dec.01.2021

COVID-19 Critical Care

Synopsis

Key Points

  • COVID-19 (coronavirus disease 2019) is a respiratory tract infection due to a novel coronavirus, SARS-CoV-2; global pandemic is ongoing
  • About 5% of diagnosed cases require critical care to manage severe manifestations and complications.r1 Among patients with COVID-19 who are critically ill, mortality rates of 39% to 72% are reportedr1
  • Remdesivir is the only FDA-approved antiviral drugr2 specifically for treatment of COVID-19. Dexamethasone and immunomodulators are also recommended
  • Intensive supportive care remains the cornerstone of care in critically ill patients; it includes oxygenation and ventilation strategies, hemodynamic control, conservative fluid administration, and prevention of complications such as thromboembolic events
  • In patients with increasing hypoxemia, high-flow nasal oxygen or noninvasive ventilation are recommended or suggested but should not delay intubation in those with indications for mechanical ventilation r3r4r5r6
  • Pharmacologic support may be necessary in patients with shock whose hemodynamic parameters do not respond to fluids and oxygen; most guidelines favor norepinephrine as the initial agent for adults, and epinephrine in children r3r4r6
  • The most common complications are acute respiratory distress syndrome, shock, acute cardiac injury, acute kidney dysfunction, and thrombotic events (both venous and arterial) r3
  • In the critical care setting, infection control strategies are essential to prevent infection of staff and other patients, with most guidelines recommending standard, contact, and airborne precautions

Urgent Action

  • Patients with respiratory distress require prompt administration of supplemental oxygen; patients with respiratory failure require intubation and mechanical ventilation
  • Patients in shock require urgent fluid resuscitation and administration of empiric antimicrobial therapy to cover possible bacterial pathogens and/or influenza

Pitfalls

  • Knowledge of this disease is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to our understanding and to clinical management

Terminology

Clinical Clarification

  • COVID-19 (coronavirus disease 2019) is a respiratory tract infection with a newly recognized coronavirus; it spread rapidly from the point of origin in China, and was officially declared by WHO to be a pandemic on March 11, 2020 r7d1d1d1d1d1d1d1d1
  • Illness ranges in severity from asymptomatic or mild to severe; about 5% of diagnosed cases require critical care to manage severe manifestations and complications, including acute respiratory distress syndrome, myocardial dysfunction, and shock r1
  • Most patients with severe COVID-19 seem to have a bimodal illness, where there is initial improvement before severe worsening with severe or critical illness. This may be related to the immunologic role in the sepsis seen with COVID-19
  • Among ICU patients with COVID-19, mortality rates of 39% to 72% have been reportedr1
  • Knowledge of this disease is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to our understanding and to clinical management

Classification

  • Pathogen is a betacoronavirus,r8 similar to the agents of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) r8
    • Classified as a member of the species Severe acute respiratory syndrome–related coronavirusr9r10
    • Designated as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); earlier provisional name was 2019-nCoV (2019 novel coronavirus) r9r10
  • Variants
    • In late 2020 and early 2021, variants with potential impact on clinical disease were recognized. CDC classifies them as variant being monitored, variant of interest, variant of concern, or variant of high consequence, depending on transmission, severity, and treatment r11
      • Classification is based on potential for increased transmissibility, greater severity of disease, reduction in protective effect of antibodies generated by previous disease or vaccination, reduced efficacy of available treatments or public health countermeasures, or reduced sensitivity of testing modalities
      • Variants of concern
        • Delta (B.1.617.2 and AY lineages): first detected in India; characterized by increased transmissibility and possibly by reduced neutralization by some monoclonal antibody treatments and postvaccine serum; unclear whether associated with more severe disease
        • Omicron (B.1.1.529): first detected in South Africa; classified as variant of concern by WHO; studies are underway regarding effects on vaccine efficacy r12r13
      • Variants being monitored
        • Primary examples below; consult CDC website for more r11
          • Alpha (B.1.1.7 and Q lineages): appears to have emerged in the United Kingdom; thought to be more easily transmitted and possibly associated with more severe disease
          • Beta (B.1.351 and descendent lineages): first noted in South Africa; certain vaccines may be modestly less effective (e.g. Janssen)
          • Gamma (P.1 and descendent lineages): seems to have originated in Brazil; may mitigate protective effect of antibodies to the original strain
          • Epsilon (B.1.427 and B.1.429): first detected in California; slight increase in transmissibility, significant decrease in neutralization effect of monoclonal antibody treatments, and moderate decrease in neutralization effect of convalescent serum
      • CDC COVID Data Tracker maintains information about geographical distribution of variants in the United States and globally; at this time, more than 99% of circulating virus in the United States is Delta variant r14

Diagnosis

Clinical Presentation

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 r15r16
    • Patients may or may not report close contact with an infected person
  • 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 r17
    • 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 r17r18r19
    • Fever is often not present at presentation, even in hospitalized patients, and may be very mild (less than 38 °C) r17
    • Myalgia, headache, and fatigue are common; fatigue may be profound r17r18
    • Upper respiratory tract symptoms (eg, rhinorrhea, sneezing, sore throat) may be present in up to 20% of symptomatic infections r18
    • Gastrointestinal symptoms (eg, abdominal pain, nausea, vomiting, diarrhea) are present in 10% to 20% of symptomatic infections r17r18
    • Alteration in smell and/or taste is less common but highly suggestive r18r20r21
  • 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 r22
  • Patients with moderate to severe disease often complain of dyspnea;r17 however, it has been recognized that many patients with severe hypoxemia due to COVID-19 do not perceive dyspnear23r24r18
    • Hemoptysis has been reported in a small percentage of patients r17
    • Pleuritic chest pain has been reported r16
  • 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 r25
      • 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 r26

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 r23r24c7
    • Oxygenation should be assessed promptly by peripheral saturation (eg, pulse oximetryr4); 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 r27c8
  • 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 r17r22c9
  • Conjunctival secretions, injection, and chemosis have been reported r28
  • 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 r29c10c11
  • Other reported neurologic findings in severe disease include hyperactive deep tendon reflexes, ankle clonus, and positive Babinski sign r30c12c13c14
  • Patients may be agitated, confused, or poorly responsive r30c15c16
  • A variety of skin changes have been described, including purpurar32 and petechiaer33; vesicularr34 and nonspecific erythematous exanthemsr35 typical of viral infections; and acral lesions 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 r31c17c18c19
  • Hypotension, tachycardia, and cool/clammy extremities suggest shock c20c21c22
    • In children, shock manifests as hypotension plus 2 or more of the following criteria: r4
      • 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 and Risk Factors

Causes

  • Infection due to SARS-CoV-2 c33
    • Person to person transmission has been documentedr16 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 r36
      • Highest risk 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) r36
      • Infection through contact with infected surfaces and fomites is possible but is not the primary mode of transmission r37
        • 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) may acquire SARS-CoV-2 from humans, and cases of animal to human transmission have been reported, but the extent to which humans may acquire infection from animals is unclear r38c34
    • There is currently no evidence for transmission via food or water

Risk factors and/or associations

Age
  • Age distribution of cases has shifted substantially during the pandemic, as vaccinations and public health responses have changed
    • During the first peak in the United States (April 2020), the incident case rate per 100,000 population was highest in the age groups of 75 years or older, 50 to 64 years, 40 to 49 years, and 65 to 74 years r39
    • In January 2021, the incident case rate per 100,000 population was highest in the age groups of 18 to 29 years, 30 to 39 years, 40 to 49 years, and 16 to 17 years r39
    • By August 2021, the incident case rate per 100,000 population was highest in the age groups of 16 to 17 years, 12 to 15 years, 30 to 39 years, and 18 to 29 years r39
    • Incident case rate for 0 to 4 years in August 2021 (155 per 100,000) was higher than that of 75 years or older in April 2020 (122 per 100,000) r39
  • All age groups appear susceptible to COVID-19, but the risk of severe disease and death increases with age r40
    • In data from China early in the pandemic, case fatality rates were 14.8% for patients aged 80 years or older, 8% for those aged 70 to 79 years, and 3.6% for those aged 60 to 69 years r1
    • In data from the United States early in the pandemic, case fatality rates were 10% to 27% among patients aged 85 years or older, 3% to 11% for those aged 65 to 84 years, and 1% to 3% for those aged 55 to 64 years r40
    • Despite the change in case rates in the United States, those aged 75 years or older, 65 to 74 years, and 50 to 64 years have remained the age groups with the most deaths per 100,000 population throughout the pandemic r39
    • Percentage of total mortality in the United States by age group: r39
      • 0 to 39 years: 2%
      • 40 to 49 years: 3.4%
      • 50 to 64 years: 16%
      • 65 to 74 years: 21.7%
      • 75 to 84 years: 26.98%
      • 85 years or older: 29.9%
Sex
  • Overall, where sex or gender data are available, it appears that females are more often affected, but disease is more severe in males r39
    • Male sex may be a risk factor for severe disease; in a series of 5700 hospitalized patients with COVID-19, 60.3% were male; among ICU patients, 66.5% were male r41c35
Ethnicity/race
  • In the United States, persons in racial and ethnic minority groups, including Black, Hispanic, and Native populations, have been disproportionately affected by COVID-19, including increased risk of infection, severe disease, and death; this risk is mediated through complex inequities and not genetic or biologic factors r42
Other risk factors/associations
  • Various underlying medical conditions have been associated with increased risk for severe disease, and many conditions are under investigation r43
  • Conditions which have been associated with higher risk for severe disease (based on systematic review or meta-analysis): r43
    • Cerebrovascular disease
    • Chronic kidney disease
    • Chronic lung diseases: interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchopulmonary dysplasia, bronchiectasis, and chronic obstructive pulmonary disease
    • Chronic liver diseases: cirrhosis, nonalcoholic fatty liver disease, alcoholic liver disease, and autoimmune hepatitis
    • Diabetes mellitus, type 1 and type 2
    • Malignancy
    • Mental health disorders: mood disorders including depression; schizophrenia spectrum disorders
    • Obesity (BMI of 30 kg/m² or higher)
    • Pregnancy and recent pregnancy
    • Serious cardiac conditions (eg, heart failure, coronary artery disease, cardiomyopathy)
    • Smoking, current and former
    • Tuberculosis
  • Conditions which might be associated with higher risk for severe disease (based on observational data, or small sample size): r43
    • Children with medically complex conditions (eg, neurologic, metabolic, genetic, cardiac)
    • Down syndrome
    • HIV disease
    • Neurologic dysfunction, including dementia
    • Overweight (BMI more than 25 kg/m² but less than 30 kg/m²)
    • Sickle cell disease
    • Solid organ or blood cell transplant
    • Substance use disorder
    • Immunodeficiency due to use of corticosteroids or other agents with immunosuppressive effects
    • Cystic fibrosis
    • Thalassemia
  • Conditions which may be associated with higher risk for severe disease (based on mixed evidence): r43
    • Asthma
    • Hypertension
    • Immunodeficiency (undifferentiated)
  • However, studies indicate that many people who develop severe disease (hospitalization and/or death) have no comorbidities r43
  • Residents of nursing homes and long-term care facilities are at high risk for acquiring infection and for severe disease, probably owing to a combination of heightened transmission in a close-quarters community and prevalence of compromised health status r44
  • In areas where vaccines are widely available, being unvaccinated (compared with being fully vaccinated) confers substantially higher risk for infection, hospitalization, and death r26

Diagnostic Procedures

Primary diagnostic tools

  • Polymerase chain reaction tests are the standard for diagnosis; antigen testingr48 is also widely available in the United States. Public health authorities may assist in testing in some areas. Attempts to culture the virus are not recommended. Serologic testsr49 are not recommended for diagnostic purposes in most circumstances r45r46r47
  • CDCr47 and WHOr4 both recommend diagnostic testing in everyone with compatible symptoms, regardless of vaccination status, but they differ slightly on screening
    • WHO r50r51
      • All individuals who meet the suspected or probable case definition should be tested; testing of asymptomatic individuals is recommended to be limited to contacts of confirmed or probable COVID-19 and health care workers, including long-term care workers, who are frequently exposed; widespread screening of asymptomatic individuals is not currently recommended
        • Case definitions: suspected case r51
          • Acute onset of fever and cough or acute onset of any 3 or more of a specified list of symptoms (ie, fever, cough, general weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental status) plus 1 of the following:
            • Living or working in a setting with high risk of transmission of SARS-CoV-2 (eg, closed residential facilities, refugee camps) at any time during the 14 days preceding symptom onset
            • A history of travel to or residence in an area reporting local transmission of COVID-19 during the 14 days preceding symptom onset
            • Working in any health care setting at any time during the 14 days preceding symptom onset
          • Onset within the past 10 days of a severe acute respiratory tract infection requiring hospital admission without an alternative etiologic diagnosis
          • Asymptomatic person with positive antigen test result (but no epidemiologic link); recommend polymerase chain reaction for confirmation
        • Case definitions: probable case r51
          • Someone with the clinical symptoms above, or who died of an unexplained respiratory illness, who is a contact of a confirmed or probable case or is part of a cluster
          • Someone with acute lack of taste or smell with no alternative diagnosis
          • Someone with a suspected case who also has chest imaging suggestive of COVID-19
            • Characteristic chest radiograph findings include hazy opacities with peripheral and lower lung distribution; CT findings include multiple bilateral ground-glass opacities with peripheral and lower lung distribution; lung ultrasonography findings include thickened pleural lines, B lines, and consolidative patterns
      • In situations where it is not possible to test all who meet the case definitions, WHO recommends prioritizing the following: r50
        • Those at high risk for severe disease
        • Health care workers
        • Inpatients in health facilities
        • First symptomatic persons in closed space environment (eg, schools, long-term care facilities, hospitals, prisons), representing possible index cases in a suspected outbreak
    • CDC r47
      • Recommends that all individuals with signs or symptoms, or with known or suspected exposure, be offered diagnostic testing; routine testing to end isolation is no longer recommended but may be considered in immunocompromised patients, who may still be infectious longer than 20 days from symptom onset
        • Polymerase chain reaction and antigen tests both have a role in diagnosis, with advantages and disadvantages for each (see Table 1 of CDC recommendationsr47)
          • For a person with symptoms, a positive result on polymerase chain reaction or antigen test indicates that the person has COVID-19; a negative antigen result needs to be confirmed with polymerase chain reaction test
          • For a person with no symptoms and no known exposure, a negative result on polymerase chain reaction or antigen test indicates that the person does not have current infection
          • For a person with exposure but no symptoms, a negative result suggests no current infection but the test may need to be repeated or confirmed with additional testing (eg, in cases of high probability of infection or ongoing exposure)
  • Specimens from upper or lower respiratory tract are recommended for viral testing.r52 Care must be taken to minimize risks associated with aerosolization during specimen collection
    • 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 r52
      • 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. Nasopharyngeal or nasal washings or aspirates are also acceptable. 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 mucous 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 of nonbacteriostatic saline) are also acceptable
        • 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
        • A deep cough sputum specimen (collected after mouth rinse) is also acceptable
          • 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 r53
      • Favor nasopharyngeal, nasal, or midturbinate specimens, saliva specimen, or combined anterior nasal/oropharyngeal swab over oropharyngeal swab alone for SARS-CoV-2 RNA testing
      • 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 r54
  • 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 or adults (MIS-C or MIS-A); in other situations in which retrospective confirmation of disease is indicated) r49
  • 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 r4d2d2d2d2d2d2d2d2
    • Coinfections have been reported, but the frequency is unknown r55r56
    • 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 r57
    • 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 r58r59
      • 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 r19
    • 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 at the time; and the public health goal of detecting and isolating all infected persons r60
      • 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 r61c36c37c38
    • 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 worsenr60r19c39c40
      • 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) r60
  • 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) r4d3d3d3d3d3d3d3d3
  • 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. r3r47
    • 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 r3r53
  • 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 r48
      • False-positive results are uncommon, but occur, and are more likely in a low-prevalence setting
      • False negatives 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 the CDC. r48
    • 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% r62
      • 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 multisystem inflammatory syndrome in children or adults (MIS-C or MIS-A); 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 on patients of varying severity of illness: r16r17r19
      • Abnormalities of blood counts are common: leukopenia, relative lymphopenia, anemia, thrombocytopenia, and thrombocytosis r16r17r19
      • 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, or elevated fibrinogen r16r17r19r63
      • 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 r17
      • 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 r64
        • Some experts caution against measuring these biomarkers in the absence of suggestive clinical findings,r64 whereas others note the possibility that elevations suggest noncoronary myocardial involvement that may benefit from early use of vasopressors and inotropesr3
    • Information from patients with severe or critical illness similarly shows common patterns r25
      • A majority of patients showed elevated C-reactive protein and D-dimer levels (83.5% and 73.3%, respectively)
      • Many patients had white blood cell count abnormalities; most common were lymphopenia (70.3%), leukocytosis (21.7%) and leukopenia (18.2%) but 56.9% had normal leukocyte counts
      • Other common findings were liver function test abnormalities (39.8%), elevated procalcitonin (36.6%) and thrombocytopenia (19.0%)
        • Elevated levels of procalcitonin above normal were associated with significantly higher risk of severe infection r65
      • Lactate level of 2 mmol/L or higher suggests presence of septic shock r4

Imaging

  • Chest imaging (eg, plain radiography, CT, ultrasonography) has been found to be sensitive but not highly specific to COVID-19 r66
  • 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 r8r16r17r19r67c42
  • CT appears to be more sensitiver68r66r60 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19r69
    • 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 r70
  • 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 r3r71

Differential Diagnosis

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 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
      • Mitigation measures for COVID-19 may alter the timing and amount of circulating respiratory viruses, including influenza r57
    • 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 r58r59
      • CDC recommends nucleic acid detection over antigen testing for both pathogens, either by 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 a number of common viral respiratory pathogens such as respiratory syncytial virus, adenovirus, and others
    • As with influenza, timing and amount of circulating respiratory viruses may be altered by COVID-19 mitigation measures r57
  • 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

Treatment

Goals

  • Ensure adequate oxygenation and hemodynamic support during acute phase of illness
  • Prevent complications where possible (eg, thromboses); monitor for and treat unavoidable complications (eg, myocardial dysfunction)

Disposition

Admission criteria

Criteria for ICU admission
  • NIH treatment guidelines describe the spectrum of clinical illness as asymptomatic/presymptomatic, mild, moderate, severe, or critical r59
    • Severe illness is defined as SpO₂ less than 94% (room air, sea level), PaO₂/FIO₂ ratio less than 300 mm Hg, respiratory rate more than 30 breaths per minute, or lung infiltrates more than 50%
      • Rapid clinical deterioration is possible; thus, admission to ICU may be indicated if needed for close monitoring or in patients with risk factors for more severe disease, where resources allow
    • Critical illness is defined by presence of respiratory failure, acute respiratory distress syndrome, sepsis, shock, cardiac dysfunction, or any other conditions typically requiring intensive care
  • WHO guidelines describe the spectrum of clinical illness as nonsevere, severe, or critical r4
    • Severe illness is defined by presence of any of the following:
      • Oxygen saturation less than 90% (room air)
      • Respiratory rate (breaths per minute) as follows:
        • More than 30 in adults, adolescents, and children older than 5 years
        • 40 or more in children aged 1 to 5 years
        • 50 or more in infants aged 2 to 11 months
        • 60 or more in infants or neonates younger than 2 months
      • Signs of severe respiratory distress (eg, accessory muscle use, inability to complete full sentences, and, in children, very severe chest wall retractions, grunting, central cyanosis, or presence of any other pediatric danger signs)
    • Critical illness is defined by the criteria for acute respiratory distress syndrome, sepsis, septic shock, or other conditions that would normally require the provision of life-sustaining therapies such as mechanical ventilation (invasive or noninvasive) or vasopressor therapy
    • WHO suggests use of clinical judgment to determine hospital or ICU admission, rather than clinical prediction models for prognosis, which have little evidence for utility in COVID-19 as yet

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

Treatment Options

Current standard treatment options include infection control measures, routine supportive care, and medications including antiviral, monoclonal antibody, immunomodulator, and corticosteroid drugs

  • Many other drugs (of several classes) have been or still are being used under clinical trial and compassionate use protocols based on in vitro activity (against this or related viruses) and clinical experience r72
    • Information on therapeutic trials and expanded access is available at ClinicalTrials.gov and WHO International Clinical Trials Registry Platform r72r73
    • American Society of Health-System Pharmacists has summarized evidence for many therapeutics which have been tried in COVID-19 treatment r74
  • A strategy has emerged by which drugs are selected according to the mechanism of action most likely to be effective against the dominant pathophysiology at various stages in the disease process. Thus, antivirals and monoclonal antibodies directed at viral components are most effective when used early in the course of infection (to prevent cell entry and viral replication); antiinflammatory drugs (eg, dexamethasone) and immunomodulators are of most benefit during the hyperinflammatory response in later phases of severe disease r59
  • Recommendations below summarize major treatment guidelines from NIH, WHO, Surviving Sepsis Campaign, Infectious Diseases Society of America, and American Society of Hematology r4r6r59r75r76

Infection control measures include isolation, source control, and transmission precautions r77

  • Individuals with COVID-19 in a health care setting should wear a face mask (or, if supplies are critically low, at least a cloth face cover) to reduce droplet spread, should be placed in a single-person closed room pending further evaluation and disposition decisions, and should have standard precautions, contact precautions, and droplet or airborne precautions as resources allow
    • Health care personnel should wear N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection r77
      • Some guidelines suggest that a medical face mask, rather than N95 respirator, is sufficient when not performing aerosol-generating procedures r4
    • If available, the patient room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)

Initiate supportive care for hospitalized patients, including oxygenation and ventilation, conservative fluid support, and measures to prevent common complications (eg, pressure injury, stress ulceration, secondary infection) r4

  • Appropriate testing (eg, blood cultures in those with severe or critical illness) and treatment for other pathogens (eg, influenza, malaria) should be administered in accordance with the severity of clinical disease, site of acquisition (hospital or community), epidemiologic risk factors, and local antimicrobial susceptibility patterns r4
    • Evidence does not support routine use of antibiotics for all patients with COVID-19, especially in those with low suspicion of bacterial infection. If empiric coverage is begun, use antibiotic de-escalation protocols (eg, daily reassessment of need for antibiotics) when patient has been stabilized and there is no evidence of bacterial coinfection r4r59
  • Coagulopathy is common and both venous and arterial thromboembolism have been reported in patients with COVID-19. Guidelines recommend or suggest use of prophylactic dose anticoagulation r4r6r59r78r79
    • Where specified, low-molecular-weight heparin is preferred over unfractionated heparin r6
    • Guidelines also recommend monitoring and evaluation for thromboembolic disease when clinically indicated, but they do not suggest universal screening r4r59
    • American Society of Hematology suggests prophylactic-intensity over intermediate-intensity in critical illness, and suggests prophylactic-intensity over therapeutic-intensity in hospitalized patients. Evidence from ongoing trials is expected to inform guidance on prophylactic-intensity versus therapeutic-intensity in critical illness, and on prophylactic-intensity versus intermediate-intensity in hospitalized patients r78r79
    • NIH guidelines also recommend continuation of anticoagulation in hospital for those already on therapeutic doses for another indication r59
    • NIH and American Society of Hematology recommend against continuing prophylaxis after discharge from hospital for those without venous thromboembolism r59r80
      • Extended prophylaxis against venous thromboembolism after hospital discharge can be considered for patients with indications similar to those in patients without COVID-19 who qualify
    • Therapeutic doses of anticoagulation should be used for patients with documented venous or arterial thrombosis, or for those with high clinical suspicion of thromboembolic disease when diagnostic imaging is not possible r59r78
    • Patients on extracorporeal membrane oxygenation or continuous renal replacement therapy should have the same anticoagulation as patients on those therapies without COVID-19 r59
  • Management of septic shock includes use of vasopressors if fluid administration does not restore adequate perfusion. Surviving Sepsis Campaign,r6NIH,r59 and WHOr4 treatment guidelines provide guidance specific to treatment of shock in patients with COVID-19 d3d3d3d3d3d3d3d3
    • WHO definitions for septic shock: r4
      • Adults: suspected or confirmed infection; vasopressors are needed to maintain mean arterial pressure at or above 65 mm Hg; and lactate level is 2 mmol/L or more, in the absence of hypovolemia
      • Children: hypotension (systolic blood pressure less than the 5th percentile or more than 2 standard deviations below normal for age), or 2 or more of the following: altered mental status; bradycardia or tachycardia (heart rate less than 90 or more than 160 beats per minute in infants, or less than 70 or more than 150 beats per minute in children); prolonged capillary refill more than 2 seconds or weak pulses; tachypnea; oliguria; hypothermia or hyperthermia; increased lactate level; or skin that is mottled, cold, or with petechial or purpuric rash
    • Conservative fluid resuscitation is advised over liberal fluid strategy, owing to risk of volume overload
      • Crystalloids are recommended for fluid resuscitation; Surviving Sepsis and NIH guidelines recommend balanced crystalloids over unbalanced crystalloids r6r59
      • WHO, NIH, and Surviving Sepsis guidelines recommend against starches or gelatins
      • Surviving Sepsis and NIH guidelines recommend against the use of albumin (weak or moderate recommendations) r6r59
        • WHO does not offer guidance specific to albumin in recommending against hypotonic crystalloids, starches, or gelatins but mentions that the weak recommendation for the use of albumin in those receiving large volumes of crystalloids in the Surviving Sepsis general guideline (non–COVID-19–specific guideline) is based on low-quality evidence r4r81
    • In adults for whom vasopressors are needed, begin with norepinephrine; epinephrine or vasopressin is preferred as second line over dopamine if norepinephrine is unavailable r4r6r59
      • Hemodynamic goal: mean arterial pressure of 60 to 65 mm Hg (NIH and Surviving Sepsis guidelines); WHO suggests mean arterial pressure of 65 mm Hg or more r4r6r59
      • In patients without adequate response to usual doses of norepinephrine, Surviving Sepsis guideline recommends adding vasopressin rather than further titrating norepinephrine r6
    • For adults with COVID-19, refractory shock despite fluid and norepinephrine, and evidence of cardiac dysfunction, Surviving Sepsis and NIH guidelines recommend adding dobutamine rather than further titrating norepinephrine r6
    • For adults with refractory septic shock, NIH guideline recommends addition of low-dose corticosteroids if corticosteroids are not already being administered for other indications r59
    • In children, epinephrine is considered the first line agent, and norepinephrine may be added if necessary r4

Corticosteroid therapy is suggested or recommended for hospitalized patients with an oxygen requirement r6r59r75r76

  • For patients with critical illness, guidelines recommend or strongly recommend use of corticosteroids; guidelines that specify a corticosteroid recommend dexamethasone (when available) over alternatives
  • For patients with severe illness, guidelines suggest or recommend use of corticosteroids, and those which specify a corticosteroid suggest dexamethasone
  • In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used

Immunomodulators are being used for mitigation of cytokine release syndrome believed to be a factor in severe acute respiratory distress syndrome and shock in COVID-19 (eg, monoclonal antibodies against interleukin-6 receptors, such as tocilizumabr82 and sarilumabr83; Janus kinase inhibitors such as baricitinibr84 and tofacitinibr85)

  • Surviving Sepsis guideline does not address immunomodulators; WHO guidelines do not address Janus kinase inhibitors r4r6r76
  • Baricitinib (Janus kinase inhibitor)
    • Baricitinib, currently approved for use in refractory rheumatoid arthritis owing to its antiinflammatory effect, has received emergency use authorization for treatment of adult and pediatric patients (aged 2 years or older) on oxygen supplementation (including mechanical ventilation or extracorporeal membrane oxygenation) r86r87
      • FDA reviewed data from the ACTT-2 trial (Adaptive COVID-19 Treatment Trial 2), which compared remdesivir plus baricitinib (515 patients) against remdesivir plus placebo (518 patients) in patients with documented SARS-CoV-2 infection and either pulmonary infiltrates, O₂ saturation less than 94%, or requirement for some degree of oxygen supplementation. Patients who received baricitinib were more likely to have better clinical status (based on an 8-point score) at day 15 than those who did not. Median time to recovery was 7 days in the baricitinib group versus 8 days in the placebo group. The odds of dying or progressing to noninvasive/high-flow oxygen or invasive ventilation were significantly lower for patients in the baricitinib group r87
      • Additional data from COV-BARRIER trial (studying efficacy and safety of baricitinib for hospitalized adults with COVID-19) indicated that baricitinib was associated with reduced mortality but not a reduction in the frequency of disease progression r88
      • NIH guidelines recommend use of baricitinib (or tocilizumab) with dexamethasone, or with remdesivir and dexamethasone, in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) r59
        • In patients receiving just supplemental oxygen, the guideline panel found insufficient evidence to determine whether adding baricitinib to dexamethasone is of benefit; they recommend baricitinib plus remdesivir for such patients when corticosteroids cannot be used
        • Guideline recommends against giving tocilizumab or other interleukin-6 inhibitors to patients receiving baricitinib
        • There is insufficient evidence to recommend baricitinib over tocilizumab or vice versa
      • Infectious Diseases Society of America guideline suggests use of baricitinib in hospitalized patients with severe COVID-19 with elevated inflammatory markers (along with remdesivir and corticosteroids), and it suggests use of baricitinib with remdesivir for those with severe COVID-19 who cannot receive corticosteroids r75
        • Patients receiving baricitinib should not receive tocilizumab or other interleukin-6 inhibitors
        • Benefits of baricitinib in patients requiring mechanical ventilation are uncertain, but limited data suggest a mortality benefit even among those requiring mechanical ventilation
  • Tofacitinib (Janus kinase inhibitor)
    • NIH guideline recommends use of tofacitinib when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers), along with dexamethasone or dexamethasone plus remdesivir r59
      • In the STOP-COVID trial (Study of Tofacitinib in Hospitalized Patients with COVID-19 Pneumonia), hospitalized patients treated with tofacitinib had a lower risk of death or respiratory failure through day 28 than those on placebo, but overall the evidence for tofacitinib is less extensive than that for baricitinib, to date r59r89
    • Infectious Diseases Society of America guideline suggests use of tofacitinib in hospitalized patients with severe COVID-19 who do not require mechanical ventilation (noninvasive or invasive), along with remdesivir and corticosteroids (unless contraindicated) r75
      • Patients should also receive at least prophylactic dose of anticoagulant
      • Patients receiving tofacitinib should not receive tocilizumab or other interleukin-6 inhibitors
  • Tocilizumab (monoclonal interleukin-6 receptor blocker)
    • WHO guideline summarizes evidence for use of interleukin-6 inhibitors (tocilizumab or sarilumab) from up to 27 studies for 6 outcomes; overall, interleukin-6 inhibitors reduce mortality, decrease need for mechanical ventilation, and may decrease decrease duration of mechanical ventilation and hospitalization, with little evidence for adverse events leading to discontinuation of drug, including secondary bacterial infections r76
      • There is insufficient evidence to recommend tocilizumab over sarilumab or vice versa
      • A review of data from 5 randomized controlled trials comparing tocilizumab to usual care (with or without placebo) did not show a 28-day mortality benefit, but it did show a lower relative risk of clinical deterioration (ie, ICU admission, mechanical ventilation, death), although evidence was of low certainty r75
      • REMAP-CAP and RECOVERY trials both indicate a mortality benefit for tocilizumab among patients who experienced rapid respiratory decompensation and were recently admitted to ICU, and the RECOVERY trial showed benefit in those who require high-flow oxygen or noninvasive ventilation r90r91
    • NIH guidelines recommend use of tocilizumab in 2 situations, as follows: r59
      • Use tocilizumab (or baricitinib) with dexamethasone alone or with remdesivir and dexamethasone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers)
        • There is insufficient evidence to recommend tocilizumab over baricitinib or vice versa
      • Use tocilizumab with dexamethasone within 24 hours of admission to ICU for patients requiring mechanical ventilation or extracorporeal membrane oxygenation
      • In patients receiving supplemental oxygen, the guideline panel found insufficient evidence to determine whether adding tocilizumab to dexamethasone is of benefit; they recommend tocilizumab plus remdesivir for such patients when corticosteroids cannot be used
      • Guideline recommends against giving baricitinib to patients on tocilizumab
    • In patients admitted to hospital with COVID-19, Infectious Diseases Society of America guideline suggests tocilizumab in addition to standard care (steroids) for patients with progressive severe or critical COVID-19 who have elevated levels of markers of systemic inflammation r75
    • WHO guidelines recommend use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids r76
  • Sarilumab (monoclonal interleukin-6 receptor blocker)
    • NIH guidelines recommend use of sarilumab only when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers), along with dexamethasone or dexamethasone plus remdesivir r59
    • WHO guidelines recommend use of sarilumab (or tocilizumab) for patients with severe or critical COVID-19, along with corticosteroids r76
    • REMAP-CAP trial found that sarilumab plus dexamethasone was noninferior to tocilizumab plus dexamethasone, but the evidence for the use of tocilizumab is more extensive r59r91

Antiviral agent remdesivir is FDA-approved specifically for treatmentr2 of COVID-19 in hospitalized adults and children aged 12 years or older weighing 40 kg or more. Emergency use authorization has been granted for the use of remdesivir for hospitalized children weighing 3.5 kg or more r2r92

  • For patients with critical illness, guidelines suggest against initiation of remdesivir, as the benefit of remdesivir has not been shown for patients requiring mechanical ventilation
    • If remdesivir has already been started and the patient worsens to require mechanical ventilation, NIH suggests completion of the course
  • For patients with severe illness requiring oxygen, guidelines from NIH, Infectious Diseases Society of America, and Surviving Sepsis suggest use of remdesivir; WHO suggests against use of remdesivir r6r59r75r76
    • Infectious Diseases Society of America suggests a 5-day course rather than a 10-day course; NIH suggests a 5-day course that may be extended to 10 days if there is no substantial clinical improvement by day 5; Surviving Sepsis makes no recommendation on duration of therapy

Monoclonal antibodies against SARS-CoV-2 spike protein

  • Emergency use authorizations exist for 3 monoclonal antibody products (bamlanivimab-etesevimabr93r94 in combination, casirivimab-imdevimabr95r96 in combination, and sotrovimabr97) for prevention of progression to severe disease, but there is currently no indication for use in those who are already hospitalized

Several medications with a mechanism of action which could potentially alter response to COVID-19 have been evaluated either for use in treatment and prevention, or for discontinuation to prevent harms r98

  • NIH guidelines recommend that patients taking ACE inhibitors, angiotensin receptor blockers, statin drugs, NSAIDs, corticosteroids (oral, inhaled, or intranasal), and acid suppressive drugs for underlying medical conditions should not discontinue these medications r59
  • In addition, none of the above classes of medications should be started for the purpose of treatment or prevention of COVID-19, except as noted above for corticosteroid treatment
  • Infectious Diseases Society of America guidelines similarly do not recommend initiating or discontinuing any of the above medications for treatment or prevention of COVID-19 r75

Several other potential treatments are not currently recommended under any guidelines, but continue to be studied

  • These include lopinavir-ritonavir and other HIV protease inhibitors, ivermectin, chloroquine, hydroxychloroquine, azithromycin, convalescent plasma, nitazoxanide, colchicine, fluvoxamine, famotidine, stem cells, immunomodulators and antivirals not mentioned above, and various vitamin supplements r59r75r76d1

Drug therapy

  • Antiviral agent
    • Remdesivir r92r99c46
      • 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 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 the following: (1) recommended with dexamethasone (with or without remdesivir) IF on noninvasive ventilation or high-flow oxygen AND there is evidence of clinical progression or increased markers of inflammation; (2) some Panel members support use in patients not yet requiring noninvasive ventilation or high-flow oxygen but show signs 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 (or equivalent corticosteroid) to treat recently hospitalized adults with rapid respiratory decompensation due to COVID-19 who meet the following criteria:1) 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) OR2) not 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 NIH 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 c49
      • IV dosage
        • Sarilumab Solution for injection; Adults: The NIH COVID-19 treatment guidelines recommend a single 400 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:1) admitted to the ICU within the prior 24 hours and require mechanical ventilation or high-flow nasal canula oxygen (greater than 0.4 FiO2/30 L/min) OR2) not in the ICU but have rapidly increasing oxygen needs requiring noninvasive mechanical ventilation or high-flow nasal canula AND have significantly increased markers of inflammationSarilumab 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 recently hospitalized adults 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; 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.
      • 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; 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.
  • Anticoagulants (therapeutic intensity for those with suspected or proven thromboembolism)
    • Enoxaparin
      • Enoxaparin Sodium (Porcine) Solution for injection; Infants 2 months and older†, Children†, and Adolescents†: Initially, 1 mg/kg/dose subcutaneously every 12 hours is recommended in clinical guidelines; adjust 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. Alternatively, higher doses have been recommended for younger children: 1.5 mg/kg/dose subcutaneously every 12 hours (infants 3 to 12 months) and 1.2 mg/kg/dose subcutaneously every 12 hours ( children 1 to 5 years).
      • Enoxaparin Sodium (Porcine) Solution for injection; Infants 2 months and older†, Children†, and Adolescents†: Initially, 1 mg/kg/dose subcutaneously every 12 hours is recommended in clinical guidelines; adjust 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. Alternatively, higher doses have been recommended for younger children: 1.5 mg/kg/dose subcutaneously every 12 hours (infants 3 to 12 months) and 1.2 mg/kg/dose subcutaneously every 12 hours ( children 1 to 5 years).
      • 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 within 3 days, but preferably on day 1. Give LMWH for at least 5 days and until target INR is reached.
    • 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; 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,r4NIH,r59 and Surviving Sepsis Campaignr6 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 r4c65
      • 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 r100c66c67
      • 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 r6r59
    • 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 r4
      • Given the potential for noninvasive ventilation techniques to aerosolize the virus, airborne precautions are recommended r4
    • 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 finds insufficient evidence to make a recommendation r59c68
      • 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 r6r59
        • 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 r4
      • 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 r6r59r76
      • 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 r4
      • 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) r4r6r59c70d5d5d5d5d5d5d5d5
      • For patients with moderate to severe acute respiratory distress syndrome on mechanical ventilation, prone positioning for 12 to 16 hours/day is recommended r4r6r59c71
        • Lateral decubitus position may be used for pregnant patients, especially in the third trimester r4
      • Sedation with or without neuromuscular blockade may be necessary for comfort and optimal ventilation; the Society of Critical Care Medicine offers guidance on appropriate agentsr101 (eg, propofol, dexmedetomidine) and monitoring; shortages may occur and the American Society of Health-System Pharmacists offers guidance on substitutionsr102
        • Guidelines suggests intermittent neuromuscular blockade as needed (eg, rocuronium) rather than continuous infusion r4r6r59c72c73
          • 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 r6r59
      • 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 r6r59
      • 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 usedr17 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 r4r6r59c74
      • 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 r103
    • In patients with shock:
      • Administration of crystalloids is recommended (preferably buffered/balanced, eg, lactated Ringer solution); WHOr4 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 Hgr6 (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 r59
      • 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
Procedures
Extracorporeal membrane oxygenation c75
General explanation
  • Heart-lung bypass is a technique in which blood is circulated from patient through bypass machine, where transmembrane exchange of oxygen and carbon dioxide occurs before blood is returned to patient; can also be used to support arterial blood pressure
Indication
  • Refractory hypoxemia with or without hemodynamic compromise despite standard supportive measures
  • May be helpful if resources and expertise are available r6
Contraindications
  • Neurologic impairment
  • Severe preexisting disease
Complications
  • Limb ischemia distal to vascular access catheters

Comorbidities

  • Severe COVID-19 has been associated with various underlying chronic conditions (eg, diabetes, hypertension) c76c77

Special populations

  • Pregnant patients
    • American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine have published guidelines for management of pregnant patients with COVID-19, and NIH guideline contains a summary of considerations for pregnant and breastfeeding patients r59r104r105
    • There may be an increased risk of ICU admission, mechanical ventilation, and death in pregnant patients compared with nonpregnant patients r104
    • COVID-19 in pregnancy may be associated with increased risk for complications such as preterm birth, stillbirth, and hypertensive disorders of pregnancy r104
    • 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 r59

Monitoring

  • Standard critical care monitoring, including oxygen saturation and hemodynamic measures, is appropriate c78c79
  • Patients who are undergoing a trial of high-flow oxygen or noninvasive ventilation require especially close attention pending sustained improvement or decision to intubate

