Treatment Options
Overview
- 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. Information on therapeutic trials and expanded access is available at ClinicalTrials.gov r86
- 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
- Given new medications, novel use of existing medications, and the rapid change in guidelines, consulting a drug interaction checkerr87 is advised
Infection control measures: these include isolation, source control, and transmission precautions r88
- People with COVID-19 at home should isolate at home, keep separate from others in the household as much as possible, wear a mask when near other people or pets in the household, monitor for serious or worsening symptoms requiring additional medical care, and increase cleaning and disinfection r89
- Patients 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 r88
- Some guidelines suggest that a medical face mask, rather than N95 respirator, is sufficient when not performing aerosol-generating procedures r35
- 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)
Supportive care: for all patients; in hospitalized patients, such care includes oxygenation and ventilation, conservative fluid support, and measures to prevent common complications (eg, pressure injury, stress ulceration, secondary infection) r35
- Until a diagnosis of COVID-19 is confirmed by polymerase chain reaction or antigen test, appropriate antimicrobial therapy for other viral pathogens (eg, influenza virus) or bacterial pathogens 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 r35
- Surviving Sepsis Campaignr90r91 guideline, NIH COVID-19 treatmentr8 guideline, and WHO guidancer35 provide recommendations specific to treatment of shock in patients with COVID-19. Management of shock and other complications requiring intensive care are addressed in detail in the Clinical Overview on COVID-19 critical care d4
Antiviral agents
- Remdesivir: FDA-approved for treatment of COVID-19 in hospitalized adults and children aged 28 days or older weighing 3 kg or more, and in those with mild to moderate test-positive COVID-19 who are not hospitalized but who are at high risk for progression to severe disease r92r93r94
- Preliminaryr95 and follow-upr96 results of the Adaptive COVID-19 Treatment Trial, a placebo-controlled randomized trial in 1062 patients, showed a statistically significant improvement in time to recovery and a nonsignificant trend in lower mortality; several other trials remain active, as wellr97
- On the basis of these and other data from clinical trials, the NIH guideline recommends, and the Infectious Diseases Society of America and Surviving Sepsis Campaign guidelines suggest, remdesivir for hospitalized patients with COVID-19 who require supplemental oxygen r8r90r91r98
- In patients who require oxygen via high-flow device or noninvasive ventilation, NIH offers the option of remdesivir with dexamethasone or dexamethasone alone, because remdesivir appears to confer maximum benefit before onset of more severe disease, in which dexamethasone alone is associated with markedly reduced mortality
- NIH recommends against use of remdesivir in patients who require mechanical ventilation or extracorporeal membrane oxygenation, and both Infectious Diseases Society of America and Surviving Sepsis Campaign guideline suggests that remdesivir not be used in patients with critical COVID-19
- For patients whose condition worsens while they are receiving remdesivir and who require institution of high-flow oxygen, ventilation, or extracorporeal membrane oxygenation, NIH recommends that the treatment course be completed
- For hospitalized patients with no current oxygen requirement, NIH guidelines suggest consideration of remdesivir for patients at high risk of disease progression, and Infectious Diseases Society of America guidelines suggest use of remdesivir (3-day course)
- Infectious Diseases Society of America suggests, and NIH recommends, use of remdesivir in ambulatory patients with mild to moderate COVID-19 who are at high risk for progression to severe disease, to be initiated within 7 days of symptom onset r8r98
- For this patient population, NIH guidelines prefer use of ritonavir-boosted nirmatrelvir, when available
- In a randomized placebo controlled trial of 562 nonhospitalized patients with COVID-19, a 3-day course of remdesivir was associated with an 87% reduction in risk of hospitalization or death r99
- WHO suggests against remdesivir use outside of clinical trials r100
- Evidence base: remdesivir has significant in vitro activity against coronaviruses,r101r102 evidence of efficacy in an animal model of MERS,r101 and evidence of efficacy in COVID-19r96
- Ritonavir-boosted nirmatrelvir has received emergency use authorization in the United States for treatment of nonhospitalized persons aged 12 years or older and weighing 40 kg or more who test positive for COVID-19, who are at high risk for progressing to severe disease, and for whom alternative treatments are not available or not clinically appropriate r103
- Ritonavir-boosted nirmatrelvir was studied in a randomized placebo-controlled trial of 2246 patients with documented COVID-19 who met criteria for high risk of progression to severe disease. The primary end point was COVID-19–related hospitalization or death from any cause within 28 days. The relative risk reduction in patients who received the study drug was 88% r103
- Ritonavir-boosted nirmatrelvir is associated with numerous potential drug interactions
- Patients with HIV taking a ritonavir- or cobicistat- based antiretroviral regimen should continue to take their antiretroviral regimen as prescribed during ritonavir-boosted nirmatrelvir treatment r104
- NIH recommends and Infectious Diseases Society of America suggests use of ritonavir-boosted nirmatrelvir in ambulatory patients with mild or moderate COVID-19 at high risk for progression to severe disease, to be initiated within 5 days of symptom onset r98
- Molnupiravir, another oral antiviral agent, has emergency use authorization in the United States for treatment of nonhospitalized adults positive for COVID-19 who are at high risk of progression to severe disease, and for whom alternative treatments are not available or not clinically appropriate r105
- Molnupiravir was compared with placebo in a randomized trial of 1433 patients with mild to moderate COVID-19 who met criteria for high risk of progression to severe disease. The primary end point was all-cause hospitalization or death through day 29. The relative risk reduction was 30%
- Molnupiravir is not recommended during pregnancy or breastfeeding; before prescribing to persons of childbearing potential, test for pregnancy and (including for biologic males) ensure reliable contraception through treatment and for 4 days (females) or 3 months (males) after the last dose. Breast milk should be discarded during treatment and for 4 days after the last dose r105
- Mechanism of action of molnupiravir is inducing lethal viral mutations; concerns have arisen regarding emergence of resistance and emergence of new variants as a result. Use of molnupiravir should be accompanied with robust pharmacovigilance r100
- Infectious Diseases Society of America suggests use of molnupiravir in ambulatory adults (aged 18 years or older) with mild to moderate COVID-19 at high risk for progression to severe disease who have no other treatment options (eg, nirmatrelvir-ritonavir or remdesivir), to be initiated within 5 days of symptom onset, rather than no molnupiravir r98
- Similarly, NIH recommends use of molnupiravir (or bebtelovimab) in ambulatory adults at high risk of progression to severe disease ONLY when ritonavir-boosted nirmatrelvir and remdesivir are unavailable, because it has lower efficacy than the preferred treatments r8
- WHO suggests use of molnupiravir for adults with nonsevere disease at highest risk of hospitalization; alternative treatments may be preferable where available
Monoclonal antibodies with antiviral action (against SARS-CoV-2 spike protein)
- Emergency use authorizations have been issued in the United States for several monoclonal antibody products: bamlanivimab-etesevimabr4r5 in combination, casirivimab-imdevimabr3r106 in combination, sotrovimab,r107r2bebtelovimab,r1 and tixagevimab-cilgavimabr6 in combination. Given the predominance of the Omicron variant in the United States and the lack of activity of bamlanivimab-etesevimab, casirivimab-imdevimab, or sotrovimab against specific Omicron subvariants, FDA has modified the emergency use authorizations for these monoclonal antibodies to state that they are not authorized for use in regions where infection is likely to be caused by a nonsusceptible strain,r108r109 effectively suspending their use in the United States
- These authorizations apply to patients aged 12 years or older, weighing 40 kg or more, who have mild to moderate disease and who are at high risk (by virtue of older age or concomitant conditions) for progression to severe disease and/or hospital admission; the authorizations exclude persons who are already hospitalized for COVID-19 or who require supplemental oxygen for COVID-19. The emergency use authorizations list recognized criteria for high risk of progression; updated guidance notes that risk is not limited to these conditions:
- BMI of 25 or higher (for ages 12 to 17 years, BMI in 85th percentile or higher)
- Chronic kidney disease
- Diabetes
- Pregnancy
- Immunosuppression due to disease or treatment
- Sickle cell disease
- Chronic lung disease (eg, chronic obstructive pulmonary disease, moderate to severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)
- Cardiovascular disease (including congenital heart disease) or hypertension
- Neurodevelopmental disorders
- Dependence on a medical technology such as tracheostomy, gastrostomy, or positive pressure ventilation
- Older age (ie, 65 years or older)
- Infectious Diseases Society of America guideliner98 suggests use of monoclonal antibodies in ambulatory patients who are at high risk of progression to severe COVID-19, with selection of the most appropriate agent based on known activity against predominant circulating variants
- Distribution of monoclonal antibodies is currently coordinated through state/territorial health departments, based on circulating variants, case burden, and product utilization rates r8r110r111
- In areas with logistical constraints, administration to all eligible persons may not be possible r8
- Prioritize treatment of COVID-19 over postexposure prophylaxis
- Prioritize treatment of persons at high risk of progression to severe disease who are not fully vaccinated, and vaccinated persons who may not have an adequate immune response, over fully vaccinated persons who are expected to have adequate immune response to immunization
- Tixagevimab and cilgavimab are monoclonal antibodies which block spike protein attachment, binding to 2 different regions of the receptor-binding domain of the spike protein
- FDA granted an EUA in December 2021 for preexposure prophylaxis in adults and children aged 12 years or older weighing at least 40 kg who have moderate to severe immunocompromise or who are unable to be immunized owing to severe allergic reaction r6
- Based on decreased susceptibility of BA.1 and BA.1.1 subvariants of Omicron variant to this combination, the recommended dose was increased on February 24, 2022
- Those who received the original dose of 150 mg each should receive a second dose of 150 mg each as soon as possible
- Infectious Diseases Society of America suggests use and NIH recommends use of tixagevimab-cilgavimab as preexposure prophylaxis in adults and adolescents who have moderate to severe immunocompromise or who are unable to be fully immunized owing to documented severe allergy
- Bebtelovimab is a recombinant neutralizing human monoclonal antibody that binds to the spike protein of SARS-CoV-2 (including the Omicron variant), preventing its attachment to the ACE2 receptor (for angiotensin-converting enzyme 2) r1
- Limited clinical data indicate a reduction in viral load in treated patients and improvement in symptoms; the emergency use authorization issued by FDA on February 11, 2022 states that "based on the totality of evidence available … it is reasonable to believe that bebtelovimab may be effective for the treatment of patients with mild-to-moderate COVID-19 to reduce the risk of progression to hospitalization or death"
- NIH recommends use of bebtelovimab (or molnupiravir) in ambulatory adults at high risk of progression to severe disease only when ritonavir-boosted nirmatrelvir and remdesivir are unavailable or not clinically feasible r8
- Infectious Diseases Society of America guideline recommends use of bebtelovimab only in clinical trials, owing to lack of data
- Sotrovimab targets a highly conserved region in the receptor-binding domain of the SARS-CoV-2 spike protein r2
- Interim data from the ongoing COMET-ICE clinical trial show that in 583 patients with symptomatic COVID-19 and at least 1 comorbidity or age-related risk factor for progressing to severe disease who were randomized to receive sotrovimab or placebo, the risk of progression to severe disease was 85% lower in the sotrovimab arm r2
- Although sotrovimab is active against the Omicron BA.1 and BA.1.1 subvariants, it has substantially decreased in vitro activity against the Omicron BA.2 subvariant, and as of April 5, 2022, it is no longer authorized by FDA for use in the United States r2r8r108
- NIH guidelines no longer recommend using sotrovimab, bamlanivimab-etesevimab, or casirivimab-imdevimab, owing to their ineffectiveness against the prevailing Omicron variant/subvariants in the United States r8
- WHO suggests treatment with sotrovimab for those at highest risk of hospitalization r100
- Benefit of use is unclear for patients with severe or critical illness who are seronegative; use depends on availability of rapid and accurate antibody testing before treatment
- Bamlanivimab and etesevimab are monoclonal antibodies designed to target the SARS-CoV-2 spike protein, disabling viral attachment and entry into human cells; the 2 antibodies target different regions of the spike protein r5
- Preliminary data from clinical trials on bamlanivimab (before emergence of Omicron variant) demonstrated a reduction in the incidence of COVID-19–associated emergency department visits and hospital admissions (3% for patients treated with bamlanivimab versus 10% for patients who received placebo) r4
- A subsequent trial (BLAZE-1) of bamlanivimab in combination with etesevimab showed a 70% reduction in COVID-19–related hospitalization or death by any cause r4
- Based on these data, FDA issued emergency use authorizations; however, the emergency use authorization for bamlanivimab alone was since revoked because virus variant prevalence reduced its effectiveness, and similarly, for bamlanivimab in combination with etesevimab, the emergency use authorization has subsequently been revised to preclude use when infection is likely to be caused by a nonsusceptible variant, such as Omicron r4
- Bamlanivimab and etesevimab, even in combination, appear to have reduced in vitro activity against a number of circulating variants: beta (eg, B.1.351), gamma (eg, P.1), epsilon (ie, B.1.427 or B.1.429), eta (eg, B.1.526) and Omicron (eg, B.1.1. 529), which has become the dominant circulating variant in the United States r4r112
- Casirivimab-imdevimabr8r106
- This combination appears to have reduced activity against the Omicron variant prevalent in late 2021 and early 2022; the emergency use authorization was modified on January 24, 2022, to preclude use of this product when infection is likely to be caused by a nonsusceptible variant such as Omicron, which is now the prevailing variant in the United States r3
- Similarly, with Omicron predominating worldwide, WHO no longer recommends use of casirivimab-imdevimab except in cases where rapid genotyping confirms infection with a variant that is susceptible r100
- Data on efficacy against susceptible variants
- Preliminary clinical studies (conducted before emergence of Omicron variant) evaluated effect on viral load and on medically attended illness. In a placebo-controlled trial of 799 patients with mild to moderate COVID-19, reduction in viral load in days 1 through 7 was significantly greater for the monoclonal antibody combination compared with placebo (P < .0001). Treatment was also associated with fewer emergency department visits and hospital admissions (2.8% for patients treated with casirivimab-imdevimab versus 6.5% for those who received placebo) r3
- An updated statement from the manufacturer includes data from 4567 patients with at least 1 risk factor for severe COVID-19, randomized to 2 different doses (either 600 mg or 1200 mg of each component) or placebo. The 2 doses resulted in a 70% and 71% reduction in risk for hospitalization r3
- Data submitted with the updated statement indicated efficacy against the major variants circulating as of June 2021, but Omicron subvariants in 2022 have defeated this efficacy r3
- In a phase 3 trial of nonhospitalized patients with COVID-19, patients randomized to casirivimab-imdevimab treatment had a lower risk of hospitalization and of death, and had faster resolution of symptoms, than those randomized to placebo. Relative risk reduction of hospitalization plus death was 71.3% in the group that received a 2400-mg dose, and was 70.4% in those who received the 1200-mg dose r113
Immunomodulators are also being investigated 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 tocilizumabr114 and sarilumabr115; Janus kinase inhibitors such as baricitinibr116 and tofacitinibr117)
- Baricitinib (a Janus kinase inhibitor)
- Baricitinib is FDA-approved for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation r118
- 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, oxygen 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 r119r120
- In another phase 3 randomized trial of hospitalized adults with documented SARS-CoV-2 infection, pneumonia or active and symptomatic COVID-19, and at least 1 elevated inflammatory marker who were receiving standard of care, including corticosteroids and/or antivirals, there was no significant difference in disease progression (defined as progression to high-flow oxygen, noninvasive mechanical ventilation, invasive mechanical ventilation, or death) with baricitinib (764 patients) versus placebo (761 patients). However, the 28-day all-cause mortality was significantly lower in patients treated with baricitinib (8%) compared to placebo (13%), a 38.2% relative reduction in mortality. r121
- NIH guidelines recommend use of baricitinib (or tocilizumab) 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) r8
- Guideline recommends against giving tocilizumab or other IL-6 inhibitors to patients on baricitinib
- There is insufficient evidence to recommend baricitinib over tocilizumab or vice versa
- Infectious Diseases Society of America guidelines suggest use of baricitinib in hospitalized patients with severe COVID-19 along with corticosteroids (unless contraindicated) or remdesivir in patients who cannot receive a corticosteroid r98
- Patients receiving baricitinib should not receive tocilizumab or other IL-6 inhibitors
- Some data suggest a reduction in mortality even in patients who require mechanical ventilation
- WHO guideline strongly recommends baricitinib for patients with severe or critical disease; choice of baricitinib versus IL-6 blockers should be based on clinical factors and availability r100
- Tocilizumab (monoclonal IL-6 receptor blocker)
- NIH guidelines recommend use of tocilizumab in 2 situations, as follows: r8
- 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
- A systematic review and meta-analysis of retrospective trials with data from 240 patients who received tocilizumab and 352 controls concluded that the low-quality evidence available did not demonstrate clear benefit from tocilizumab r122
- 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 r98
- REMAP-CAP and RECOVERY trials both indicate a mortality benefit for tocilizumab among patients who experienced rapid respiratory decompensation and were recently admitted to the ICU, and the RECOVERY trial showed benefit in those who require high-flow oxygen or noninvasive ventilation r123r124
- In patients admitted to hospital with COVID-19, Infectious Diseases Society of America suggest 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 r98
- WHO guidelines recommend use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids r100
- Sarilumab (monoclonal IL-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 r8
- WHO guidelines recommend use of sarilumab (or tocilizumab) for patients with severe or critical COVID-19, along with corticosteroids r100
- 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 r8r123
- Tofacitinib (a Janus kinase inhibitor)
- Infectious Diseases Society of America guidelines suggest use of tofacitinib in hospitalized patients with severe but noncritical COVID-19 (ie, not on mechanical ventilation), along with remdesivir and corticosteroids (unless contraindicated)
- Patients should also receive at least prophylactic dose of anticoagulant
- Patients receiving tofacitinib should not receive tocilizumab or other IL-6 inhibitors
- NIH guidelines recommend use of tofacitinib 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
- WHO guideline suggests against use of tofacitinib or ruxolitinib (another Janus kinase inhibitor) unless baricitinib, tocilizumab and sarilumab are unavailable r100
- Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 does not address immunomodulators r90r91
- Monoclonal antibodies against GM-CSF (granulocyte-macrophage colony-stimulating factor), such as lenzilumab, mavrilimumab, namilumab, gimsilumab, and otilimab, are under investigation and are not currently recommended under any guidelines r8r98
Corticosteroid therapy is suggested or recommended for hospitalized patients with an oxygen requirement r35
- A randomized controlled trial in more than 6000 hospitalized patients with COVID-19 found that dexamethasone reduced deaths in patients with severe respiratory complications requiring supplemental oxygen r7r125
- Compared with usual care alone, deaths in ventilated patients receiving usual care plus dexamethasone were reduced by a third; among patients receiving oxygen without mechanical ventilation, deaths were cut by 20%
- Overall 28-day mortality was reduced by 17% in the dexamethasone group
- A smaller study comparing standard care with and without a 3-day course of methylprednisolone early in the disease course showed an association between corticosteroid use and a reduction in the 3 components of the composite end point: transfer to ICU, need for mechanical ventilation, and mortality. Guidelines do not currently support administration of steroids early in the disease course r126
- Based on these data, NIH COVID-19 treatment guideline recommends use of dexamethasone in any hospitalized patient who requires supplemental oxygen, and recommends against use of dexamethasone in patients who do not require oxygen supplementation r8
- In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used
- Similarly, Infectious Diseases Society of America guideline suggests use of dexamethasone in hospitalized patients with severe illness, and recommends use in those with critical illness r98
- Infectious Diseases Society of America suggests against the use of steroids in patients who have no oxygen requirement, and suggests against the use of inhaled steroids in ambulatory patients with mild to moderate disease
- Guideline provides equivalent doses of alternative glucocorticoids if dexamethasone is unavailable
- Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 strongly recommends using corticosteroids (preferably dexamethasone) for up to 10 days in patients with severe or critical COVID-19 r90r91
- WHO recommends use in patients with severe and critical COVID-19, and suggests against use in patients with nonsevere COVID-19 r35r100
Antithrombotic Therapy
- COVID-19 is associated with inflammation and prothrombotic state, including macrovascular and microvascular thromboembolism in both the venous and arterial vessels, as well as disseminated intravascular coagulation r8r91r127r128r129r130r131
- The most current guidelines to address antithrombotic therapy are the NIH, American Society of Hematology, and CHEST (American College of Chest Physicians) guidelines. Recommendations are summarized below: r8r130r131
- NIH guideline recommends prophylactic dose heparin for hospitalized adults, including pregnant patients, without evidence of venous thromboembolism; CHEST guideline suggests therapeutic dose heparin with careful balance of the risk of thrombosis and the risk of bleeding
- Therapeutic-dose heparin is recommended for hospitalized nonpregnant patients requiring oxygen who have elevated D-dimer levels (NIH guideline) or other indicators of increased risk of thrombosis (CHEST guideline), if they do not have increased risk of bleeding; there is insufficient evidence in pregnant patients
- Prophylactic-dose heparin is recommended in both guidelines for patients in the ICU, including switching from therapeutic to prophylactic dose in patients transferred to an ICU unless a thrombosis has been documented
- Standard therapeutic treatment is recommended for patients with COVID-19 and thromboembolism (highly suspected or proven), and for those on extracorporeal membrane oxygenation or continuous renal replacement therapy or who have thrombosis related to catheters or extracorporeal filters
- Prophylactic therapy is not recommended for nonhospitalized patients, and guidelines also recommend against continuing prophylactic therapy following hospitalization in patients without thromboembolic disease
- Based on additional evidence, the American Society of Hematology also now recommends against posthospitalization thromboprophylaxis r132
- Generally low molecular weight heparin is preferred over unfractionated heparin, and heparin is preferred over oral anticoagulants
- Risk of bleeding is increased in the following situations:
- Bleeding within the past 30 days that required an emergency department visit or hospitalization, or gastrointestinal bleeding within the past 3 months
- History of inherited or acquired bleeding disorder
- Thrombolysis within the past 7 days or major surgery within the past 14 days
- Platelet count less than 50 × 10⁹ cells/L; hemoglobin level less than 8 g/dL; or baseline INR more than 2 or activated partial thromboplastin time more than 50 seconds
- Dual antiplatelet therapy
- Ischemic stroke, intracranial hemorrhage, or intracranial malignancy
- Uncontrolled hypertension (systolic more than 200 mm Hg or diastolic more than 120 mm Hg)
- Presence of epidural or spinal catheter
- Risk of thrombosis is increased in those with elevated D-dimer levels, prior venous thromboembolism, or additional known risk factors for venous thromboembolism
- American Society of Hematology guideline also recommends anticoagulation for hospitalized patients and for patients in intensive care; however, this guideline is expected to be revised with additional information from trials comparing prophylactic dose, intermediate dose, and therapeutic dose r127r132
Convalescent plasma continues to be investigated; only high-titer formulations have shown any benefitr133
- Infectious Diseases Society of America suggests use of high-titer convalescent plasma in ambulatory patients with mild to moderate disease at high risk of progression who have no other treatment options. It recommends against use in hospitalized patients r98
- Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 suggests that convalescent plasma not be used outside of clinical trials r91
- NIH COVID-19 treatment guideline recommends against use of convalescent plasma in most situations, except in a clinical trial, and recommends against use of convalescent plasma that was collected before the emergence of the Omicron variant r8
- There is insufficient evidence to recommend for or against use of convalescent plasma that was collected after the emergence of the Omicron variant (in hospitalized patients with impaired immunity, or nonhospitalized patients)
- WHO strongly recommends against use of convalescent plasma in nonsevere disease, and recommends against use in severe or critical disease outside of a clinical trial r100
- FDA has issued and revised an emergency use authorization, citing, among other reasons, the observational safety and efficacy data from 20,000 patients who received convalescent plasma through a program sponsored by the Mayo Clinic: r134r135
- Serious adverse events were uncommon, and they were judged not to exceed the known incidence in transfusion of plasma to critically ill patients
- There was some evidence of improved survival in the subset of patients treated with convalescent plasma containing higher titers of neutralizing antibody compared with patients who received plasma with lower levels (ie, there appeared to be a dose-response gradient)
- Expanded access use focuses on high-titer product used in patients with immunosuppressive disease or receiving immunosuppressive treatment
- Early administration (eg, before mechanical ventilation is required) appeared more likely to be beneficial, but the possibility of benefit even to intubated patients could not be excluded
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 r136
- 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 r8r137r138
- 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 r98
Other options not currently recommended under any guidelines (although some are still under study in clinical trials)
- Interim results of the WHO SOLIDARITY trial have been published. Remdesivir, lopinavir-ritonavir, hydroxychloroquine, and interferon were compared with one another (open-label) and with standard care (no placebo) in a total population of over 11,000 patients in over 400 hospitals in 30 countries worldwide r139
- End points were in-hospital mortality, initiation of ventilation, and duration of hospital stay. No differences among the groups were noted for any of these parameters. The authors acknowledge that length of stay may have been influenced in some cases by the requirements of antiviral administration (eg, 10 days of IV administration for remdesivir), but they argue that the similarity in percentages of patients in each group remaining in the hospital beyond the course of the study drug indicates a lack of benefit to any treatment arm
- Lopinavir-ritonavir is FDA-approved for treatment of HIV infection. It has been used in China in conjunction with interferon alfa for treatment of some patients with COVID-19, but reported results have been disappointing
- 3 randomized placebo-controlled trials have evaluated the effects of lopinavir-ritonavir in the treatment of COVID-19. The combined datar98 did not show significant differences in progression to mechanical ventilation or mortality
- NIH COVID-19 treatmentr8 guideline, Infectious Diseases Society of America guideline on treatment and management of COVID-19,r98 and Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19r91 recommend against use of lopinavir-ritonavir
- Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 recommends against use of recombinant interferons, based on lack of data in COVID-19 and on data from studies on MERS showing lack of efficacy r90r91
- WHO recommends against use of lopinavir-ritonavir outside of a clinical trial r100
- Ivermectin, an antiparasitic drug with some activity against viruses, has been proposed for COVID-19 treatment or prevention
- Infectious Diseases Society of America and WHO guidelines suggest against use of ivermectin, and NIH guidelines recommend against use, outside clinical trials r8r98r100
- CDC issued a health advisory warning clinicians that ivermectin is not approved by FDA for treatment of COVID-19 and that adverse effects from the use and misuse of ivermectin are increasing r140
- FDA issued a consumer update warning the public against use of ivermectin, particularly medications meant for animal use r141
- Chloroquine and hydroxychloroquine: letters reporting favorable results in China and South Korea early in the pandemicr142 suggested promise, leading to an emergency use authorization by FDA in the United States. Subsequent studies have found no significant benefit, but they highlighted the risk of QT prolongation and cardiac arrhythmias. As a result, FDA emergency use authorization was withdrawn,r143 although some clinical trial use may still be in progress
- Azithromycin has been used in combination with hydroxychloroquine in some protocols; however, azithromycin is also associated with cardiac arrhythmias, and the possible increased risk posed by the combination must be considered r144
- Scoring systems are available to determine risk of arrhythmia r145r146
- A systematic review and meta-analysis of studies comparing standard care with and without hydroxychloroquine included 6 studies comprising 1331 patients. There was no difference in mortality between the 2 groups, although a subgroup receiving hydroxychloroquine plus azithromycin experienced significantly higher mortality than the standard care group r147
- A subsequently published randomized controlled open-label trial (RECOVERY) of 1561 patients treated with hydroxychloroquine and 3155 treated without showed no survival advantage among patients treated with hydroxychloroquine r148
- Infectious Diseases Society of America, NIH, and WHO guidelines all recommend against using hydroxychloroquine, with or without azithromycin, and the Surviving Sepsis guideline recommends against using hydroxychloroquine (but does not mention azithromycin) r8r91r98r100
Drug therapy
- Antiviral agents c259
- Remdesivir
- For patients requiring oxygen but NOT invasive mechanical ventilation and/or extracorporeal membrane oxygenation
- Remdesivir Solution for injection; Adults NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement. The NIH recommends treatment for 5 days or until hospital discharge.
- Dosages for patients who REQUIRE mechanical ventilation or extracorporeal membrane oxygenation have been established r149r150d4
- Remdesivir Solution for injection; Adults requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days. The NIH recommends against starting remdesivir; but, treatment may be continued (in combination with dexamethasone) in patients who progress to mechanical ventilation or ECMO.
- 3-day regimen for persons with mild to moderate disease at high risk for progression
- Remdesivir Solution for injection; Adults: 200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days. According to the NIH, up to 5 days of therapy may be considered for patients with new/increasing need for oxygen but who cannot be admitted to the hospital because resources are limited.
- Nirmatrelvir-ritonavir
- Nirmatrelvir Oral tablet, Ritonavir Oral tablet; Adults weighing 40 kg or more: 300 mg nirmatrelvir (two 150 mg tabs) and 100 mg ritonavir (one 100 mg tab) taken together by mouth twice daily for 5 days. Start as soon as possible after the positive test for SARS-CoV-2 and within 5 days of symptom onset.
- Molnupiravir
- Molnupiravir Oral capsule; Adults: 800 mg PO every 12 hours for 5 days. Start as soon as possible and within 5 days of symptom onset.
- Monoclonal antibodies with antiviral action
- Tixagevimab and cilgavimab in combination
- Cilgavimab Solution for injection, Tixagevimab Solution for injection; Children and Adolescents 12 years and older weighing 40 kg or more: 300 mg tixagevimab and 300 mg cilgavimab given as 2 separate consecutive IM injections. For persons who received the previously authorized lower dose, give an additional 150 mg tixagevimab and 150 mg cilgavimab dose as soon as possible if the initial dose was within the past 3 months; if the initial dose was more than 3 months ago, give 300 mg tixagevimab and 300 mg cilgavimab as soon as possible. Data are currently insufficient to recommend repeat dosing.
- Cilgavimab Solution for injection, Tixagevimab Solution for injection; Adults weighing 40 kg or more: 300 mg tixagevimab and 300 mg cilgavimab given as 2 separate consecutive IM injections. For persons who received the previously authorized lower dose, give an additional 150 mg tixagevimab and 150 mg cilgavimab dose as soon as possible if the initial dose was within the past 3 months; if the initial dose was more than 3 months ago, give 300 mg tixagevimab and 300 mg cilgavimab as soon as possible. Data are currently insufficient to recommend repeat dosing.
- Bebtelovimab
- Bebtelovimab Solution for injection; Adults: 175 mg as a single intravenous injection. Administer as soon as possible after positive test for SARS-CoV-2 and within 7 days of symptom onset.
- Sotrovimab
- For use only when infection is likely to be caused by a susceptible variant (but Omicron subvariant BA.2 is nonsusceptible)
- For patients aged 12 years or older, weighing 40 kg or more, with mild to moderate disease (not requiring supplemental oxygen and not hospitalized) at risk for progression
- Sotrovimab Solution for injection; Adults weighing 40 kg or more: 500 mg as a single IV infusion. Give as soon as possible after the positive test for SARS-CoV-2 and within 7 days of symptom onset.
- Casirivimab-imdevimab c260
- For use only when infection is likely to be caused by a susceptible variant (but Omicron is nonsusceptible)
- For patients aged 12 years or older, weighing 40 kg or more, with mild to moderate disease (not requiring supplemental oxygen and not hospitalized) at risk for progression
- Casirivimab, Imdevimab Solution for injection; Children and Adolescents 12 to 17 years weighing 40 kg or more: Give 600 mg casirivimab and 600 mg imdevimab via 4 subcutaneous injections at different sites. Give as soon as possible after the positive test for SARS-CoV-2 and within 10 days of symptom onset.
- Bamlanivimab-etesevimab c261
- Context of use
- For use only when infection is likely to be caused by a susceptible variant (but Omicron is nonsusceptible)
- Bamlanivimab and etesevimab MUST be administered in combination. Neither drug is authorized for administration as a single agent (ie, monotherapy)
- For patients aged 12 years or older with mild to moderate disease (not requiring supplemental oxygen and not hospitalized) at risk for progression
- Bamlanivimab component
- Bamlanivimab Solution for injection; Adults: 700 mg of bamlanivimab and 1,400 mg of etesevimab together in a single IV infusion. Give as soon as possible after the positive SARS-CoV-2 test and within 10 days of symptom onset.
- Etesevimab component c262
- Etesevimab Solution for injection; Adults: 700 mg of bamlanivimab and 1,400 mg of etesevimab together in a single IV infusion. Give as soon as possible after the positive SARS-CoV-2 test and within 10 days of symptom onset.
- Immunomodulators
- Baricitinib c263
- Baricitinib Oral tablet; Adults: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines recommend use with dexamethasone (with or without remdesivir) IF on supplemental oxygen, including noninvasive ventilation or high-flow oxygen, AND there is evidence of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone.
- Tocilizumab c264
- Tocilizumab Solution for injection; Adults: 8 mg/kg (max: 800 mg) IV infusion once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first. The EUA requires concurrent use with a systemic corticosteroid. The NIH COVID-19 treatment guidelines recommend a single 8 mg/kg (actual body weight, up to 800 mg) IV dose given with dexamethasone (with or without remdesivir) for hospitalized patients on supplemental oxygen, including high-flow oxygen and noninvasive ventilation, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, NIH recommends use with dexamethasone for patients on mechanical ventilation or ECMO IF admitted to an ICU within the prior 24 hours.
- Sarilumab c265
- Sarilumab Solution for injection; Adults: The NIH COVID-19 treatment guidelines recommend a single 400 mg IV dose given with dexamethasone (with or without remdesivir) to treat hospitalized adults on supplemental oxygen, including high-flow oxygen and noninvasive ventilation, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, may be given with dexamethasone for patients on mechanical ventilation or ECMO IF admitted to an ICU within the prior 24 hours. Sarilumab is an alternative if tocilizumab is not available or cannot be used.
- Tofacitinib
- Tofacitinib Oral tablet; Adults: The NIH COVID-19 treatment guidelines recommend 10 mg PO twice daily for up to 14 days or until hospital discharge (whichever comes first) to treat hospitalized adults on supplemental oxygen, including noninvasive ventilation and high-flow oxygen, with rapidly increasing oxygen needs and systemic inflammation. MUST be given with dexamethasone (with or without remdesivir). Tofacitinib is an alternative if baricitinib is not available or cannot be used.
- Corticosteroid
- Dexamethasone c266
- 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.
- Various guidelines provide recommendations for alternative glucocorticoids if dexamethasone is not available r8r98
- Methylprednisolone c267
- 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 c268
- Prednisone Oral tablet; 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.
Nondrug and supportive care c269
- Excellent supportive care remains the mainstay of treatment to date in COVID-19 c270
- WHO,r35NIH,r8 and Surviving Sepsis Campaignr90 provide specific guidance for oxygenation, ventilation, and fluid management in COVID-19 d4
- Patients with severe respiratory distress, obstructed or absent breathing, central cyanosis, shock, seizures, or coma require aggressive airway management (which may include intubation) and oxygen d4
- Oxygenation and ventilation c271
- Begin supplemental oxygen therapy when oxygen saturation falls below 90% to 92% r90
- Nasal cannula at 5 L/minute or face mask with reservoir bag at 10 to 15 L/minute r35
- Titrate to reach SpO₂ of 94% or more initially
- Once stable, target SpO₂ of 90% or higher in nonpregnant adults; 92% or higher in pregnant patients
- In most children the target SpO₂ is 90% or greater; for those who require urgent resuscitation (eg, those with apnea or obstructed breathing, severe respiratory distress, central cyanosis, shock, seizures, or coma), a target SpO₂ of 94% or higher is recommended
- High-flow nasal oxygen or noninvasive ventilation has been used to achieve adequate oxygenation in some patients r151c272c273c274c275c276
- High-flow nasal oxygen is recommended by Surviving Sepsis Campaignr90 and NIHr8 for patients with COVID-19 who develop hypoxemic respiratory failure despite conventional oxygen therapy; there is some evidence that it averts the need for intubation and mechanical ventilation. Noninvasive positive pressure ventilation may be used if high-flow nasal oxygen is not available
- However, there is concern that these techniques may result in higher risk of aerosolization of the virus. Additionally, sudden deterioration may require emergent intubation, which is associated with more risk to both patient and provider. Therefore, some authorities reserve these options for settings in which airborne precautions can be taken and close monitoring provided r90
- Mechanical ventilation may become necessary for patients in whom oxygenation targets cannot be met with less invasive measures or who cannot maintain the work of breathing (eg, PaO₂/FIO₂ ratio of less than 300 mm Hg)r75c277
- Although optimal technique has not been fully defined, COVID-19–specific recommendations are emerging d4
- Extracorporeal membrane oxygenation has been usedr21 in severely ill patients, and it can be considered if resources and expertise are available c278
- Fluid management
- Overhydration should be avoided, because it may precipitate or exacerbate acute respiratory distress syndrome c279
- 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 r152
Comorbidities
- Severe COVID-19 has been associated with chronic conditions such as diabetes, hypertension, and other cardiovascular conditions r8c280c281c282
- Owing to the role of the ACE2 receptor in the pathogenesis of COVID-19, controversy has arisen over the positive or negative effects that ACE inhibitors and angiotensin receptor blockers may have on the disease. A joint statement by the American College of Cardiology, American Heart Association, and Heart Failure Society of Americar153 recommends that persons who are currently taking these medications for appropriate indications should continue to do so; the NIH guidelines for treatmentr8 concur
- Several analyses of data from large numbers of patients with COVID-19 have shown no association between ACE inhibitors or angiotensin receptor blockers and either acquisition of COVID-19 or severity of infection r154r155r156r157r158r159
- A prospective cohort study based on routinely collected data from more than 8 million persons enrolled in general practices in England identified more than 19,000 persons with COVID-19. Use of ACE inhibitors or angiotensin receptor blockers was associated with reduced risk of COVID-19 disease and was not associated with increased risk of requiring intensive care. The reduction in risk was less for Black people of Caribbean and African descent r160
Special populations
- Pregnant patients
- Pregnant patients are at higher risk for severe disease (including increase risk for hospitalization, requiring mechanical ventilation, and death) and for adverse pregnancy outcomes such as preterm birth and stillbirth r161
- Vaccination is recommended for pregnant persons and those who may become pregnant, by the CDC, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine r8r161r162r163
- American College of Obstetricians and Gynecologists recommends that the mode of delivery be determined based on obstetric indications and patient preference; cesarean delivery is recommended only for the usual medically justified indications r164
- There is little evidence to suggest vertical transmission;r166r35r164 however, an infected mother may transmit the virus by the airborne route to the neonate. CDC and WHO differ somewhat in their recommendations r165
- Because of concerns for transmission, CDC has recommended that separation of neonates from mothers known or suspected to have COVID-19 can be considered until isolation can be discontinued per usual protocol. The decision is best individualized in consultation with patient wishes. If temporary separation is chosen, breast milk may be pumped and fed to the infant by another caregiver r165
- Focusing on ensuring successful initiation of breastfeeding, WHO advises that postpartum females and their neonates room in (cohabit), including the practice of skin-to-skin and kangaroo care r35
- Breastfeeding patients r167
- Vaccination is recommended
- People without suspected or confirmed COVID-19 and who have not been in close contact with someone who has COVID-19, or who have received a COVID-19 vaccine, do not need to take special precautions when feeding at the breast or expressing milk
- A breastfeeding person who is not fully vaccinated against COVID-19 should take precautions to protect themselves and the breastfed child when either of them has suspected or confirmed COVID-19
- CDC strongly recommends vaccination for adults, with few contraindications
- Patients with HIV
- Vaccination is recommended r8r168
- Well controlled HIV infection may not alter risk for infection or severe outcome. Advanced HIV infection (eg, CD4 count less than 200 cells/mm³) may increase the risk for severe disease or complications r55r168
- It is recommended that patients continue their current antiretroviral regimen; specifically, empiric addition of lopinavir-ritonavir (for possible efficacy against or protection from SARS-CoV-2) is not recommended outside of a clinical trial
- A guideliner168 by the US Department of Health and Human Services offers strategies for ensuring continuity of antiretroviral medication
- Recommendations for management of patients with HIV who develop COVID-19 do not differ from standard recommendations
- Potential for drug interactions may complicate eligibility for enrollment in a clinical trial for COVID-19 or treatment; drug interaction checkerr87 is recommended