COVID-19, SARS CoV-2

by Editorial Board last updated 2020-12-02 16:31:02.058712-05:00 © Antimicrobial Therapy, Inc.
Coronavirus, SARS CoV-2, COVID-19

 

Recent Updates

  • WHO SOLIDARITY trial results (unpublished, not peer-reviewed) here (see Comments for overview).
  • Regeneron monoclonal antibodies (casirivimab and imdevimab); FDA EUA letter 21 Nov 2020 (for further discussion see Comments)
  • Current IDSA Guidelines on COVID-19 serological testing here
  • Update on COVID-19 antigen testing (see Testing/Diagnostics)
  • Current summary of vaccine development pipeline, see COVID-19, Prevention; Both Pfizer / BioNTech and Moderna mRNA vaccines demonstrate 95% efficacy in Phase III studies EUA submissions being filed; vaccines should begin to be available for use in January 2021 with peak distribution occurring in 2nd Q 2021

Clinical Setting

Transmission

  • Modeling of Diamond Princess COVID-19 outbreak (MedRxIV, unpublished, not peer-reviewed) suggests that aerosol transmission was a dominant contributor to COVID-19 infection. A more comprehensive epidemiological analysis (Emerg Infect Dis 2020 Aug 21;26(11)) suggested that transmission was likely a common source event and due to close contact. 
    • Avoid cruise ships, including river cruises. 
  • Transmission is highly efficient:
    • Droplet is the primary mode of transmission is most settings.
    • Airborne/aerosol transmission of greatest concern, hence critical importance of prevention measures (see Prevention, below)
    • Highest transmission rates from close contacts and within households (Clin Infect Dis. 2020. PMID: 32301964) but in most cases the exposure responsible for transmission is unknown (Science 10.1126/science.abb3221 (2020)).
    • Fomite transmission is possible but likely has is a minor role. 
    • Efficient transmission in youth-centric overnight setting: Overnight camp, camper median age range 12 yrs, staff median age range 17: 44% positive in 11-17 yr age group. MMWR 31 Jul 2020
  • Maximum viral shedding begins 5-8 hours 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. Transmission can occur from an infected person who is asymptomatic (prior to onset of symptoms; see above)
  • Viral shedding (References: Nature. 2020;581(7809):465-469; Lancet Infect Dis. 2020;20(5):565-574; van Kampen, et al, pre-print and not peer reviewed):
    • Careful studies of COVID-19 patients with mild-to-moderate disease (more than 90% of cases) have shown that infectious virus could not be isolated after more than 8 days of symptoms. Viral loads in asymptomatic and symptomatic individuals at time of diagnosis are similar; some evidence shows less likelihood of transmission to contacts of asymptomatic individuals.
    • Robust data from patients with severe or critical COVID-19 show the duration of infectious virus shedding ranged from 0 to 20 days (median 8 days) after symptom onset. The probability of detecting infectious virus dropped below 5% after 15 days. Implications from these latter data are for hospital inpatient infection control.
    • Severe or critical patients typically require 30 or more days of hospitalization and prolonged home convalescence; these data have no implications for return to work or the community for typical patients.
    • For mildly ill patients, shedding of viral RNA assayed by RT-PCR from saliva and nasopharyngeal secretions is at peak value on the day of symptom onset, remains high for approximately 6 days, declines significantly in the second week of illness, and usually ceases by day 14.

    • The maximum duration of positive nasopharyngeal PCR testing in several large series is 43 days from symptom onset and 28 days from symptom resolution; 19% of patients are PCR positive 2 weeks after symptom resolution. One outlier case of viral RNA shedding for 95 days following symptom onset has been reported in a patient with prolonged illness.

Prevention / Isolation

  • Prevention measures
    • Systematic review and meta-analysis (Lancet, published online June 1, 2020) of social distancing, N95 respirators, surgical masks, eye protection in community and healthcare settings indicates that each provides a level of protection against COVID-19.
    • Frequent handwashing (alcohol-based sanitizer and/or soap and water)
    • Sanitize common surfaces (see cautions regarding improper use of disinfectant and cleaning products in MMWR June 5, 2020 early release)
    • Community responsibility
      • Social distancing  (1m somewhat protective, at least 6 feet / 1.8 meter preferred) 
      • WEAR A FACE MASK IN PUBLIC WHEN IN THE PRESENCE OF OTHERS: Protective of yourself and others by preventing spread of nasal/respiratory droplets 
      • AVOID CROWDS, CONGESTED PLACES, particularly indoor spaces (restaurants, bars, churches),  which continue to be transmission focal points
    • Respiratory hygiene, i.e., cover nose and mouth when sneezing or coughing
    • Avoid touching eyes, nose, mouth
  • Travel
    • Consult Federal, State and local authorities for current guidance on travel (interstate and intrastate), testing, quarantine and permissible activities. Varies widely.
  • 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
  • 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)
  • Healthcare Personnel
    • Personal protective equipment (PPE) when caring for a patient with COVID-19
      • Patients not undergoing aerosol generating procedures: N95 respirator preferred, surgical mask acceptable; face shield, gown, gloves
      • Patient undergoing nasopharyngeal swab, aerosol generating procedures: N95 respirator or PAPR, face shield, gown, gloves
    • Return to work after COVID-19: see CDC interim guidance 17 Jul 2020
      • 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
  • Vaccine development pipeline: see COVID-19, Prevention for summary of vaccine development and clinical trials.

Clinical Manifestations

  • Mean incubation time is estimated to be ~5 days after exposure (range 4.1 - 7.0 days), but as short as 36 hours.
  • 25-50% of cases may be asymptomatic or minimally symptomatic (Euro Surveill. 2020 Mar;25(10). doi: 10.2807/1560-7917.ES.2020.25.10.2000180).
  • Presentation / symptoms:
    • Common presenting signs and symptoms (See CDC listing of symptoms):
      • Headache, arthralgias / myalgias, fatigue, fever, cough, shortness of breath, loss of taste and/or smell, nausea / vomiting, diarrhea, sore throat, "fuzzy thinking", delirium 
      • Loss or taste/smell alone indicative of infection (PLOS Med 10/01/20 online ahead of print)
    • One week to 10 days prodrome, which may  progress to difficulty breathing at any time, often in the second week.
    • Average 8 days to development of dyspnea and average 9 days to onset of pneumonia/pneumonitis.
    • Key presentation vitals (at triage): temp > 38ºC (30.7%), O2 sat < 90% (20.4%), heart rate > 100 beats/min (43.1%)
    • Approximately 15% of patients will develop severe disease with 5% requiring mechanical ventilation.
  • Associated co-morbidities / risk factors
    • Most common: hypertension (56.6%), obesity (41.7%), diabetes (33.8%)
    • Risk factors for:
    • High red blood cell distribution width (RDW; > 14.5%) on admission associated with significant relative risk of mortality: RR for the cohort (N=1641) was 2.73, and was highest among patients younger than 50 yrs (RR 5.25) JAMA Open Network, Sept 23, 2020
  • Other manifestations, often associated with severe disease: myocarditis, heart failure, myocardial infarction; stroke; thromboembolic events; acute kidney injury; ARDS, multiple organ failure
  • Complications in children and adolescents, see Multisystem Inflammatory Syndrome in Children (MIS-C)
  • Clinical Course
    • Mild / moderate illness (outpatient). Illness may be prolonged, even in healthy younger adults. Among 170 symptomatic adults surveyed from Mar-Jun 2020, 35% (20% in the 18-34 yr age group) had not returned to a usual state of health 14-21 days from positive RT-PCR for SARS CoV-2. MMWR 24 Jul 2020.
  • Mortality (JAMA online 10 July 2020 doi:10.1001/jama.2020.12839)
    • U.S. death rates shown in the table below:
      Age (Yrs)
      		 Death rate/1000
      <18 0.4
      18-29 1.1
      30-39 3.5
      40-49 8.6
      50-64 29.7
      65-74 105.0
      75-84 210.5
      85+ 304.9
             

Testing / Diagnostics

  • Review of COVID-19 diagnostic testing: JAMA. 2020 May 6. doi: 10.1001/jama.2020.8259. Epub ahead of print
  • Testing Recommendations (updated August 24, 2020): 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.

Treatment

Primary Regimens

  • See also Critical Care Considerations, below
  • Patients with hypoxia
    • Remdesivir
      • Adult dosing (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
        • 5 day course if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days
        • 10 day course for patients on mechanical ventilation/ECMO
      • Pediatric dosing (wt 3.5 - 40 kg): 5 mg/kg loading dose on day 1, then 2.5 mg/kg maintenance dose
        • 5 day course if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days
        • 10 day course for patients on mechanical ventilation/ECMO
    • Dexamethasone (see Comments)
      • 6 mg once daily IV or po x 10 days for patients on supplemental oxygen or receiving mechanical ventilation
      • Do not use in patients who do not require supplemental oxygen or mechanical ventilation: no benefit, possible harm (see Comments).
    • Monoclonal Antibody Therapy recommended for outpatients as single dose Rx.
      • Bamlanivimab (Lilly) 700 mg administered as a single infusion in a healthcare setting.  For use in SARS-CoV-2 confirmed adults and  pediatric patients (12 years of age and older weighing at least 40 kg) with mild to moderate COVID-19 who are at high risk for progressing to severe COVID-19 and/or hospitalization
      • Casirivimab + Imdevimab (Regeneron) combination 2,400 mg (casirivimab 1200 mg + imdevimab 1,200 mg) single IV infusion
        • Indicated in adults and pediatric patients (12 years of age or older weighin at least 40 kilograms) with mild to moderate, SARS-CoV-2 confirmed, COVID-19  who are at high risk for progressing to severe COVID-19
  • Patients without hypoxia
    • Supportive care

Alternative Regimens

  • None

Critical Care Considerations

  • Critical illness, hospitalized in ICU, on mechanical ventilation. For suuggested interventions see NIH COVID-19 Treatment Guidelines
    • Fluids: balanced crystalloids
    • Pressors: norepi > vasopression/epi; cardiogenic shock - dobutamine; not dopamine
    • Steroids:
      • Refractory shock: consider low dose hydrocortisone
      • Dexamethasone: see Primary Regimens above
    • Anti-inflammatory: acetaminophen and/or ibuprofen
    • Antithrombotic therapy guidelines here
    • Antiviral therapy for SARS CoV-2: Remdesivir (See Primary Regimens, above)
    • Co-infection (Lancet Microbe online 24 Apr 2020, Cleve Clin J Med online May 2020)
      • Bacterial and fungal co-infection 
        • Meta-analysis of 28 studies (22 from China, 2 US, 1 UK, I Spain, 1 Singapore, 1 Thailand) with 3448 hospitalized patients between 12/25/19 and 3/31/20 (Clin Microbiol Infect 220; Jul 22;S1198-743X(20)30423-7): 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. Rates of infection in critically ill patients and fatal cases were 8.1% and 11.6%, respectively. 71% of patients received systemic antibacterial therapy. Most common bacterial species (n=41 total) identified in infected patients were Mycoplasma spp. (29.3%), Haemophilus influenzae (19.5%), Pseudomonas aeruginosa (12.2%), Enterobacteriaceae (30%).
        • 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): 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. The fatality rate in patients with bacterial or fungal co-infection was 57% with 28% still in hospital at the time of publication.  Most common isolates were Staphylococcus aureus (44% respiratory, 30% blood, Pseudomonas aeruginosa (16% respiratory, 6% blood), Klebsiella spp. (10% respiratory, 3% blood), Enterobacter spp. (8% respiratory, 3% blood), E. coli (4% respiratory, 7% blood), S. epidermidis (12% blood), Streptococcus spp. (12% blood), and Enterococcus spp. (7% blood). There was 8 cases of candidemia and 1 case of pulmonary aspergillosis. 71% of COVID-infected patients, whether co-infected or not, received antimicrobial therapy. A significant decline in antimicrobial susceptibility of Enterobacteriaceae  was observed.
      • Empiric antimicrobial therapy:
        • Reasonable to consider but data above suggest bacterial co-infection occurs only in a minority of patients. Low prevalence of bacterial co-infection in cohort study of 1705 hospitalized patients in 38 hospitals (Clin Infect Dis 21 Aug 2020, online).
        • If initiated, re-evaluate at 2-3 days and adjust or discontinue antimicrobials, as appropriate, based on clinical status and microbiology.

Comments

  • NIH COVID-19 Treatment Guidelines.
  • IDSA Guidelines on Treatment and Management of Patients with COVID-19
  • Remdesivir
    • Efficacy demonstrated in one placebo-controlled randomized trial.Superior to placebo in shortening time to recovery in hospitalized adults (N Engl J Med online 22 May 20): Randomized, double-blind, placebo controlled trial of 1059 patients (NCT04280705) sponsored by NIAID found that patients that remdesivir treated patients had a median time to recovery of 11 days compared to 15 days for patients who received placebo (p<0.001). The odds of clinical improvement, a secondary outcome, were higher in the remdesivir group  at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50; 95% CI, 1.18 to 1.91; P = 0.001; 844 patients). Results also suggested a survival benefit, with a 14-day mortality rate of 7.1% for the group receiving remdesivir versus 11.9% for the placebo group (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04; 1059 patients). Rates of adverse events were similar. Subgroup analysis suggested benefit across multiple subgroups with the notable exception of patients receiving mechanical ventilation or ECMO, suggesting a lack of efficacy in those with advanced disease. 
    • Efficacy of 5-day and 10-day courses of Remdesivir similar for patients with severe COVID-19 not requiring mechanical ventilation (N Engl J Med, May 27, 2020, doi: 10.1056/NEJMoa201530) (JAMA 2020).
    • Randomized, open-label trial (JAMA 2020 Aug 21;e2016349) of Remdesivir administered for 10 days or administered for 5 days compared to standard of care (SOC) for hospitalized patients with moderate COVID-19 infection (infiltrates on chest x-ray, room air O2 saturation > 94%) found no significant difference in clinical status measured on a 7-point ordinal scale for 10-day therapy compared to SOC, and a modest difference of improved status for 5-day therapy versus SOC, which the authors interpreted as being of uncertain clinical significance. 
    • Press release from Gilead: greater clinical improvement in patients with moderate COVID-19 (pneumonia "without reduced oxygen levels") who were treated with remdesivir for 5 days compared to standard of care.
    • Guidance from NIH, in times of drug shortages, remdesivir should be prioritized for use in hospitalized patients who require supplemental oxygen but who are not on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
  • The WHO SOLIDARITY trial enrolled 11,266 adults from 405 hospitals in 30 countries (all ex-US) with COVID-19 between March 22 and October 4, 2020, into one of 5 arms: Remdesivir, Hydroxychloroquine, Lopinavir-Ritonavir, Interferon-β1a, and local standard of care. Compared to local standard of care, none of the study drugs reduced 28-day mortality, initiation of mechanical ventilation for those not already ventilated, or time to discharge. Meta-analysis of SOLIDARITY and three published studies of Remdesivir suggested a possible mortality benefit in lower risk patients, i.e. not requiring mechanical ventilation, Relative Risk (RR) 0.80 [95% CI 0.63-1.01]; and overall, RR 0.91 [95% CI 0.79-1.05]. None of the regimens showed even a suggestion of efficacy for mechanically ventilated patients, suggesting that earlier the therapy in the course of illness, the better. Significant limitations to the study include open-label design, lack of information on duration of illness prior to randomization, and very likely significant variability in what constituted local standard of care practices across 405 hospitals, including possible effects of non-study medications (anticoagulation, non-study antivirals, anti-IL-6, steroids, non-study interferon, covalescent plasma). 
  • Dexamethasone
    • Efficacy demonstrated in an open-label, randomized controlled trial:

      • The RECOVERY trial  (see N Engl J Med. 2020 Jul 17. doi: 10.1056/NEJMoa2021436) an open-label, randomized controlled trial comparing dexamethasone, 6 mg once daily for up to 10 days  (n= 2104) to usual care (n=4321) found lower 28-day mortality in dexamethasone-treated patients (22.9%) compared to usual care (25.7%) (age adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.75 to 0.93; P<0.001).  Dexamethasone reduced deaths in patients receiving invasive mechanical ventilation (29.3% vs. 41.4%, RR 0.64 [95% CI 0.51 to 0.81), and in patients receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%, RR 0.82 [95% CI 0.72 to 0.94]).  Dexamethasone did not reduce mortality in patients not receiving respiratory support at randomization (17.8% vs. 14.0%, RR 1.19 [95% CI 0.91 to 1.55]). Dexamethasone was associated with fewer hospital days (median 12 days vs. 13 days) and a greater probability of discharge within 28 days (rate ratio 1.10 [95% CI 1.03 to 1.17]), which  was greatest for those receiving mechanical ventilation at baseline. For patients not on mechanical ventilation at baseline, the risk for progression to the pre-specified composite secondary outcome of invasive mechanical ventilation or death was lower in dexamethsone-treated patients (risk ratio 0.92 [95% CI 0.84 to 1.01]); the effect was greater for patients receiving oxygen at randomization.

