COVID-19, SARS CoV-2

Coronavirus, SARS CoV-2, COVID-19

 

Recent Updates

  • Update on bacterial and fungal co-infections in hospitalized patients with COVID-19
  • Update on Testing Recommendations under Testing / Diagnostics
  • Updated isolation and self-isolation guidelines: See Prevention / Isolation
  • Lack of efficacy for hydroxychloroquine with or without azithromcyin for mild to moderate COIVD-19 in hospitalized patients (See comments).
  • Lack of efficacy of IL-6 receptor inhibitors for severe COIVD-19 in two randomized controlled trials (see comments).
  • We are beginning to divide COVID-19 material into sub-pages given the continually growing body of information:

Clinical Setting

Transmission

  • Analysis of Diamond Princess COVID-19 outbreak (MedRxIV, unpublished, not peer-reviewed) suggests that aerosol inhalation likely the dominant contributor to COVID-19 transmission.
  • 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
  • Transmission is highly efficient:
    • Droplet is the primary mode of transmission is most settings.
    • Airborne/aerosol transmission possible, but probably not the primary mechanism in most settings (see JAMA 2020 Jul 13. doi: 10.1001/jama.2020.12458) with potential for transmission from aerosol generating procedures such as nasophayngeal swab sampling, intubation, invasive and non-invasive ventilation, nebulizers, high-flow oxygen nasal cannula, bronchoscopy.
    • 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. 
  • Transmission occurs 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:

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
    • Consult Federal, State and local guidance for reopening and containment measures in specific situations
  • Home Care & Ending Self Isolation. See CDC Clinical Care Interim Guidance 20 Jul 2020.
    • For persons 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 
    • 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
  • 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 July 17, 2020): see https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html
    • Individuals with signs or symptoms consistent with COVID-19
    • Asymptomatic individuals with recent known or suspected exposure to SARS-CoV-2 to control transmission
    • 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
    • Antigen tests detect viral protein fragments of proteins from samples collected from the nasal cavity using swabs. 
    • The utility of this approach compared to PCR-based testing in diagnosis of COVID-19, its advantages and disadvantages, are a work in progress.
  • Viral dynamics
    • Study 9 patients without medical co-morbidities and relatively mild disease (Nature, April 1, 2020): Virus was readily cultured from nasopharyngeal swabs, throat and lung specimens, but not stool; no virus was isolated from urine or serum. No live virus was isolated from any specimen after 8 days. Viral RNA loads were highest in the early symptomatic period, declining slowly and remained detectable into the second or third week after onset of illness, despite resolution of symptoms.
    • Study of RT-PCR for viral RNA (Clin Infect Dis, April 19, 2020, ahead of print) in respiratory samples of 56 patients with mild to moderate COVID-19: 66% converted to negative by the 4th week, 95% by the 5th week, 100% by the 6th week.  It is unknown whether patients with persistent +PCR can transmit virus after 14 days following onset of symptoms
  • Serological (Antibody) testing
    • Variety of tests available of varying reliability (see CDC Interim Guidelines for COVID-19 Antibody Testing); exact role of these tests in manage of COVID patients and determining protective immunity is evolving.
    • Mt Sinai study or 624 NYC patients with mild disease found that IgG antibodies develop over a  period of 7 to 50 days from symptom onset and 5 to 49 from symptom resolution, with a median of 24 days from symptom onset to higher antibody titers, and a median of 15 days from symptom resolution to higher antibody titers. All but 3 (0.5%) subjects with PCR-confirmed infections seroconverted; optimal time frame for widespread antibody testing is at least three to four weeks after symptom onset and at least two weeks after symptom resolution. 
    • Cochrane review of serological testing here.

Treatment

Primary Regimens

  • See also Critical Care Considerations, below
  • Patients with hypoxia
    • Remdesivir (U.S. FDA Emergency Use Authorization 05/01/2020) (See Comments and provider Fact Sheet). Randomized trial demonstrating efficacy (for possible remdesivir drug-drug interaction, see 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).
    • No other therapies are of proven efficacy: enrollment in a randomized clinical trial, if available, is strongly encouraged 
  • 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
    • Anti-thrombolytic 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
        • If initiated, re-evaluate at 2-3 days and adjust or discontinue antimicrobials, as appropriate, based on clinical status and microbiology.

Comments

  • 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).
    • 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)
  • 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.

  • Convalescent plasma
    • Efficacy unproven.
    • 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%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = 0.26). 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). For those with life-threatening disease the primary outcome occurred 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). 28-day mortality was not statistically significantly different (15.7% vs 24.0%; OR, 0.65 [95% CI, 0.29-1.46]; 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% (OR, 11.39 [95% CI, 3.91-33.18]; 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.
  • 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.
  • Updates on COVID-19 research here.
  • Other therapeutic options under evaluation: