COVID-19, SARS CoV-2
Management of COVID-19
Initial Clinical Evaluation
- Symptomatic person with positive test result (PCR or antigen)
- Initial clinical evaluation focuses on:
- Date of onset of symptoms, not date of first positive test (to determine duration of illness and timing of treatment)
- Risk factors
- Age > 65 years, immune-compromised state, obesity (BMI >35), diabetes mellitus, chronic kidney disease
- Potential treatment-limiting organ dysfunction (renal, hepatic)
- Severity of disease (see table below)
- Child or adolescent, see also MIS-C / MIS-A
- See COVID-19 Vaccines, Prevention for vaccines summary coverage and prevention, including prophylaxis. See individual vaccine pages for additional details.
- General Refs: NIH COVID-19 Treatment Guidelines; N Engl J Med 2020;382:1708; Lancet 2020;395:497; JAMA 2020;323:1061; JAMA 2020;323:1239.
- Important note re Delta variant (Aug 2021):
- Key characteristics: hypertransmissibility and high peak viral loads.
- Much of the knowledge of clinical, epidemiologic, therapeutic, and diagnostic aspects of infection and COVID-19 are based on studies done in the pre-Delta era and recommendations based on references that pre-date Delta should be interpreted in that context. Of course, we will continue to update COVID-19 information and recommendations based on new developments.
- Important note re Initial Omicron variant (BA.1) (Dec 2021):
- Omicron is at least twice as transmissible as Delta. Early evidence suggests clinical disease is less severe than Delta, especially in "Fully Vaccinated" (meaning, those who have had 2 initial injections with an mRNA vaccine and boosted with a third shot); unclear regarding the virulence of Omicron among unvaccinated individuals.
- Treatment options for Omicron:
- Sotrovimab has activity against Omicron BA.1 (but NOT BA.2; see below)
- Two newly approved oral antivirals: Paxlovid (nirmatrelvir + ritonavir) and molnupiravir also have activity against Omicron.
- Neither (casirivimab + imdevimab) nor (bamlanivimab + etesevimab) monoclonal antibody preparations work against Omicron and should NOT be used.
- Important note re Omicron variant (BA.2.1) (March 2022):
- Omicron BA.2.1 is at least twice as transmissible as Omicron BA.1. Early evidence suggests clinical disease is similar to earlier Omicron variant, especially in "Fully Vaccinated" (meaning, those who have had 2 initial injections with an mRNA vaccine and boosted with a third shot)
- For those who are > 5 - 6 months out from their last shot (Booster; shot #3), a 4th shot (2nd booster) is recommended for those at high risk for more severe disease.
- Treatment options for Omicron BA2.1:
- Bebtelovimab, a novel anti-SARS-CoV-2 monoclonal antibody has activity vs Omicron BA.2 and BA.1 and is the monoclonal antibody of choice against these variants.
- Sotrovimab DOES NOT HAVE activity against Omicron BA.2 and should not be used.
- Two approved oral antivirals: Paxlovid (nirmatrelvir + ritonavir) and molnupiravir also have activity against both Omicron variants (BA.1 and BA2.1). Paxlovid is more potent than molnupiravir and is the preferred oral antiviral agent.
- Remdesivir retains activity against all variants of SARS-CoV-2. While usually administered in the inpatient setting, a 3-day outpatient regimen works well.
- Neither (casirivimab + imdevimab) nor (bamlanivimab + etesevimab) monoclonal antibody preparations work against Omicron and should NOT be used.
- See Isolation / Quarantine for current CDC recommendations based on vaccination status.
- See COVID-19 Prevention for pre-exposure prophylaxis, post-exposure prophylaxis and authorized vaccines and information.