      • A prospective meta-analysis (JAMA 2020; doi: 10.1001/jama.2020.17023) 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 (odds ratio 0.66 [95%CI, 0.53-0.82]) in those treated with systemic corticosteroids.  Survival benefit was driven largely by the dexamethasone studies

  • Monoclonal Antibodies
    • Bamlanivimab (Lilly)Monoclonal neutralizing IgG1 monoclonal antibody that binds to the receptor binding domain of the spike protein of SARS-CoV-2.
      Early Use Authorization by FDA issued 10 Nov 2020; (Prescribing information here). Specifically, EUA issued for those who are defined as high risk (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

      • Clinical Trial Data (BLAZE-1: NCT04427501)
        • Phase II randomized, double-blind, placebo- controlled, dose finding trial of bamlanivimab  single-dose, monotherapy in outpatients with mild to moderate COVID-19.   Doses of 700 mg [N=101], 2,800 mg [N=107], or 7,000 mg [N=101]) or placebo (N=156) were used.

        • Pre-specified primary endpoint in this Phase 2 trial was change in viral load from baseline to Day 11 for bamlanivimab versus placebo.  No differences in 'viral clearance were observed, but there was a significant reduction in hospitalizations and ER visits for the Bamlanivimab treated subjects (e.g., 1% in 700 mg group vs 6% Placebo).  These data, combined with safety profile of the drug, led to issuance of EUA

