COVID-19, SARS CoV-2

by Editorial Board last updated 2022-09-12 12:38:00.975433-04:00 © Antimicrobial Therapy, Inc.
Coronavirus, SARS CoV-2, COVID-19

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 for development of severe disease 
      • 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
  • 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.

Variants

  • Omicron variant (BA.4/5) (July 2022):
    • Omicron BA.4 and BA 5 are even more transmissible than Omicron BA 2.. Among "Fully Vaccinated" (meaning, those who have had 2 initial injections with an mRNA vaccine and boosted with a third shot) individuals, infection still occurs but protection against hospitalization / death remains high.  BA 4 and BA 5 appear to be more virulent than BA 1 or BA 2.1.
    • 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, BA.1 and BA 4/5, although activity against BA 4/5 is diminished a bit.  Bebtelovimab remains the monoclonal antibody of choice against these variants.
      • 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.
  • 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.
  • 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:
    • Neither (casirivimab + imdevimab) nor (bamlanivimab + etesevimab) monoclonal antibody preparations work against Omicron and should NOT be used. 
  • 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.
  • See Isolation / Quarantine for current CDC recommendations based on vaccination status.
  • Prevention

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
    • 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

Recommendations Based on Disease Severity

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

 

 

 

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)

 
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.

Remdesivir


Prophylactic anticoagulation (see below)

 Dexamethasone NOT recommended
Hospitalized, severe disease (O2 saturation <94% and/or PaO2/FiO2 <300) requires supplemental O2.

Remdesivir + Dexamethasone + Tocilizumab

Therapeutic anticoagulation: For nonpregnant patients with D-dimer levels >ULN who are not at increased bleeding risk, and do not require high-flow oxygen or ICU-level care (for details see Anticoagulation below)

For all others:  Prophylactic anticoagulation (for details see Anticoagulation 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 (for details see Anticoagulation 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. Use of therapeutic anticoagulation with heparin for non-pregnant patients with severe disease requiring supplemental oxygen and elevated D-dimer (> ULN). See Anticoagulation below for details)

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)

Paxlovid Rebound  (recurrence of symptoms) occurs 3 -4 days post last dose of Rx; Retreatment is recommended for those who have significant symptoms with the rebound
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 nor BA 4/5
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. 

Fully approved by US FDA

 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
  • CBC with differential, troponin, LFTs, Chem 10, CPK
  • Ferritin, CRP, LDH, d-dimer, PT/PTT/fibrinog
  • For risk stratification (repeat if patient deteriorates clinically):
    • LDH (repeat daily if elevated)
    • Troponin
    • Baseline EKG
  • Viral serologies (unless checked recently):
    • HIV
    • HCV antibody
    • HBV surface antibody, core antibody and surface antigen
  • If clinically indicated:
    • Blood cultures x 2, sputum culture(BAL recommended by some), UA with reflex to culture, and Urine
      strep/legionella antigen
    • β-HCG for women of childbearing age
Recommended daily labs
(until stable)
  • CBC with diff (esp. total lymphocyte count)
  • Complete metabolic panel
  • CPK (creatine kinase)
  • CRP first week of hospitalization; inflammatory markers hard to interpret beyond 1 week
Recommended every other day
(daily if elevated or pt in ICU)
  • PT/PTT/fibrinogen
  • D-dimer
Radiology
  • Portable chest x-ray at admission; further imaging based on evaluation, concern for
    secondary bacterial infection, pulmonary embolism, etc.

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 

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.
  • 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
  • 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

  • COVID-19 infection is associated with a hypercoaguable state. Results from several large studies comparing prophylactic to therapeutic anticoagulation suggest benefit of therapeutic anticoagulation in patients with moderate but not severe infection. Patients hospitalized for COVID-19 who require supplemental oxygen but not high-flow nasal cannula or ventilatory support are more likely to survive to discharge without requiring organ support with therapeutic compared to prophylactic heparin. Overall survival was not improved with therapeutic compared to prophylactic heparin. Severely ill patients (e.g., ICU level care, high-flow oxygen) do not benefit from therapeutic anticoagulation and may be harmed by bleeding risks. References: N Engl J Med. 2021;385:790-802 and N Engl J Med. 2021; 385:777-789). Link to NIH guidelines here.
  • Prophylactic heparin-based anticoagulation
    • Dosing: sub-cutaneous heparin or enoxaparin for standard venous thromboembolism (VTE) prophylaxis
    • Recommended for:
      • Patients with no requirement for supplemental oxygen or who are hospitalized for reasons other than COVID-19.
      • Patients who require supplemental oxygen but patient or provider preference for prophylactic rather than therapeutic dosing, for example if risk of bleeding outweighs the benefit.
      • Patients who require non-invasive positive-pressure ventilation, oxygen therapy >20L, or ICU-level care 
    • Contraindications:
      • Any contraindication to therapeutic or prophylactic anticoagulation, such as active CNS bleed, severe thrombocytopenia with platelet count < 25,000, history of heparin-induced thrombocytopenia
  • Therapeutic heparin-based anticoagulation
    • Dosing: Standard VTE treatment dosing of heparin-based anticoagulation should be used, continued for no more than 14 days and discontinued on discharge.
      • Enoxaparin is preferable to unfractionated heparin unless CrCl < 15 or other contraindication.
      • Decreasing to prophylactic dose may be considered with resolving clinical course (e.g. discontinuation of oxygen) or if clinical severity increases to ICU level support or oxygen >20L at the discretion of the provider given lack of clear data in this area.
      • For patients already on chronic full dose anticoagulation (e.g. DOAC, warfarin), this may be continued instead of heparin-based anticoagulation
      • Recommended for
        • Non-critically ill patients requiring supplemental oxygen or stable/improving HFNC < 20L. Note: the decision to initiate therapeutic versus prophylactic anticoagulation, must weigh potential benefits with risks and patient preference.  
          • Potential benefits: decreased need for organ support but no difference in survival  
          • Potential risks: bleeding complications 
      • Contraindications:
        • Any contraindication to heparin or therapeutic anticoagulation, such as dual antiplatelet therapy, major bleeding with the last 30 days, known acquired or inherited bleeding disorder, history of heparin induced thrombocytopenia, recent ischemic stroke, platelet count < 50 x 10^9/L, Hemoglobin < 8 g/dL, or clinical discretion of the treating physician.

    Transmission

    SARS CoV-2 Transmission Curve.png

    • 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.
    • 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.

    Exposure / Quarantine / Isolation

    Exposure

    • Start precautions immediately: Wear a mask as soon as you find out you were exposed. Continue precautions for 10 full days after exposure.
    • Get tested at least 5 days after last exposure. If negative, continue precautions through day 10. If positive, isolate immediately

    Isolation

    • Regardless of vaccination status, isolate from others if COVID-19 positive.
    Status Period Post-Period Precautions
    COVID-19 negative test result May end isolation after day 5
    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 moderate or 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