COVID-19, SARS CoV-2

by Editorial Board last updated 2021-01-27 12:38:42.136680-05:00 © Antimicrobial Therapy, Inc.
Coronavirus, SARS CoV-2, COVID-19

 

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Recent Developments

  • SARS CoV-2 B.1.1.7 variant first identified in the UK in fall 2020. More efficient transmission; becoming the dominant circulating strain in England; identified in 30+ countries including the U.S.. Higher rate of transmission may lead to more cases (hence emphasis on vaccination and continued mitigation measures), but no difference in clinical outcomes based on current evidence. See MMWR 15 Jan 2021, early release.
  • Another variant with mutation in the receptor binding domain, E484K, first described in South Africa and Brazil, is 10-fold less sensitive to polyclonal antibodies and may have reduced susceptibility to monoclonal antibody therapies (BioRxiv)
  • Results of ACTT-2 trial comparing Baricitinib + Remdesivir to Remdesivir alone summarized in Comments
  • Available vaccines
  • WHO SOLIDARITY trial results (N Engl J Med 2020 Dec 2. doi: 10.1056/NEJMoa2023184) (see Comments for overview).

Clinical Setting

Transmission

  • In-flight transmission risk analysis based on 18-hour flight in fall 2020: https://wwwnc.cdc.gov/eid/article/27/3/20-4714_article
  • Modeling of Diamond Princess COVID-19 outbreak (MedRxIV, unpublished, not peer-reviewed) suggests that aerosol transmission was a dominant contributor to COVID-19 infection.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):
    • 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.
    • 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

  • See Vaccines (approved and development pipeline)
  • 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. Restrictions / requirements vary 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

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, neuropsychiatric complications
  • 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: See CDC Weekly Updates here
          

Testing / Diagnostics

  • 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

Treatment

Principles of Treatment

  • General Guidelines of Treatment of COVID-19:
    • Diagnose COVID as early as possible
    • All treatment is based on the time of Onset of Symptoms (not the date of a positive test)
    • Understand that COVID infection occurs in two stages
      • Viremic phase (Day 1 – 8)
      • Immune Dysfunction Phase (Day 8 – 14)
    • Treatment is radically different based on the phase of disease
      • Viremic Phase:  Antivirals (e.g., Monoclonal Antibody)
      • Immune Dysfunction Phase (immune suppression, for those with respiratory compromise and / or severe disease)
    • NEVER use SYSTEMIC STEROIDS in the outpatient setting during the Viremic Phase (days 1 - 8 ); They are Contraindicated
    • Monoclonal Antibody should be used as early as possible, but not after day 9 – 10; indications:
      • Age > 65 years
      • Immune-compromised state (either from a condition or from immunosuppressive treatment)
      • Obesity (BMI >35)
      • Diabetes Mellitus
      • Chronic kidney disease
      • Age > 55 years with
        • Hypertension
        • Heart Disease
        • Chronic Lung Disease
    • 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
    • There are no conclusive data supporting use of hydroxychloroquine, ivermectin, vitamin supplements (B, C or D ) or zinc

Primary Regimens

Setting Therapy Comments
Not hospitalized, mild-to-severe COVID-19
outpatient, high risk of disease progression
Supportive care
Monoclonal antibody:
Bamlanivimab or (Casirivimab + Imdevimab)
Should be administered early in the course of disease; do not give after day 7- 9 of symptoms (earlier is better).
Do Not Use systemic steroids in the first 7- 10 days of symptoms in the outpatient setting; this prolongs viremic phase and worsens clinical outcomes
Hospitalized, no supplemental oxygen requirement. Patient at risk of disease progression
Remdesivir  
Hospitalized, requires mechanical ventilation or extracorporeal membrane oxygenation Dexamethasone + Remdesivir Benefit of Remdesivir unproven, but recommended by some authorities
  • Recommended dosing
    • 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
        • 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
      • Pediatric (wt 3.5 - 40 kg):
        • 5 mg/kg loading dose on day 1, then 2.5 mg/kg maintenance dose
        • Duration: as for Adult
    • Dexamethasone (see Comments)
      • 6 mg once daily IV or po x 10 days for patients on supplemental oxygen or mechanical ventilation
      • Do not use in patients who do not in the viremic phase of illness (1st 7 - 8 days) (see Comments).
    • Monoclonal Antibody Therapy 
      • Outpatient: Indicated for use in SARS-CoV-2 confirmed adults and children (age ≥12 years, wt ≥40 kg) with mild to moderate COVID-19 who are at high risk for progressing to severe COVID-19 and/or hospitalization
      • Bamlanivimab (Lilly) 700 mg administered as a single infusion in a healthcare setting.  
      • Casirivimab + Imdevimab (Regeneron) combination 2,400 mg (casirivimab 1200 mg + imdevimab 1,200 mg) single IV infusion
        • More complicated to administer than Bamlanivumab
  • See also Critical Care Considerations, below
  • Click here for current NIH treatment guidelines

Alternative Regimens

  • Baricitinib 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.  Baricitinib should only be used in the rare situation where corticosteroids cannot be used (see Comments)
  • Convalescent plasma (as an alternative to monoclonal antibodies if not available)(see Comments)

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%), H. influenzae (19.5%), P. 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 S. aureus (44% respiratory, 30% blood, P. 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

Primary Therapy

  • Remdesivir
    • Efficacy demonstrated
  • Dexamethasone
    • Efficacy demonstrated
      • The RECOVERY trial  (see N Engl J Med. 2020 Jul 17. doi: 10.1056/NEJMoa2021436) 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 oxygen without invasive mechanical ventilation  but did not reduce mortality in patients not receiving respiratory support 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.
  • Monoclonal Antibodies
    • Monoclonal antibody therapy works best in early (viremic) stages of infection  
    • 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)
        • Assthma, 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
      • Phase 1/2/3 trial of REGN-COV2 used in 275 non-hospitalized COVID-19 patients  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 .
        • 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.
    • Bamlanivimab (LY-CoV555)(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 for outpatients issued 10 Nov 2020; (Prescribing information here). 
      • Oupatient clinical trial data (BLAZE-1: N Engl J Med. 2020 Oct 28;NEJMoa2029849)
        •  Doses of 700 mg [N=101], 2,800 mg [N=107], or 7,000 mg [N=101]) or placebo (N=156) were used.
        • There was a significant reduction in hospitalizations and ER visits for the bamlanivimab treated subjects (e.g., 1.6% in bamlanivimab recipients vs 6.3% Placebo).  These data, combined with more rapid improvement in symptoms with bamlanivimab and a favorable safety profile of the drug, led to issuance of EUA.d no high dose patients. There were no deaths in the trial.
      • Hospitalized patients clinical trail data (ACTIV-3: N Engl J Med. 2020 Published Online Dec 22; DOI: 10.1056/NEJMoa2033130)
        • Randomized, double-blind trial of hospitalized patients with COVID-19 without end-organ failure comparing a single 7000 mg of Bamlanivimab (N=163) to placebo N=151). 
        • 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.

Alternative Therapy

  • 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)
        • The primary endpoint was time to recovery during the first 28 days:  The median time to recovery was shorter in the baricitinib plus remdesivir group (7 days) than in the placebo plus remdesivir group (8 days) in the overall cohort (rate ratio 1.16; 95% CI, 1.01–1.32; P = 0.03). 
        • Recovery time was improved by 8 days in the subset of patients receiving non-invasive ventilation of 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 (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09), which did not achieve statistical significance. 
        • Patients were excluded from the trial if they were receiving corticosteroids: Risks and benefits of baricirinib vis-a-vis dexamethasone, the latter having been shown in the RECOVERY trial to improve survival, 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

  • Convalescent plasma
    • Efficacy unproven, consider for patients presenting within 3 days of symptom onset and ideally as part of a clinical trial. 
    • Uncontrolled, non-randomized trial of 35,322 hospitalized patients with COIVD-19 found that earlier use (within 3 days versus > 4 days after diagnosis) 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.
    • 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%. 

Other Therapies Under Study

  • IL-1 inhibitors
    • Efficacy unproven, not recommended outside of a clinical trial.
  • IL-6 receptor antagonists
    • Efficacy unproven, not recommended outside of a clinical trial.
    • 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).
  • 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: 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. 
    • 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.  
      • 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:
  • Interferon-beta 
    • 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.
  • 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-3 (NCT04492475) will evaluate the combination of interferon beta-1a and remdesivir compared to remdesivir alone for hospitalized patients with COVID-19.
    • Updates on COVID-19 research here.
  • Other therapeutic options under evaluation:

References