COVID-19, SARS CoV-2

by Editorial Board last updated 2021-04-20 06:51:01.491847-04:00 © Antimicrobial Therapy, Inc.
Coronavirus, SARS CoV-2, COVID-19

Management of COVID-19

Initial Clinical Evaluation

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 1-10: active viral replication
      • Antiviral therapies most likely to be efficacious at this early stage
        • E.g., Remdesivir, anti-viral monoclonal antibodies and convalescent plasma
      • Not recommended: 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

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.

Dexamethasone NOT recommended

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

Monoclonal antibody:
(Bamlanivimab + Etesevimab) or (Casirivimab + Imdevimab)

Alternative:  convalescent plasma

Dexamethasone 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
Hospitalized, mild disease (no lower respiratory tract disease). Patient at high risk of disease progression

Monoclonal antibody if admitted for reason other than COVID-19

Alternative:  convalescent plasma

Dexamethasone NOT recommended

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

 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

 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

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
  • For use of anticoagulants and other therapies under study and/or therapy that is not recommended, see Comments

Recommended Regimens, Dosing

Treatment Type  Dose/duration Indication Comments
Remdesivir Antiviral

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.  
Dexamethasone Anti-inflammatory

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
Baricitinib Anti-inflammatory (JAK inhibitor) 4 mg orally daily (for up to 14 days) + Remdesivir 200 mg on day 1, then 100 mg IV daily for up to 10 days.  Hospitalized patients with severe and critical disease who are unable to tolerate corticosteroids Should only be used in the rare situation where corticosteroids cannot be used (see Comments)

Bamlanivimab +
Etesevimab		 Antiviral (monoclonal antibody)

(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.

Casirivimab + Imdevimab		 Antiviral (monoclonal antibody) Casirivimab + Imdevimab (Regeneron) combination 2,400 mg (casirivimab 1200 mg + imdevimab 1,200 mg) single IV infusion 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.
Convalescent plasma Antiviral Various: Single transfusion 250-700 mL or two transfusions of 200-500 mL given 24h apart If used, for inpatients with mild-moderate disease at high risk for progression to more severe disease and not eligible for monoclonal antibody combinations Use high antibody titer given within 72 hours of symptoms onset to maximize possible benefit (See Notes on Recommended Regimens). 
Tocilizumab Anti-inflammatory (Il-6 inhibitor) 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.

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, 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.

Notes on Recommended Regimens

  • Remdesivir
    • Efficacy demonstrated in hospitalized patients with respiratory disease: no benefit shown for those requiring high-flow oxygen, non-mechanical ventilation, mechanical ventilation, or extracorporeal membrane oxygenation
  • Dexamethasone
    • Efficacy demonstrated in hospitalized patients requiring supplemental oxygen
      • The RECOVERY trial  (see N Engl J Med. 2021; 394:755) found lower 28-day mortality in dexamethasone-treated patients compared to usual care.  Dexamethasone reduced deaths in patients receiving invasive mechanical ventilation and in patients receiving supplemental oxygen without invasive mechanical ventilation, but no mortality benefit and possible harm in patients not receiving supplemental or other respiratory support at randomization.
      • Meta-analysis (JAMA 2020;324:1330) of seven recent randomized controlled trials of steroids (3 dexamethasone, 3 hydrocortisone, 1 methyprednisolone) for critically ill COVID-19 patients found improved 28-day survival in those treated with systemic corticosteroids.  Survival benefit was driven largely by the dexamethasone.
  • Monoclonal Antibodies
    • Most likely to be efficacious in days 1-10 from onset of symptoms in outpatients
    • Early Use Authorization by FDA for outpatients only who are defined as high risk of progression, defined as patients who meet at least one of the following criteria:
      • Body mass index (BMI) ≥35
      • Chronic kidney disease
      • Diabetes
      • Immunosuppressive disease
      • Age ≥65 years
      • Age ≥55 years and one of the following:
        • Cardiovascular disease
        • Hypertension
        • Chronic obstructive pulmonary disease/other chronic respiratory disease
      • Age 12-17 years and one of the following:
        • BMI ≥85th percentile for their age and gender based on CDC growth
        • Sickle cell disease
        • Congenital or acquired heart disease
        • Medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19)
        • Asthma, reactive airway or other chronic respiratory disease that requires daily medication for control
    • Casirivimab + Imdevimab (Regeneron) 
      • Combination of two monoclonal antibodies (casirivimab and imdevimab) designed to specifically block two areas of the 'Spike Protein' of SARS-CoV-2  and, hence, infectivity of the virus
      • FDA issued an Emergency Use Authorization (EUA) letter on 21 Nov 2020 (see also: Medical Letter Dec 28, 2020)
      • Among seronegative patients, median time to symptom alleviation (defined as symptoms becoming mild or absent) was 13 days in placebo, 6-8 days with the monoclonal combination. Those with high viral loads at baseline had the most benefit in terms of time to symptom alleviation. 
        • Serious adverse events occurred in 2 placebo patients, 1 low dose patient and no high dose patients. There were no deaths in the trial.
    • Bamlanivimab + Etesevimab (Lilly)
      • Monoclonal neutralizing IgG1 monoclonal antibodies that bind to distinct but overlapping epitopes within the receptor binding domain of the spike protein of SARS-CoV-2.
      • Early Use Authorization by FDA for outpatients issued 10 Nov 2020 for Bamlanivimab; (Prescribing information here; see also Medical Letter Nov 30, 2020) and for Etesevimab on 9 Feb 2021 (EUA and FDA fact sheet)
      • Oupatient clinical trial data
        • BLAZE-1: N Engl J Med. 2020 Oct 28;NEJMoa2029849: Reduction in hospitalizations and ER visits for the bamlanivimab treated subjects (e.g., 1.6% in bamlanivimab recipients vs 6.3% Placebo), more rapid improvement in symptoms with bamlanivimab and a favorable safety profile. There were no deaths in the trial.
        • No significant effect on viral load unless used in combination with a second monoclonal antibody, Etesevimab (JAMA. 2021 Jan 21;e210202).
      • Hospitalized patients  (ACTIV-3: N Engl J Med. 2020 Published Online Dec 22; DOI: 10.1056/NEJMoa2033130): Study terminated on the recommendation of the data and safety monitoring board due to futility in meeting the primary efficacy outcomes of time to sustained recovery and ordinal outcome scores at 5 days.
  • Janus Kinase (JAK) Inhibitors
    • Baricitinib (Lilly)
      • Specific JAK-1 and JAK-2 inhibitor.  
      • EUA issued by US FDA on 19 Nov 2020 based on ACTT-2 trial that showed modest improvement when administered in combination with remdesivir in hospitalized adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)
        • Recovery time was improved by 8 days in the subset of patients receiving non-invasive ventilation or high-flow oxygen devices at baseline (10 days versus 18 days).
        • Rate of progression to death or invasive ventilation was lower in the combination therapy group (12.2% vs. 17.2%; rate ratio, 0.69; 95% CI, 0.50 to 0.95).
        • Trend toward lower 28-day mortality in the combination therapy group.

        • Patients were excluded from the trial if they were receiving corticosteroids: Risks and benefits of baricirinib vis-a-vis dexamethasone are unknown and will require further study. Accordingly, remdesivir plus dexamethasone is preferred over bariticinib + remdesivir, which should be used only in situations where corticosteroids cannot be used

  • Convalesent plasma
    •  Efficacy uncertain, most likely to be effective in patients with early stage of disease and at risk of progression to severe disease (see Critical Care Medicine DOI: 10.1097/CCM.0000000000005068)
      • Lower rate of severe respiratory disease observed in older adults (age 75 and older and age 65 to 74 for those with a co-existing condition for progression to sever disease) with administration of high titer anti-SARS-CoV-2 antibody (anti-spike protein IgG titer > 1:1000) convalescent plasma within 3 days of symptom onset compared to placebo in one randomized trial (N Engl J Med. 2021; 384:610). An observational study (N Engl J Med 2021;384:1015) found similar results with improved mortality in patients treated with high titer anti-S antibody convalescent plasma within 3 days of diagnosis; no benefit in younger patients or those on mechanical ventilation.
      • Meta-analysis (JAMA 2021; 325:1185) of 1060 patients in 10 randomized trials found no benefit in all-cause mortality or other outcomes for convalescent plasma compared to placebo or standard care.
  • IL-6 receptor antagonists
    • Tocilizumab
      • The most recent IDSA guidelines make a conditional recommendation, low certainty of evidence, for use of Tocilizumab in addition to standard of care, including corticosteroids, for progressive severe or critical disease in patients with COVID-19 pneumonia.  (Link to most recently published IDSA review of IL-6 inhibitor studies here.) Revised NIH guidelines make similar recommendations.  Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid at an equivalent dose).  Use of Tocilizumab should be avoided in patients with any of the following: (1) significant immunosuppression, particularly in those with a history of recent use of other biologic immunomodulating drugs; (2) alanine transaminase >5 times the upper limit of normal; (3) high risk for gastrointestinal perforation; (4) an uncontrolled, serious bacterial, fungal, or non-SARS-CoV-2 viral infection; (5) absolute neutrophil count <500 cells/µL; or (6) platelet count <50,000 cells/µL.
      • Clinical trial results:
        • Roche announced in a press release of that its phase III tocilizumab failed to meet its primary endpoint (7- category ordinal scale based on need for supplemental oxygen requirements, and intensive care and/or ventilator use) in hospitalized adult patients with severe COVID-19 associated pneumonia. 
        • Phase III double-blind randomized trial (N Engl J Med. 2020; 383:2333) of tocilizumab compared to placebo for hospitalized, moderately ill patients with confirmed COVID-19 found no difference in intubation or death, worsening of disease; or time to discontinuation of supplemental oxygen.
        • Randomized controlled trial (N Engl J Med. 2021; 384:20) of tocilizumab versus placebo for hospitalized patients with COVID-19 pneumonia found that tocilizulmab reduced likelihood of progression to the composite outcome of mechanical ventilation or death, but did not improve survival.
        • Randomized ongoing international, multifactorial, adaptive platform trial (NEJM 2021, Feb 25; NEJMoa2100433. doi: 10.1056/NEJMoa2100433) of ICU patients receiving high-flow nasal cannula oxygen support, non-invasive or mechanical ventilation, or pressor support reported improved outcomes, including mortality with Tocilizumab (353 patients).
        • RECOVERY open-label trial (pre-print in medRxIV, not peer reviewed) of 2022 patients randomized to tocilizumab compared with 2094 patients randomized to usual care (82% of patients overall were taking a systemic corticosteroids) reported a mortality benefit at 28 days with tocilizumab , 596 deaths (29%) vs. 694 deaths (33%) (p=0·007). Tocilizumab also increased the probability of discharge alive within 28 days from 47% to 54% (p<0·0001). Trends toward benefit, not reaching statistical significance in most cases, were seen in several patient subgroups , including those requiring only supplemental oxygen and non-invasive ventilation, but not mechanical ventilation.  Tocilizumab in combination with corticosteroids  reduced mortality compared to those receiving corticosteroids and usual care 457/1664 (27%) vs. 565/1721 (33%), RR= 0.80 (95% CI 0.70−0.90)], but not in those not receiving corticosteroids).
    • Sarilumab: Regeneron Pharmaceuticals and Sanofi announced in a press release that the U.S. Phase 3 randomized controlled trial of sarilumab added to best supportive care compared to best supportive care alone (placebo) failed to meet its primary and  secondary endpoints.

Stewardship Considerations:

  • Concomitant bacterial pneumonia is uncommon. Hence, routine 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

Anticoagulation

Other Therapies Under Study

  • 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: Efficacy unproven: not recommended outside of a clinical trial.
    • Limited data, mostly unpublished and not peer-reviewed.
  • IL-1 inhibitors: Efficacy unproven, not recommended outside of a clinical trial.

Other Therapies Studied: Efficacy Not Shown

  • 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
  • Vitamin supplements (B, C or D) or zinc: No conclusive evidence supporting benefit

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.
  • 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.

Mitigation / Quarantine / Isolation

  • Masks Work: Reduction in transmission documented in multiple studies, summarized here (JAMA, Feb 2021;  MMWR March 5, 2021)
  • Interim CDC guidance (2 Apr 2021) on how fully vaccinated persons can visit safely with others and travel.
    • If fully vaccinated, can: 1) visit with others who are fully vaccinated without wearing a mask, 2) visit with low-risk unvaccinated persons in a single household and 3) refrain from quarantine / testing following asymptomatic exposure
    • Fully vaccinated persons should continue to: 1) wear masks and practice physical distancing in public, when visiting with high-risk persons, visiting persons from multiple households, 2) avoid medium and large sized public gatherings, 3) get tested if experiencing COVD-19 symptoms and 4) follow employer guidance and health department travel recommendations
    • Fully vaccinated people can resume domestic travel and do not need to get tested before or after travel or self-quarantine after travel.
    • Fully vaccinated people do not need to get tested before leaving the United States (unless required by the destination) or self-quarantine after arriving back in the United States.
  • CDC Federal mask mandate for conveyances and transportation hubs (effective 1 Feb 2021).
  • Quarantine following exposure to COVID-19
    • Updated CDC Guidance (2 Dec 2020) here.
      • 10 days without testing and no symptoms
      • 7 days with negative test result (within 48 hrs of intended discontinuance) and no symptoms
      • Fully vaccinated people with no COVID-like symptoms do not need to quarantine or be tested following an exposure to someone with suspected or confirmed COVID-19, as their risk of infection is low.
      • Fully vaccinated people who do not quarantine should still monitor for symptoms of COVID-19 for 14 days following an exposure. If they experience symptoms, they should isolate themselves from others, be clinically evaluated for COVID-19, including SARS-CoV-2 testing, if indicated.
  • Isolation following positive test ± symptoms. See CDC Clinical Care Interim Guidance 20 Jul 2020.
    • For persons who are COVID-19 positive and symptomatic who were directed to self-care at home (or hotel, dormitory), isolation may be discontinued:
      • After 10 days from symptom onset and after 24 hours from fever resolution (without use of fever-reducing medication) and other symptoms have improved
    • For persons who remain asymptomatic after a positive RT-PCR for SARS CoV-2:
      • After 10 days from date of positive test
    • Test-based strategy no longer recommended to determine when to end home isolation (except in specific situations, i.e., immunocompromised)
  • Return to work for Healthcare providers after COVID-19: see CDC guidance.
    • Mild / moderate illness: 10 days from symptom onset + 24 hours from resolution of fever (without fever-reducing meds) + improved symptoms
    • Severe illness: 20 days from symptom onset + 24 hours from resolution of fever (without fever-reducing meds) + improved symptoms

Testing / Diagnostics

  • Testing Recommendations: see https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html. 
    • Asymptomatic individuals with recent known or suspected exposure to SARS-CoV-2 to control transmission. 
    • Individuals with signs or symptoms consistent with COVID-19
    • Asymptomatic individuals without known or suspected exposure to SARS CoV-2 in special settings that can lead to rapid spread (e.g., long-term care facilities, correctional/detention facilities, homeless shelters, congregate work or living settings)
    • Selected individuals being tested to determine resolution of infection (e.g., test-based strategy for early return to work for healthcare providers, immunocompromised patients)
    • Individuals being tested for purposes of public health surveillance for SARS-CoV-2
  • RT-PCR and nucleic acid amplification tests
  • Antigen tests (See CDC guidance and FDA website for details)
    • Antigen tests detect viral protein fragments of proteins from samples collected from the nasal cavity using swabs. 
    • Anitigen tests, performed on nasal or nasopharyngeal swab specimens are relatively inexpensive, rapid, point-of-care tests that can be useful for screening in high risk congregant settings, in diagnosis of infection in those exposed to a known case of COVID-19, and in diagnosis of infection in symptomatic patients. Sensitivity is less than RT-PCR; specificity is high. Rapid antigen tests are most sensitive in individuals who are tested during early stages of infection when viral load is generally highest. 
  • Serological (Antibody) testing (See FDA website for details)
    • IDSA Guidelines on COVID-19 serological testing here.
    • Cochrane review of serological testing here.

References