COVID-19, SARS CoV-2

by Editorial Board last updated 2022-01-07 16:17:25.138787-05:00 © 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)
    • 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
  • 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 Omicron variant (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 and should be the monoclonal antibody treatment of choice. 
      • 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. 
  • See Isolation / Quarantine for current CDC recommendations issued in light of the Omicron variant
  • 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
    • 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 Severity

  • See table 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

Paxlovid or Molnupiravir (both po) OR

Remdesivir (IV)

Dexamethasone NOT recommended

 Close clinical monitoring
Not hospitalized, mild-to-severe disease, high risk of disease progression

Monoclonal antibody:
(Casirivimab + Imdevimab) has good activity vs all variants except Omicron

 

Sotrovimab:  Good activity vs all variants, including Omicron


(Bamlanivimab + Etesevimab) retains ~full activity vs wild-type, alpha, and Delta variants but loses activity vs Omicron. It is not as active vs Beta, Gamma, Mu, and Delta-plus variants (don't use in regions where these variants are > 5% of cases)

 

Dexamethasone / systemic steroids NOT recommended

Monoclonal antibody strongly preferred over convalescent plasma. It should be administered as early as possible in the course of disease; not recommended after day 7- 9 of symptoms as unlikely to be effective.  Sotrovimab is a single antibody preparation that retains activity vs Omicron variant.

 

Casi-Imde and Bam-Ete DO NOT have activity vs Omicron variant. 
Hospitalized, mild disease (no lower respiratory tract disease). Patient at high risk of disease progression

Remdesivir OR

Monoclonal antibody if admitted for reason other than COVID-19

 

Dexamethasone NOT recommended

Prophylactic anticoagulation (see below)

Monoclonal antibody strongly preferred over convalescent plasma. Should be administered as early as possible in the course of disease; do not give after day 7- 9 of symptoms.
Hospitalized, moderate disease (evidence of lower respiratory tract disease) with no supplemental O2 requirement. Patient at high risk of disease progression.

Remdesivir

Dexamethasone NOT recommended

Prophylactic anticoagulation (see below)

 Can use convalescent plasma if ≤ 3 days of symptoms, but benefit unclear (see Comments below).
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) 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
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.
 Other Convalescent plasma Various: Single transfusion 250-700 mL or two transfusions of 200-500 mL given 24h apart Efficacy limited; uncertain coverage of variants. Not recommended Difficult to determine antibody titer; dose to dose variability.

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 

  • 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

  • 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.

Transmission

  • 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.

Fully Vaccinated Persons

  • Fully vaccinated persons, see Interim CDC guidance (updated 19 Nov 2021) 
    • May participate in many pre-pandemic activities
    • Resume domestic travel and refrain from testing or quarantine before / after travel
    • Refrain from testing before international travel unless required by the destination and refrain from self-quarantiine upon return
    • Refrain from routine screening testing if feasible
    • Should wear a mask indoors in public if in area of substantial or high transmission
    • Get tested if experiencing COVID-19 symptoms
    • Get tested 5-7 days after close contact with a person with suspected or confirmed COVID-19. Wear a mask indoors for 14 days or until negtaive test result.
    • Follow any applicable Federal, state, local, tribal or territorial laws, rules and regulations
    • Immunocompromised persons:
      • Potential for reduced immune response from vaccines, therefore, use prevention measures (mask, 6 feet distancing, avoid crowds and poorly ventilated indoor spaces)
  • Masks Work: Reduction in transmission documented in multiple studies, summarized here (JAMA, Feb 2021;  MMWR March 5, 2021)

Isolation / Quarantine

Status Who Recommendation
Tested positive for COVID-19 Everyone Isolate for 5 days. If no symptoms or symptoms resolving after 5 days, end isolation.
Wear mask around others for an additional 5 days
If fever, continue isolation until fever resolves.
Exposed to someone with COVID-19, recently fully vaccinated Boosted OR
Completed primary series (Pfizer or Moderna) within 6 months OR
Completed primary series (J&J) within 2 months		 Quarantine. Wear a mask around others for 10 days.
Get tested on day 5 day if possible.
If symptoms develop, get tested and isolate.
Exposed to someone with COVID-19, unvaccinated, remotely vaccinated

Completed primary series (Pfizer or Moderna) over 6 months ago and not boosted OR
Completed primary series (J&J) over 2 months ago and are not boosted OR

Are unvaccinated

Quarantine. Stay at home for 5 days then wear a mask around others for an additional 5 days.

If unable to quarantine, wear a mask around others for 10 days.
Get tested on day 5 if possible.
If symptoms develop, get tested and isolate.