    • Casirivimab + Imdevimab (Regeneron)
      • Product is a combination of two monoclonal antibodies (casirivimab and imdevimab) that were designed to specifically block two areas of the 'Spike Protein' of SARS-CoV-2  and, hence, infectivity of the virus.
      • The FDA issued an Emergency Use Authorization (EUA) letter on 21 Nov 2020 for treatment of mild to moderate COVID-19 in adults and children (age > 12 years, wt > 40 kg) who are at risk of progression to severe disease and/or hospitalization.
      • Data was released 29 Sept 2020 highlighting (non-peer-reviewed) results from a combination Phase 1/2/3 trial of REGN-COV2 used in non-hospitalized COVID-19 patients:  
        • 275 subjects were enrolled in the trial and were randomized 1:1:1 to receive a one-time infusion of 8 grams of REGN-COV2 (high dose), 2.4 grams of REGN-COV2 (low dose) or placebo.
        • Subjects were stratified based on their serologic status ( seronegative or seropositive) at time of enrollment;  45% of patients were seropositive, 41% were seronegative and 14% were categorized as "other" due to unclear or unknown serology status.
          • Serological status highly correlated with baseline viral load , with seronegative subjects having statistically higher baseline VL (p<0.0001)
          • In the placebo group,  seropositive patients cleared symptoms in 7 days compared to seronegative patients who cleared symptoms in 13 days.
          • Re change in nasopharyngeal (NP) viral load through Day 7:  The high-dose seronegative group experienced a 0.60 log10 copies/mL greater reduction in VL vs placebo patients, while the lower dose recipients experienced a  0.51 log10 copies/mL greater reduction compared to placebo. Those subjects with higher baseline viral levels had correspondingly greater reductions in viral load at Day 7 with REGN-COV2 treatment. 
        • Among seronegative patients, median time to symptom alleviation (defined as symptoms becoming mild or absent) was 13 days in placebo, 8 days in high dose , and 6 days in low dose. 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.
  • Convalescent plasma (recommended only as part of clinical trials; monoclonal Ab better choice)
    • Efficacy unproven.
    • FDA issued a hold on Emergency Use Authorization (EUA) approval, and 24 hrs later issued the EUA(!), based on the 35,322 patient, non-randomized, non-controlled study described below.
    • Pre-print, not peer-reviewed, uncontrolled, non-randomized trial of 35,322 hospitalized patients with COIVD-19 found that earlier use (within 3 days versus > 4 days after diagnosis) of convalescent plasma and administration of plasma with higher antibody titers (stratified into low, medium, and high) were associated with improved 7-day and 30-day mortality.  Although these results are encouraging, there are numerous limitations to the study that preclude a definitive assessment of efficacy of convalescent plasma for treatment of COVID-19.  These include, first and foremost, its non-randomized observational design and lack of a control group; secular changes in mortality over the course of the study; heterogeneity of patients who were enrolled; use of concomitant medications that could have affected outcome; and uncertain generalizability to current standard of care therapies with Remdesivir and dexamethosone.  
    • Small, under-powered, open-label randomized controlled trial (JAMA. 2020 Jun 3. doi: 10.1001/jama.2020.10044) comparing convalescent plasma in addition to standard treatment (n=52) to the control of standard treatment alone (n=51) found no statistically significant difference in time to clinical improvement at 28 days, the primary endpoint: 51.9% in the convalescent plasma group vs 43.1% in the control group (difference, 8.8% [95% CI, -10.4% to 28.0%].  For those with severe disease the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = 0.03) of those with severe disease and  in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = 0.83) of those with lifer-threatening disease. 28-day mortality was not statistically significantly different (15.7% vs 24.0%; P = 0.30). Convalescent plasma treatment vs. control was associated with conversion of viral PCR to negative at 72 hours: 87.2%  vs 37.5% (P < 0.001).
    • A case series (J Clin Invest. 2020 Jun 1;130(6):2757-2765) of more than 5,000 patients with COVID-19 who received convalescent plasma found the incidence of serious adverse events in the first 4 hours of transfusion to be <1%. 
  • IL-6 receptor antagonists
    • Efficacy unproven.
    • 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. 
    • Tocilizumab: 
      • Roche announced in a press release of that its phase III tocilizumab failed to  meet its primary endpoint in hospitalized adult patients with severe COVID-19 associated pneumonia. The primary endpoint was clinical status, which was measured by a 7-category ordinal scale based on need for supplemental oxygen requirements, and intensive care and/or ventilator use.
      • Phase III double-blind randomized trial (N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836) of tocilizumab compared to placebo for hospitalized, moderately ill patients with confirmed COVID-19 found no difference in intubation or death, hazard ratio 0.83 (95% CI, 0.38 to 1.81); worsening of disease HR 1.11 (95% CI, 0.59 to 2.10); or median time to discontinuation of supplemental oxygen (5.0 days versus 4.9 days).
  • IgG1 monoclonal antibody
    • Bamlanivimab. FDA EUA (11/9/20) for outpatient use in mild to moderate COVID-19 in adolescents (age >12 yrs and wt > 40 kg) and adults who are at risk of progression to severe disease.
  • Chloroquine or Hydroxychloroquine ± Azithromycin
    • Not recommended in any setting due to lack of efficacy and risk of serious, potentially fatal cardiac arrhythmia.
    • FDA Emergency Use Authorization (EUA) revoked on June 15, 2020.
    • Outpatient, mild disease; post-exposure prophylaxis:
      • Double-blind randomized placebo controlled trial (NCT04308668) of 491symptomatic, non-hospitalized patients with confirmed (58%) or probable COVID-19 and high risk exposure within 4 days of symptom onset: hydroxychloroquine for 5 days did not significantly reduce symptom severity (Ann Intern Med online 16 Jul 2020).
      • Double-blind randomized placebo controlled trial of hydroxychloroquine (N Engl J Med.2020 Jun 3. doi: 10.1056/NEJMoa2016638): lack of efficacy of hydroxychloroquine as post-exposure prophylaxis. 
    • Hospitalized, mild-to-moderate disease:
      • Multicenter, randomized, open label trial (N Engl J Med . 2020 Jul 23. doi: 10.1056/NEJMoa2019014) of hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as assessed with a seven-level ordinal scale as compared with standard care.  QTc prolongation and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin. 
    • Hospitalized, severe disease:
      • Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial (NCT04381936): hydroxychloroquine arm terminated with 1,542 patients randomized to hydroxychloroquine and 3,132 patients randomized to usual care alone due to lack of clinical benefit in hospitalized patients with COVID-19: no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10); no beneficial effects on hospital stay duration or other outcomes. 