Severity of Disease
Severity | Indicators |
Asymptomatic | No symptoms |
Mild disease | Fever, cough, sore throat, N/V, diarrhea, loss of taste or smell but no dyspnea; normal O2 saturation and normal chest X-ray |
Moderate disease | Symptoms of mild disease plus evidence of lower respiratory tract infection (exam and/or imaging), O2 saturation ≥94% on room air |
Severe disease | Symptoms of moderate disease but O2 saturation <94%, PaO2/FiO2 <300 mmHg, respiratory frequency >30 breaths per minute, or lung infiltrates >50% |
Critical disease | Symptoms of severe disease but intubated with respiratory failure, septic shock, and/or multiorgan dysfunction |
Treatment
General Principles of Therapy
- Early diagnosis of COVID-19
- Important note: date of onset of first symptoms drives treatment decision making (not the date of first positive test).
- Two stages of disease:
- Day 1-7: active viral replication
- Antiviral therapies most likely to be efficacious at this early stage
- E.g., Remdesivir, anti-viral monoclonal antibodies and oral direct-acting antiviral agents (Paxlovid and molnupiravir)
- Not recommended: Systemic corticosteroids and other immune modulators (e.g., IL-6 inhibitors)
- Unlikely to be beneficial, may be harmful, may prolong the period of viral replication
- Antiviral therapies most likely to be efficacious at this early stage
- Day 8-14 or longer: immune dysfunction (e.g., respiratory compromise, other severe disease)
- Antiviral therapies less effective, and maybe ineffective, in this stage of the disease
- Corticosteroids and other immune modulators likely to be beneficial for those with severe disease
- Day 1-7: active viral replication
Recommendations Based on Disease Severity
- See Recommended Regimens, Dosing below for dosing / indications, see also the drug pages.
Setting, disease severity, risk of progression | Therapy | Comments |
Not hospitalized or hospitalized, asymptomatic | None recommended | Close clinical monitoring |
Not hospitalized, mild-to-moderate disease, NOT at high risk of disease progression | None recommended | Close clinical monitoring |
Not hospitalized, mild-to-severe disease, high risk of disease progression |
In order of preference (NIH Treatment Guidelines.)
Paxlovid 300/100 po bid x 5 days OR Bebtelovimab175 mg IV x 1 dose OR
Remdesivir 200 mg IV day 1, then 100 mg IV days 2-3 OR
Molnupiravir 800 mg po bid x 5 days
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Antiviral therapy and/or monoclonal antibody should be administered as early as possible (within 3 days) after onset of symptoms: Paxlovid: within 5 days Remdesivir within 7 days Molnupiravir within 5 days
Sotrovimab and Bebtelovimab retain activity vs Omicron variant. Bebtelovimab also active vs. BA.2 subvariant
Dexamethasone / systemic steroids NOT recommended early (within the first 7 - 10 days unless hospitalized and hyperemic)
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Hospitalized, mild disease (no lower respiratory tract disease). Patient at high risk of disease progression |
Remdesivir (see below for dosing) OR Monoclonal antibody if admitted for reason other than COVID-19 Prophylactic anticoagulation (see below) |
Monoclonal antibody should be administered as early as possible in the course of disease; do not give after day 7- 9 of symptoms.
Dexamethasone NOT recommended |
Hospitalized, moderate disease (evidence of lower respiratory tract disease) with no supplemental O2 requirement. Patient at high risk of disease progression. |
Prophylactic anticoagulation (see below) |
Dexamethasone NOT recommended |
Hospitalized, severe disease (O2 saturation <94% and/or PaO2/FiO2 <300) requires supplemental O2. |
Remdesivir + Dexamethasone + Tocilizumab Consider therapeutic anticoagulation (see below) |
In patients who are unable to receive dexamethasone, use as alternative Baricitinib (plus Remdesivir); see Notes on Recommended Regimens for use of Tocilizumab. |
Hospitalized, critical disease -- requires mechanical ventilation or ECMO |
Dexamethasone + Remdesivir + Tocilizumab Prophylactic anticoagulation (see below) |
Benefit of Remdesivir unproven, but recommended by some authorities Consider IL-6 receptor blocker in the first 24 hours of ICU admission (ok to use with Remdesivir and dexamethasone, would not recommend in conjunction with Baricitinib) In patients who are unable to receive dexamethasone, consider Baricitinib. See Notes on Recommended Regimens for use of Tocilizumab. |
- In outpatient setting: adjunctive therapy with acetaminophen, ibuprofen (or naproxen), guaifenesin, ondansetron, Imodium, inhaled albuterol, inhaled steroid, H2 blocker, and / or sleeping meds (e.g., melatonin) as needed prn
- Prophylactic dose anticoagulation with heparin is recommended for hospitalized patients with mild or moderate disease or for those with critical disease disease requiring mechanical ventilation or ECMO. Consider use of therapeutic anticoagulation with heparin for patients with severe disease requiring supplemental oxygen. See Comments.
Recommended Regimens, Dosing
Type | Drug | Dose/duration | Indication | Comments |
Antiviral | Molnupiravir |
800 mg (four 200 mg capsules) po q12h for five days, with or without food |
Adults with mild-moderate illness with at least one risk factor for severe disease(obesity, age >60 yrs, diabetes, CVD) | |
Antiviral | Paxlovid (nirmatrelvir + ritonavir) | 300 mg (two 150 mg tablets) nirmatrelvir + 100 mg (one tablet) ritonavir, all 3 tabs po 2x daily | Any person >12 years of age with positive SARS-CoV-2 viral test, and who have at least one risk factor for severe disease (obesity, age >60 yrs, diabetes, CVD + others, see drug page) | Watch for drug-drug interactions (ritonavir is a potent inhibitor of CYP 3A4) |
Antiviral | Remdesivir |
Adult (wt > 40 kg): 200 mg IV loading dose on day 1, then 100 mg IV daily maintenance dose. Infuse each dose over 30-120 min. Pediatric (wt 3.5 - 40 kg): 5 mg/kg loading dose on day 1, then 2.5 mg/kg maintenance dose Duration: 5 days if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days. 10 days for patients on mechanical ventilation/ECMO |
Hospitalized patients with severe disease. Consider in patients with moderate and critical disease as well. | |
Antiviral (monoclonal antibody) | Bamlanivimab + Etesevimab |
(Bamlanivimab 700 mg + Etesevimab 1400 mg) co-administered as a single infusion in a healthcare setting. |
Outpatients with mild-severe disease at high risk for progression to more severe disease and hospitalization | Benefit greatest if given early after onset of symptoms. Do not use if Delta-plus or Omicron variant suspected |
Antiviral (monoclonal antibody) | Bebtelovimab |
175 mg IV x 1 dose |
Outpatients with mild-moderate disease at high risk for progression to more severe disease and hospitalization | Active vs. Omicron BA.2 subvariant |
Antiviral (monoclonal antibody) | Casirivimab + Imdevimab |
Casirivimab + Imdevimab combination 1,200 mg (casirivimab 600 mg + imdevimab 600 mg) single IV infusion |
Outpatients with mild-severe disease at high risk for progression to more severe disease and hospitalization or death. | Benefit greatest if given early after onset of symptoms. Dose of each antibody lowered to 600 mg on June 3 2021. Do not use if Omicron variant suspected |
Antiviral (monoclonal antibody) | Sotrovimab |
500 mg IV over 30 minutes |
Outpatients with mild-severe disease at high risk for progression to more severe disease and hospitalization | Benefit greatest if given early after onset of symptoms. Works vs Omicron variant BA.1 BUT NOT BA.2 |
Anti-inflammatory (Il-6 inhibitor) | Tocilizumab |
8 mg/kg, actual body weight up to 800 mg, as a single IV infusion with a second dose 12-24h later if no improvement |
Hospitalized patient with progressive severe or critical disease; RECOVERY trial included systemic inflammation, defined as CRP > 75 mg/L, as a criterion | Benefit probably greatest if administered early, i.e., within 48h of hospitalization or < 24h after ICU admission. Possible increased risk of infection, especially is used in conjunction with corticosteroid: monitor clinically for secondary bacterial, fungal and other opportunistic infections. |
Anti-inflammatory (JAK inhibitor) | Baricitinib | 4 mg po daily (for up to 14 days) + Remdesivir 200 mg on day 1, then 100 mg IV daily for up to 10 days + dexamethasone. | Hospitalized patients not on mechanical ventilation or ECMO with severe and critical disease, ideally administered within the first 72h of hospitalization | May be used in combination with Remdesivir in the rare situation where a corticosteroid cannot be used. May also be used n place of an IL-6 inhibitor in combination with a corticosteroid; should not be used in combination with IL-6 inhibitor therapy |
Anti-inflammatory (JAK inhibitor) | Tofacitinib | 10 mg po q12h (for up to 14 days) + Remdesivir 200 mg on day 1, then 100 mg IV daily for up to 10 days + Dexamethasone | Hospitalized patients not on mechanical ventilation or ECMO with severe and critical disease, ideally administered within the first 72h of hospitalization | Possible alternative to Baricitinib. Ideally used in combination with Dexamethasone instead of an IL-6 inhibitor; should not be used in combination with IL-6 inhibitor therapy |
Anti-inflammatory | Dexamethasone |
6 mg once daily IV or po x 10 days for patients on supplemental oxygen or mechanical ventilation |
Hospitalized patients with severe and critical disease |
NOT RECOMMENDED unless patient on supplemental oxygen The RECOVERY trial (N Engl J Med. 2021; 394:755) lower 28-day mortality; Meta-analysis (JAMA 2020;324: 1330) of critically ill patients improved 28-day survival with dexamethasone. |
Suggested Laboratory Evaluation, Inpatient
When | What to order |
At hospital admission |
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Recommended daily labs (until stable) |
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Recommended every other day (daily if elevated or pt in ICU) |
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Radiology |
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Laboratory Predictors: Severe Disease, Poor Outcome
- Decreased absolute lymphocyte count
- Ratio of absolute neutrophil count to absolute lymphocyte count > 3.5
- Elevated CPK, CRP, Ferritin, D-dimer, LDH, Troponin, PT
- Thrombocytopenia
- LFTs 5x upper limit of normal
- Acute kidney injury
- See Lancet 2020;395:1054.
Stewardship Considerations:
- Concomitant bacterial pneumonia is uncommon; With on admission BAL, potential bacterial pathogen found in 21% of patients (Am J Respir Crit Care Med. 2021;204: 921)
- Hence, routine empiric coverage for bacterial co-infection is not recommended
- Hospitalized patients with COVID-19 pneumonia may develop bacterial and fungal pneumonia in the health care setting
- Overall bacterial infection rate of 7.1% with 3.5% of patients infected at presentation and with 15.5% of patients developing secondary bacterial infections over the course of illness (Clin Microbiol Infect 220; Jul 22;S1198-743X(20)30423-7)
- Single center study of 4267 hospitalized patients in New York City between 3/1/20 to 4/28/20 (Infect Control Hosp Epidemiol 2020; Jul 24, 1-13. doi: 10.1017/ice.2020.368) found overall bacterial and fungal infection rate of 3.6% with respiratory only infection in 46%, blood only in 40%, both in 14%. 95% of patients with positive respiratory cultures were intubated. Similar findings in a second multicenter study (Open Forum Infect Dis. 2020 Dec 21;8(1):ofaa578).
Comments
Other Therapies: Not Recommended
- Convalescent plasma: no proven benefit.
- NIH Treatment Guidelines recommend against use in hospitalized immunocompetent persons; insufficient evidence on which to base any recommendation for immunocompromised persons.
- NIH Treatment Guidelines recommend against use in hospitalized immunocompetent persons; insufficient evidence on which to base any recommendation for immunocompromised persons.
- Colchicine: Efficacy unproven
- Randomized placebo controlled trial (not peer reviewed, pre-print in medRXiv) of non-hospitalized patients with proven or suspected COVID-19 found no statistically significant difference in the primary efficacy composite endpoint of death or hospitalization for COVID-19 in the primary analysis population, with possible benefit (4.6% vs. 6%) in a subpopulation analysis of those who tested PCR-positive for COVID-19.
- Interferon beta 1-a: Efficacy unknown, not recommended outside of a clinical trial.
- Press release on July 20 from Synairgen announced positive results of a phase II placebo controlled trial of inhaled interferon-beta.
- Ivermectin: Not Recommended
- No efficacy observed in 2 large randomized trials. (Jama. 325, 1426, 2021; BMC Infectious Diseases.21(1):635, 2021; N Engl J Med 2022 Mar 30 )
- Manufacturing company (Merck) recommends against using ivermectin for treatment of COVID-19 disease
- IL-1 inhibitors: Efficacy unproven, not recommended outside of a clinical trial.
- Chloroquine or Hydroxychloroquine ± Azithromycin: Not recommended in any setting due to lack of efficacy and risk of serious, potentially fatal cardiac arrhythmia
- HIV protease inhibitors: Not recommended, clinical benefit not demonstrated
Anticoagulation
- Rapidly evolving area
- Two randomized controlled trials, one in non-critically ill patients (N Engl J Med. 2021;385:790-802) and the other in critically ill patients requiring ICU-level care (N Engl J Med. 2021;:777-789), compared outcomes with therapeutic anticoagulation with heparin to usual care in hospitalized patients with COVID-19.
- In non-critically ill patients, there was a 4% difference (80.2% vs 76.4%) in survival without receipt of organ support in the therapeutic anticoagulation group compared to usual care (98.6% probability of superiority); the difference in hospital survival until discharge was not statistically significantly different.
- In critically ill patients requiring ICU-level care, therapeutic anticogaulation compared to usual care did not result in improved survival or in fewer days of cardiovascular or respiratory organ support.
- Two randomized controlled trials, one in non-critically ill patients (N Engl J Med. 2021;385:790-802) and the other in critically ill patients requiring ICU-level care (N Engl J Med. 2021;:777-789), compared outcomes with therapeutic anticoagulation with heparin to usual care in hospitalized patients with COVID-19.
Transmission
- Predominantly droplet, less commonly airborne; asymptomatic persons can transmit infection
- Transmission through contact with contaminated surfaces or objects (fomites) is low (generally 1:10,000) according to CDC Guidance 5 Apr 2021
- Maximum viral shedding begins prior to onset of symptoms, see figure below (He et al, Nature on line, 15 Apr 2020 (Figure 1c excerpt used with permission)
- Mean incubation time is estimated to be ~5 days after exposure (range 4.1 - 7.0 days, but as short as 36 hours.
- Viral shedding (References: Nature. 2020;581(7809):465-469; Lancet Infect Dis. 2020;20(5):565-574; Nat Commun. 2021 Jan 11;12(1):267, N Engl J Med . 2021 Jan 27. doi: 10.1056/NEJMc2027040):
- Infectious virus unlikely to be isolated after the first week from onset of symptoms, falling to below 5% after 2 weeks.
- Shedding of viral RNA assayed by RT-PCR from saliva and nasopharyngeal secretions remains high for approximately 6 days, declines significantly in the second week of illness, and usually ceases after 2-3 weeks.
- Emerging SARS CoV-2 variants
- See CDC for current information on emerging variants and implications for vaccine efficacy and possibility of re-infection.
- Alpha and Beta variants are ~ 50 - 60% more infectious than the original wide-type strain
- Delta variant is ~60% more infectious and transmissible than the alpha strain (and by extension, ~ 90% more infectious than the original wild-type strain)
- Omicron ~ 2x as transmissible as Delta variant. Ro approaches that of Measles.
- See CDC for current information on emerging variants and implications for vaccine efficacy and possibility of re-infection.
- Re-infection
- Re-infection accounts for <1% COVID-19 cases. An observational cohort study (The Lancet, published online March 17, 2021) conducted in Denmark estimated the protective immunity of prior COVID-19 infection to be ~80% overall and ~47% in persons age 65 years and older. The protective effect was durable with protection out to 7 months and longer.
Vaccination Status
- CDC Guidance (01/16/2022)
- CDC definition of "fully-vaccinated".
- Status for purposes of public health, mandates or US entry.
- Fully vaccinated means a person has received their primary series of COVID-19 vaccines. US FDA-authorized/approved vaccine: ≥ 2 weeks following receipt of the second dose in a 2-dose series (Moderna [aged ≥ 18 years: 0.5 mL; 100 µg] or Pfizer [aged 5-11 years: 0.2 mL; 10 µg or aged ≥ 12 years: 0.3 mL; 30 µg]) or ≥ 2 weeks following receipt of 1 dose of a single-dose series (Janssen/J&J [aged ≥ 18 years: 0.5 mL; 5x1010 viral particles]). Moderately or severely immunocompromised persons need an additional primary dose to be fully-vaccinated.
- CDC definition of "up-to-date".
- Up-to-date means a person has received all recommended COVID-19 vaccines, including any booster doses when eligible (boosters not indicated for all ages). A person is considered both “boosted” and up to date right after getting their booster dose. Up to date status alone affects recommendations for quarantine/isolation.
- See COVID-19 Prevention for full coverage of vaccines.
Quarantine / Isolation
- Updated CDC Guidance (01/20/2022) on isolation and quarantine based on vaccination status.
- Well-fitted mask means KN-95, N-95 (not cloth)
- Vaccination status based on CDC Guidance (01/16/2022):
- Up-to-date means primary series completed + booster (if eligible)
- Fully vaccinated means primary series completed
Quarantine
Status | Period | Post-Period | Precautions |
COVID-19 exposure but vaccination not up-to-date |
Quarantine for 5 days Wear well-fitted mask around others Get tested 5 days after exposure |
Watch for symptoms for another 5 days If symptoms develop, isolate and get tested |
10 days from exposure Wear a mask Don't travel Avoid contact with high-risk persons |
COVID-19 exposure vaccination is up-to-date |
No quarantine unless symptoms Get tested 5 days after exposure |
Watch for symptoms for another 5 days If symptoms develop, isolate and get tested |
10 days from exposure Wear a mask Don't travel Avoid contact with high-risk persons |
COVID-19 exposure and confirmed COVID-19 (PCR) within last 90 days |
No quarantine unless symptoms | Watch for symptoms for another 5 days If symptoms develop, isolate and get tested |
10 days from exposure Wear a mask Don't travel Avoid contact with high-risk persons |
Isolation
Status | Period | Post-Period | Precautions |
COVID-19 positive or symptoms regardless of vaccination status |
Isolate for at least 5 days Isolate from others Wear a well-fitted mask |
End after 5 days if: no fever for 24 hrs & symptoms improving If severe illness: continue isolation for at least total of 10 days |
10 days from positive test or symptoms Wear a mask Avoid travel Avoid contact with high-risk persons |
Community Level Prevention Steps
- CDC guidance (02-25-2022) for community level prevention steps based on Low, Medium or High community COVID-19 levels (as determined by hospital beds occupied, hospital admission and total number of new cases by U.S. county).
- Search for applicable level by U.S. County
Low (Green) | Medium (Yellow) | High (Orange) |
Up-to-date vaccination Test if symptoms |
Up-to-date vaccination Test if symptoms Wear mask if at high risk for severe illness |
Wear mask if at high risk for severe illness Up-to-date vaccination Test if symptoms Consider other measures based on risk |