Complications and Prognosis

Complications

  • Among ICU patients, many complications have been noted:
    • Acute respiratory distress syndrome (60% to 70%) r3c80d5d5d5d5d5d5d5d5
      • In representative studies of critically ill patients in the United States, 68% to 79% required mechanical ventilation, 8% to 15% required tracheostomy, and about 3% required extracorporeal membrane oxygenation r106r107
    • Shock (30%) r3c81d3d3d3d3d3d3d3d3
      • Need for vasopressors ranged from 26% to 66% in 2 hospital systems in the United States r106
    • Acute cardiac injury, including cardiomyopathy, arrhythmias, and sudden cardiac death c82c83d6d6d6d6d6d6d6d6
      • Myocardial injury (20% to 30%) and arrhythmias (44%) r3
    • Acute kidney injury (10% to 30%) r3c84d7d7d7d7d7d7d7d7
      • Between 9% and 31% of critically ill patients (without preexisting renal disease) required acute renal replacement therapy in US samples r106
    • Altered mental status (33% of patients in one US hospital system) r107
    • Liver dysfunction
    • Thromboembolic events, including pulmonary embolism, deep venous thrombosis, catheter-related thrombosis, ischemic stroke, and arterial thromboembolism, are commonly reported; one series of 184 ICU patients in the Netherlands found a cumulative adjusted incidence of 31% to 49%, of which pulmonary embolism was the most common (65 patients) r108
    • Secondary infections, including ventilator-associated pneumonia and catheter infections, are common; in a series of more than 700 critically ill patients in Italy, 46% had hospital-acquired infections r109c85c86
    • Multiorgan failure has been reported
  • Multisystem inflammatory syndrome (both MIS-C and MIS-A, in children or adults, respectively) is associated with COVID-19
    • Case definition in children (MIS-C): a person younger than 21 years with fever, laboratory evidence of inflammation, and clinically severe illness requiring hospitalization, with involvement of 2 or more organ systems; plus no alternative diagnosis; plus current or recent COVID-19 or exposure within the past 4 weeks r110d8
      • Fever may be documented or reported subjectively, lasting 24 hours or more
      • Laboratory parameters include elevated C-reactive protein level and/or erythrocyte sedimentation rate; elevated levels of acute phase reactants or related proteins (eg, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, and/or interleukin-6); elevated neutrophil count; reduced lymphocyte count; and/or low albumin level
      • Organ systems involved may include cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic
      • Patients may meet partial or full criteria for Kawasaki disease but regardless should be reported if they meet case definition of MIS-C
    • Case definition in adults (MIS-A): a person aged 21 years or older with hospitalization for 24 hours or more, or an illness resulting in death, with clinical and laboratory criteria below, and with no alternative diagnosis: r111
      • Clinical: fever for 24 hours or more, and at least 3 of the following criteria before hospitalization or within the first 3 days of hospitalization, including at least 1 primary criterion
        • Primary: severe cardiac illness (eg, myocarditis, pericarditis, coronary artery aneurysm, new-onset ventricular dysfunction, new-onset second- or third-degree atrioventricular block, new-onset ventricular tachycardia); rash; and nonpurulent conjunctivitis
        • Secondary: new-onset neurologic dysfunction (eg, seizures, encephalopathy, meningeal signs, peripheral neuropathy, Guillain-Barré syndrome); shock or hypotension not attributable to medical treatment; abdominal pain, vomiting, or diarrhea; thrombocytopenia with count less than 150,000 cells/mm³
      • Laboratory: at least 2 of the following markers are elevated: C-reactive protein, ferritin, interleukin-6, erythrocyte sedimentation rate, procalcitonin; plus positive test result for SARS-CoV-2 (from polymerase chain reaction assay, antigen test, or serology)
    • Common features in children include persistent fever, abdominal pain, vomiting, diarrhea, skin rash, mucocutaneous lesions, hypotension, and shock; however, a wide variety of symptoms and signs have been reported, including headache, swelling of hands and feet, lymphadenopathy, and elevated troponin or B-type natriuretic peptide levels r110
      • MIS-C may be difficult to distinguish from Kawasaki disease, toxic shock syndrome, and bacterial sepsis
      • American Academy of Pediatrics and American College of Rheumatology offer guidance on MIS-C r112r113
    • In a systematic review covering 221 individuals with MIS-A, the age range was 19 to 34 years; 70% of patients were male; and Black and Hispanic patients were disproportionately affected r114
      • Common features included fever, hypotension, cardiac dysfunction, shortness of breath, and diarrhea, along with laboratory evidence of coagulopathy and/or inflammation
      • Median number of organ systems involved was 5
      • Most patients (57%) required ICU care, and 7% died
      • There are no guidelines as yet for treatment of MIS-A; clinicians are applying information from MIS-C to the young adult population

Prognosis

  • Patients who require hospital admission often require prolonged inpatient stay (interquartile range in one series was 7 to 25 days), and resulting deconditioning may be profound r17r19r107
  • Laboratory markers associated with mortality include high D-dimer levels, high C-reactive protein levels, and low lymphocyte counts r3
  • Reported mortality rates in critically ill patients are high, in the range of 40% r1r3r106r107
    • Mortality rates have decreased over the course of the pandemic to date, a finding attributed to improved knowledge of critical care in COVID-19 (including increased use of proning and noninvasive ventilation) and different patient populations over time (eg, predominance of older patients early in the pandemic, compared with younger patients later)
      • One series found 28-day in-hospital mortality decreased from 43.5% to 19.2% from March to May 2020 r107

Screening and Prevention

Screening c87

Prevention

  • Several vaccines against SARS-CoV-2 have entered use in various countries, and more are in development d1d1d1d1d1d1d1d1
  • In the critical care setting, infection control strategies are essential to prevent infection of staff and other patients (ie, standard, contact, and at least droplet precautions, with strict attention to proper donning and doffing of personal protective equipment) r77c88c89c90c91c92
    • Patients should be placed in a single room, with the door closed, and ideally with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange); but, in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)
    • Source control should be applied whenever possible; this consists of a face mask or cloth covering for nonintubated patients and measures to reduce leakage around oxygen masks and from ventilator tubing
    • Limit transport of patient from the room (eg, for studies or procedures). Arrange for portable studies and procedures if feasible; during aerosol-generating procedures, limit number of workers in room to those necessary
    • Persons entering the room should wear gloves, gowns, eye protection, and surgical/procedural mask with adherence to hospital donning and doffing protocols, including aggressive hand hygiene. For aerosol-generating procedures, a respirator at least as effective as an N95 should be used in place of a surgical/procedural mask
    • Equipment used for patient care should be single use (disposable) or should be disinfected between patients
  • Criteria for discontinuation of isolation precautions vary depending on severity of illness. CDC recommends that a symptom-based strategy should be used to determine when to discontinue isolation in most patients. Patients with severe or critical illness, or those with immunocompromise, may shed replication-competent virus for longer duration than others (for whom 10 days of transmission-based precautions are recommended) r77r115
    • For patients with severe or critical illness the following criteria apply:
      • At least 10 days and up to 20 days have passed since symptom onset and
      • At least 24 hours have passed since last fever without use of antipyretics and
      • Symptoms have improved
    • Test-based strategy is no longer advised in most cases, because many persons have prolonged positivity reflecting detection of noninfective viral particles. It may be used at discretion of provider, or in consultation with infectious disease experts, in patients who have had severe disease or who are immunocompromised
CDC: COVID-19: Interim Clinical Guidance for Management of Patients With Confirmed Coronavirus Disease (COVID-19). CDC website. Updated February 16, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.htmlFDA: FDA Approves First Treatment for COVID-19. FDA News Release. FDA website. Published October 22, 2020. Accessed November 29, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19Phua J et al: Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med. ePub, April 6, 202032272080WHO: Living Guidance for Clinical Management of COVID-19. WHO website. Updated November 23, 2021. Accessed November 29, 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-2https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-2National Heart, Lung, and Blood Institute: NIH NHLBI ARDS Clinical Network: Mechanical Ventilation Protocol Summary. ARDSNet website. Accessed November 29, 2021. http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdfhttp://www.ardsnet.org/files/ventilator_protocol_2008-07.pdfAlhazzani W et al: Surviving Sepsis Campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: first update. Crit Care Med. 49(3):e219-34, 202133555780WHO: Coronavirus Disease 2019 (COVID-19): Situation Report--51. WHO website. Published March 11, 2020. Accessed November 29, 2021. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdfhttps://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdfZhu N et al: A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. ePub, January 24, 2020https://doi.org/10.1056/NEJMoa2001017International Committee on Taxonomy of Viruses: Naming the 2019 Coronavirus. ICTV news item. ICTV website. Published April 2020. Accessed November 29, 2021. https://talk.ictvonline.org/information/w/news/1300/pagehttps://talk.ictvonline.org/information/w/news/1300/pageCoronaviridae Study Group of the International Committee on Taxonomy of Viruses: The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 5(4):536-44, 202032123347CDC: COVID-19: SARS-CoV-2 Variant Classifications and Definitions. CDC website. Updated October 4, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.htmlWHO: Classification of Omicron (B.1.1.529): SARS-CoV-2 Variant of Concern. WHO website. Updated November 26, 2021. Accessed November 30, 2021. https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concernhttps://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concernCDC: CDC Statement on B.1.1.529 (Omicron Variant). CDC website. Updated November 26, 2021. Accessed November 30, 2021. https://www.cdc.gov/media/releases/2021/s1126-B11-529-omicron.htmlhttps://www.cdc.gov/media/releases/2021/s1126-B11-529-omicron.htmlCDC: COVID Data Tracker: Variants and Genomic Surveillance: Variant Proportions. CDC website. Updated daily. Accessed November 29, 2021. https://covid.cdc.gov/covid-data-tracker/#variant-proportionshttps://covid.cdc.gov/covid-data-tracker/#variant-proportionsLauer SA et al: The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Ann Intern Med. 172(9):577-82, 202032150748Chan JFW et al: A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 395(10223):514-23, 202031986261Huang C et al: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395(10223):497-506, 202031986264Stokes EK et al: Coronavirus disease 2019 case surveillance--United States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep. 69(24):759-65, 202032555134Chen N et al: Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. ePub, January 30, 202032007143Sudre CH et al: Anosmia, ageusia, and other COVID-19-like symptoms in association with a positive SARS-CoV-2 test, across six national digital surveillance platforms: an observational study. Lancet Digit Health. 3(9):e577-86, 202134305035Spinato G et al: Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA. ePub, April 22, 202032320008COVID-19 Symptom Study: Massachusetts General Hospital, the Harvard T.H. Chan School of Public Health, King's College London, Stanford University School of Medicine, and ZOE. What Are the New Top 5 Covid Symptoms? ZOE website. Updated June 23, 2021. Accessed November 29, 2021. https://covid.joinzoe.com/post/new-top-5-covid-symptomshttps://covid.joinzoe.com/post/new-top-5-covid-symptomsBertran Recasens B et al: Lack of dyspnea in Covid-19 patients: another neurological conundrum? Eur J Neurol. ePub, April 17, 202032301553Tobin MJ et al: Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med. ePub, June 15, 202032539537Zhong Z et al: Clinical characteristics of 2,459 severe or critically ill COVID-19 patients: a meta-analysis. Medicine (Baltimore). 100(5):e23781, 202133592834Scobie HM et al: Monitoring incidence of COVID-19 cases, hospitalizations, and deaths, by vaccination status--13 U.S. jurisdictions, April 4-July 17, 2021. MMWR Morb Mortal Wkly Rep. 70(37):1284-90, 202134529637Atri D et al: COVID-19 for the cardiologist: a current review of the virology, clinical epidemiology, cardiac and other clinical manifestations and potential therapeutic strategies. JACC Basic Transl Sci. ePub, April 10, 202032292848Wu P et al: Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol. ePub, March 31, 202032232433Oxley TJ et al: Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. ePub, May 14, 202032343504Helms J et al: Neurologic features in severe SARS-CoV-2 infection. Letter to the editor. N Engl J Med. ePub, April 15, 2020https://doi.org/10.1056/NEJMc2008597Galván Casas C et al: Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. ePub, April 29, 202032348545Magro C et al: Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. ePub, April 15, 202032299776Joob B et al: COVID-19 can present with a rash and be mistaken for dengue. J Am Acad Dermatol. 82(5):e177, 202032213305Marzano AV et al: Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients. J Am Acad Dermatol. ePub, April 16, 202032305439Recalcati S: Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. ePub, March 26, 202032215952CDC: COVID-19: Scientific Brief: SARS-CoV-2 Transmission. CDC website. Updated May 7, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/sars-cov-2-transmission.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/sars-cov-2-transmission.htmlCDC: COVID-19: Science Brief: SARS-CoV-2 and Surface (Fomite) Transmission for Indoor Community Environments. CDC website. Updated April 5, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/surface-transmission.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/surface-transmission.htmlCDC: COVID-19: Animals and COVID-19. CDC website. Updated November 18, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/animals.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/animals.htmlCDC: COVID Data Tracker: Demographic Trends of COVID-19 Cases and Deaths in the US Reported to CDC. CDC website. Updated daily. Accessed November 29, 2021. https://covid.cdc.gov/covid-data-tracker/#demographicsovertimehttps://covid.cdc.gov/covid-data-tracker/#demographicsovertimeCDC COVID-19 Response Team: Severe outcomes among patients with coronavirus disease 2019 (COVID-19)--United States, February 12-March 16, 2020. MMWR Morb Mortal Wkly Rep. 69(12):343-6, 202032214079Richardson S et al: Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. ePub, April 22, 202032320003CDC: COVID-19: Introduction to COVID-19 Racial and Ethnic Health Disparities. CDC website. Updated December 10, 2020. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/racial-ethnic-disparities/index.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/racial-ethnic-disparities/index.htmlCDC: COVID-19: Underlying Medical Conditions Associated with High Risk for Severe COVID-19: Information for Healthcare Providers. CDC website. Updated October 14, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.htmlCDC: COVID-19: Interim Infection Prevention and Control Recommendations to Prevent SARS-CoV-2 Spread in Nursing Homes. CDC website. Updated September 10, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/long-term-care.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/hcp/long-term-care.htmlLa Marca A et al: Testing for SARS-CoV-2 (COVID-19): a systematic review and clinical guide to molecular and serological in-vitro diagnostic assays. Reprod Biomed Online. ePub, June 14, 202032651106Babiker A et al: SARS-CoV-2 testing. Am J Clin Pathol. ePub, May 5, 202032227199CDC: COVID-19: Overview of Testing for SARS-CoV-2 (COVID-19). CDC website. Updated October 22, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.htmlCDC: Interim Guidance for Antigen Testing for SARS-CoV-2. CDC website. Updated September 9, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.htmlHanson KE et al: Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Serologic Testing. IDSA website. Published August 18, 2020. Accessed November 29, 2021. https://www.idsociety.org/practice-guideline/covid-19-guideline-serology/https://www.idsociety.org/practice-guideline/covid-19-guideline-serology/WHO: Recommendations for National SARS-CoV-2 Testing Strategies and Diagnostic Capacities: Interim Guidance. WHO website. Updated June 25, 2021. Accessed November 29, 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-lab-testing-2021.1-enghttps://www.who.int/publications/i/item/WHO-2019-nCoV-lab-testing-2021.1-engWHO: COVID-19 Case Definition. WHO website. Published December 16, 2020. Accessed November 29, 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-Surveillance_Case_Definition-2020.2https://www.who.int/publications/i/item/WHO-2019-nCoV-Surveillance_Case_Definition-2020.2CDC: COVID-19: Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19. CDC website. Updated October 25, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/lab/guidelines-clinical-specimens.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/lab/guidelines-clinical-specimens.htmlHanson KE et al: Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19. Version 2.0.0. IDSA website. Updated December 23, 2020. Accessed November 29, 2021. https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostics/https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostics/Mohammadi A et al: SARS-CoV-2 detection in different respiratory sites: a systematic review and meta-analysis. EBioMedicine. 102903, 202032718896Ding Q et al: The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China. J Med Virol. ePub, March 20, 202032196707Fan BE et al: COVID-19 and mycoplasma pneumoniae coinfection. Am J Hematol. 95(6):723-4, 202032173883Olsen SJ et al: Changes in influenza and other respiratory virus activity during the COVID-19 pandemic--United States, 2020-2021. MMWR Morb Mortal Wkly Rep. 70(29):1013-9, 202134292924CDC: Influenza (Flu): Testing Guidance for Clinicians When SARS-CoV-2 and Influenza Viruses Are Co-circulating. CDC website. Updated October 16, 2020. Accessed November 29, 2021. https://www.cdc.gov/flu/professionals/diagnosis/testing-guidance-for-clinicians-hospitaized.htmhttps://www.cdc.gov/flu/professionals/diagnosis/testing-guidance-for-clinicians-hospitaized.htmNIH: COVID-19 Treatment Guidelines. NIH website. Updated October 27, 2021. Accessed November 29, 2021. https://covid19treatmentguidelines.nih.gov/https://covid19treatmentguidelines.nih.gov/Rubin GD et al: The role of chest imaging in patient management during the COVID-19 pandemic: a multinational consensus statement from the Fleischner Society. Chest. ePub, April 7, 202032275978American College of Radiology: ACR Recommendations for the Use of Chest Radiography and Computed Tomography (CT) for Suspected COVID-19 Infection. ACR website. Updated March 22, 2020. Accessed November 29, 2021. https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infectionhttps://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-InfectionDinnes J et al: Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. Cochrane Database Syst Rev. 3:CD013705, 202133760236Wang D et al: Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. ePub, February 7, 202032031570Januzzi JL Jr: Troponin and BNP use in COVID-19. Cardiology Magazine. ePub, March 18, 2020https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/25/troponin-and-bnp-use-in-covid19Lippi G et al: Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chim Acta. 505:190-1, 202032145275Islam N et al: Thoracic imaging tests for the diagnosis of COVID-19. Cochrane Database Syst Rev. 3:CD013639, 202133724443Shi H et al: Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet. ePub, February 24, 2020https://doi.org/10.1016/S1473-3099(20)30086-4Yoon SH et al: Chest radiographic and CT findings of the 2019 novel coronavirus disease (COVID-19): analysis of nine patients treated in Korea. Korean J Radiol. 21(4):494-500, 2020https://doi.org/10.3348/kjr.2020.0132Kanne JP: Chest CT findings in 2019 novel coronavirus (2019-nCoV) infections from Wuhan, China: key points for the radiologist. Radiology. ePub, February 4, 2020https://doi.org/10.1148/radiol.2020200241Hashemi-Madani N et al: Typical chest CT features can determine the severity of COVID-19: a systematic review and meta-analysis of the observational studies. Clin Imaging. 74:67-75, 202133444992Peng QY et al: Using echocardiography to guide the treatment of novel coronavirus pneumonia. Crit Care. 24(1):143, 202032276598US National Library of Medicine: ClinicalTrials.gov website. Accessed November 29, 2021. https://clinicaltrials.gov/ct2/results?cond=COVID-19https://clinicaltrials.gov/ct2/results?cond=COVID-19WHO: International Clinical Trials Registry Platform. ICTRP website. Accessed November 29, 2021. https://www.who.int/clinical-trials-registry-platformhttps://www.who.int/clinical-trials-registry-platformAmerican Society of Health-System Pharmacists: Assessment of Evidence for COVID-19-Related Treatments. ASHP website. Updated August 19, 2021. Accessed November 29, 2021. https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx?https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx?Bhimraj A et al: Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19. IDSA website. Version 5.6.0. Updated November 18, 2021. Accessed November 29, 2021. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/WHO: Therapeutics and COVID-19: Living Guideline. Version 7.1. MAGICapp website. Updated September 23, 2021. Accessed November 29, 2021. https://app.magicapp.org/#/guideline/5665https://app.magicapp.org/#/guideline/5665CDC: COVID-19: Interim Infection Prevention and Control Recommendations for Healthcare Personnel During the Coronavirus Disease 2019 (COVID-19) Pandemic. CDC website. Updated September 10, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.htmlCuker A et al: American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. ePub, February 9, 202133560401Cuker A et al: American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate-intensity anticoagulation in critically ill patients. Blood Adv. 5(20):3951-9, 202134474482Cuker A et al: American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on post-discharge thromboprophylaxis. Blood Adv. ePub, November 2, 202134727173Evans L et al: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. ePub, October 2, 202134599691Clinical Pharmacology powered by ClinicalKey: Tocilizumab. ClinicalKey website. Accessed September 17, 2021. https://www.clinicalkey.com/pharmacology/monograph/3599?n=Tocilizumabhttps://www.clinicalkey.com/pharmacology/monograph/3599?n=TocilizumabClinical Pharmacology powered by ClinicalKey: Sarilumab. ClinicalKey website. Accessed May 3, 2021. https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-4949https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-4949Clinical Pharmacology powered by ClinicalKey: Baricitinib. ClinicalKey website. Accessed September 17, 2021. https://www.clinicalkey.com/pharmacology/monograph/5056?n=Baricitinibhttps://www.clinicalkey.com/pharmacology/monograph/5056?n=BaricitinibClinical Pharmacology powered by ClinicalKey: Tofacitinib. ClinicalKey website. Accessed September 17, 2021. https://www.clinicalkey.com/pharmacology/monograph/3789?n=Tofacitinibhttps://www.clinicalkey.com/pharmacology/monograph/3789?n=TofacitinibKalil AC et al: Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 384(9):795-807, 202133306283Eli Lilly and Company: Fact Sheet for Healthcare Providers: Emergency Use Authorization (EUA) of Baricitinib. FDA website. Updated October 2021. Accessed November 29, 2021. https://www.fda.gov/media/143823/downloadhttps://www.fda.gov/media/143823/downloadMarconi VC et al: Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. ePub, 202134480861Guimarães PO et al: Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 385(5):406-15, 202134133856RECOVERY Collaborative Group: Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. ePub, October 5, 202033031764Angus DC et al: Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA. 324(13):1317-29, 202032876697Gilead Sciences Inc: Fact Sheet for Health Care Providers: Fact Sheet for Healthcare Providers: Emergency Use Authorization (EUA) of Veklury (Remdesivir) for Hospitalized Pediatric Patients Weighing 3.5 kg to Less Than 40 kg or Hospitalized Pediatric Patients Less Than 12 Years of Age Weighing At Least 3.5 kg. FDA website. Updated October 2020. Accessed November 29, 2021. https://www.fda.gov/media/137566/downloadhttps://www.fda.gov/media/137566/downloadEli Lilly and Company: Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Bamlanivimab and Etesevimab. FDA website. Updated September 16, 2021. Accessed November 29, 2021. https://www.fda.gov/media/145802/downloadhttps://www.fda.gov/media/145802/downloadHinton DM: [Letter granting emergency use authorization for bamlanivimab-etesevimab combination.] FDA website. Updated September 16, 2021. Accessed November 29, 2021. https://www.fda.gov/media/145801/downloadhttps://www.fda.gov/media/145801/downloadHinton DM: [Letter granting emergency use authorization for use of casirivimab and imdevimab administered together for the treatment of mild to moderate coronavirus disease 2019.] FDA website. Published November 21, 2020. Accessed November 29, 2021. https://www.fda.gov/media/143891/downloadhttps://www.fda.gov/media/143891/downloadRegeneron: Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of REGEN-COV (Casirivimab and Imdevimab). FDA website. Updated November 2021. Accessed November 29, 2021. https://www.fda.gov/media/145611/downloadhttps://www.fda.gov/media/145611/downloadGlaxoSmithKline LLC: Fact Sheet for Healthcare Providers: Emergency Use Authorization (EUA) of Sotrovimab. FDA website. Updated November 2021. Accessed November 29, 2021. https://www.fda.gov/media/149534/downloadhttps://www.fda.gov/media/149534/downloadDrake TM et al: Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study. Lancet Rheumatol. 3(7):e498-506, 202133997800Clinical Pharmacology powered by ClinicalKey: Remdesivir. ClinicalKey website. Accessed May 3, 2021. https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-5210https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-5210Murthy S et al: Care for critically ill patients with COVID-19. JAMA. ePub, March 11, 2020https://doi.org/10.1001/jama.2020.3633Devlin JW et al: Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 46(9):e825-73, 201830113379American Society of Health-System Pharmacists: Considerations for Prioritizing Medications for Mechanically Ventilated Patients in Intensive Care Units. ASHP website. Published 2020. Accessed November 29, 2021. https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/Tiered-medication-considerations-for-mechanically-ventilated-patients_ASHP-Resource.ashxhttps://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/Tiered-medication-considerations-for-mechanically-ventilated-patients_ASHP-Resource.ashxBentzer P et al: Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 316(12):1298-309, 201627673307American College of Obstetricians and Gynecologists: Practice Advisory: Novel Coronavirus 2019 (COVID-19). ACOG website. Updated July 8, 2021. Accessed November 29, 2021. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/novel-coronavirus-2019https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/novel-coronavirus-2019Society for Maternal-Fetal Medicine: Management Considerations for Pregnant Patients With COVID-19. SMFM website. Updated February 2, 2021. Accessed November 29, 2021. https://www.smfm.org/covidclinicalhttps://www.smfm.org/covidclinicalCummings MJ et al: Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 395(10239):1763-70, 202032442528Anesi GL et al: Characteristics, outcomes, and trends of patients with COVID-19-related critical illness at a learning health system in the United States. Ann Intern Med. 174(5):613-21, 202133460330Klok FA et al: Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 191:148-50, 202032381264Grasselli G et al: Hospital-acquired infections in critically ill patients with COVID-19. Chest. 160(2):454-65, 202133857475CDC: Multisystem Inflammatory Syndrome (MIS): Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C). CDC website. Updated May 20, 2021. Reviewed May 20, 2021. Accessed November 29, 2021. https://www.cdc.gov/mis/mis-c/hcp/index.htmlhttps://www.cdc.gov/mis/mis-c/hcp/index.htmlCDC: Multisystem Inflammatory Syndrome (MIS): Multisystem Inflammatory Syndrome in Adults (MIS-A) Case Definition Information for Healthcare Providers. CDC website. Updated October 7, 2021. Reviewed October 7, 2021. Accessed November 29, 2021. https://www.cdc.gov/mis/mis-a/hcp.htmlhttps://www.cdc.gov/mis/mis-a/hcp.htmlHenderson LA et al: American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19: version 2. Arthritis Rheumatol. 73(4):e13-29, 202133277976American Academy of Pediatrics: Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance. AAP website. Updated November 15, 2021. Accessed November 29, 2021. https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/Patel P et al: Clinical characteristics of multisystem inflammatory syndrome in adults: a systematic review. JAMA Netw Open. 4(9):e2126456, 202134550381CDC: COVID-19: Ending Isolation and Precautions for People with COVID-19: Interim Guidance. CDC website. Updated September 14, 2021. Accessed November 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html
;