      • Study from Brazil (JAMA Netw Open. 2020 Apr 24;3(4.23):e208857) comparing 2 dosage regimens of chloroquine diphosphate terminated early due to toxicity: ventricular tachycardia in 2 patients (both in the higher dose arm), 15% with QTc prolongation > 500 msec (11% in the lower dose group, 18% in the higher dose group).

  • Cytidine nucleoside analogs 
    • EIDD-1931: Broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and group 2b or 2c Bat-CoVs. Increased potency against CV bearing resistance mutations to remdesivir. Now entering Phase I studies in patients with COVID-19.
    • EIDD-2801: Similar compound as EIDD-1931 except it has an isopropyl ester at the 5' position.  In mice models infected with SARS-CoV and MERS Co-V, this drug reduced virus titers and body weight loss, while improving pulmonary function.  Sci. Transl. Med. 12: 541,  Apr 2020
  • HIV protease inhibitors:
    • Clinical benefit not demonstrated. 
    • Lopinavir/ritonavir
      • RCT showed no benefit and no antiviral effect vs. standard care (N Engl J Med doi: 10.1056/NEJMoa2001282)(03/18/20). High risk of adverse drug-drug interactions (see University of Liverpool compilation: https://www.covid19-druginteractions.org/). 
      • Open label, phase 2 randomized controlled trial of a 14-day triple drug combination of lopinavir/ritonavir 400 mg/100 mg + ribavirin 400 mg every 12 h + up to 3 doses of 8 million international units of interferon beta-1b on alternate days (86 subjects) versus 14 days of lopinavir/ritonavir 400 mg/100 mg every 12 h alone (41 subjects) for mild to moderate COVID-19 found that the combination reduced viral load to undetectable more rapidly (7 days vs. 12 days) and shortened time to clinical improvement (4 days vs. 8 days).  There were no deaths in either group.
    • Darunavir: no in vitro activity, no evidence of any effect - do not use (https://www.jnj.com/lack-of-evidence-to-support-darunavir-based-hv-treatments-for-coronavirus)
  • Interferon-beta 
    • Efficacy unknown.
    • Press release on July 20 from Synairgen announced positive results of a phase II placebo controlled trial of inhaled interferon-beta.
  • Anticoagulation
    • Mortality benefit among hospitalized patients (JACC.2020)
      • Among 4,389 patients, compared to no anticoagulation (AC), therapeutic and prophylactic AC  were associated with lower in-hospital mortality (aHR=0.53; 95%CI: 0.45-0.62, and aHR=0.50; 95%CI: 0.45-0.57, respectively)
      • Intubation also reduced (aHR 0.69; 95%CI: 0.51-0.94, and aHR 0.72; 95% CI: 0.58-0.89, respectively).
      • When AC initiated ≤48 hours from admission,  no statistically significant difference between therapeutic vs. prophylactic AC .
      • 89 patients (2%) had major bleeding adjudicated by clinician review, with 27/900 (3.0%) on therapeutic, 33/1959 (1.7%) on prophylactic, and 29/1,530 (1.9%) on no AC
  • Clinical trials of interest:
    • ACTT-2 (NCT04401579) will evaluate the combination of baricitinib (a Janus kinase inhibitor) and remdesivir compared to remdesivir alone in hospitalized patients with COVID-19
    • ACTT-3 (NCT04492475) will evaluate the combination of interferon beta-1a and remdesivir compared to remdesivir alone for hospitalized patients with COVID-19.
    • BLAZE-1 (NCT04427501) will evaluate a single dose of intravenously administered LY3819253 (LY-CoV555, a neutralizing IgG1 monoclonal antibody directed against the spike protein of SARS-CoV-2) compared to placebo in out-patients with Mild to Moderate COVID-19. Lilly press release of interim analysis suggests clinical benefit with a change in viral load compared to baseline and reduction in hospitalization or emergency room visits compared to placebo. Study currently paused for a safety evaluation.
    • Updates on COVID-19 research here.
  • Other therapeutic options under evaluation: