COVID-19, SARS CoV-2

by Editorial Board last updated 2020-06-27 05:42:14.484914-04:00 © Antimicrobial Therapy, Inc.
Coronavirus, SARS CoV-2, COVID-19, MIS-C

Clinical Setting

  • SARS-CoV-2 (2019-nCoV) is a respiratory coronavirus that causes the disease COVID-19.
  • Origins of the virus: SARS-CoV-2 emerged in late 2019 from live animal markets in Wuhan, China.  Bats are the reservoir species and an animal intermediate host is thought to have transmitted the virus to humans (https://www.biorxiv.org/content/10.1101/2020.03.30.015008v1).

Transmission

  • Transmission is highly efficient:
  • 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

  • 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)
    • Social distancing  (1m somewhat protective, at least 6 feet / 1.8 meter preferred)
      • AVOID CROWDS AND/OR CONGESTED PLACES. Limit the amount of time spent in congregate places as much as possible, especially when the people in the crowd are NOT wearing a mask
      • WEAR A FACE MASK WHEN IN THE PRESENCE OF OTHERS: Primarily protects others by preventing spread of nasal/respiratory droplets 
      • 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 measures in specific situations
  • 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

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 
    • 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.   Fatality rates in confirmed cases ~ 5-10%, overall mortality probably 0.5%. JAMA online 04/20/2020
  • Associated co-morbidities / risk factors
    • Most common: hypertension (56.6%), obesity (41.7%), diabetes (33.8%)
    • Risk factors
  • Other manifestations, often associated with severe disease: myocarditis, heart failure, myocardial infarction; stroke; thromboembolic events; acute kidney injury; ARDS, multiple organ failure
  • Multisystem Inflammatory Syndrome in Children (MIS-C) (CDC HAN No, 432, 05/14/20). Also called Pediatric Multisystem Inflammatory Syndrome (PMIS)
    • Case definition:
      • Age <21 years, fever, lab evidence of inflammation, hospitalized severe illness, multi-organ involvement: cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological + no alternate diagnosis + current / recent positive test for SARS CoV-2 or COVID-19 exposure within 4 weeks of symptom onset.
    • Most common symptoms:
      • Fever, abdominal pain, rash, shock.
      • Other symptoms include conjuctivitis, headache, cervical adenopathy, lip swelling
    • Most (60-80%) SARS-CoV-2 Ab positive, some (15-30%) PCR positive
    • Lab abnormaliites:
      • lymphopenia, elevated ferritin, d-dimer, CRP, ESR, soluble IL-2 receptor, transaminases
    • Many have cardiac involvement with elevated troponin, BNP, decreased function.  Coronary artery dilation in a minority
    • Clinical phenotype likely broader including shock syndrome with cardiac involvement, Kawasaki like picture, and persistent fever with inflammation
    • Lancet. 2020 Jun 6 2020; JAMA June 8 2020

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 June 13, 2020): nucleic acid amplification or antigen tests (see below and https://www.cdc.gov/coronavirus/2019-nCov/hcp/clinical-criteria.html). Former "priorities" have been eliminated in favor of recommendations for testing:
    • Persons with symptoms consistent with COVID-19
    • Asymptomatic individuals with known or suspected exposure to SARS CoV-2, i.e., close contacts, in order to control transmission
    • Asymptomatic individuals without known or suspected exposure to SARS CoV-2 in settings that can lead to rapid spread:
      • Long-term care facilities
      • Correctional /  detention facilities
      • Homeless shelters
      • Other congregate work or living settings
      • High-density critical infrastructure settings where continuity of operations is essential, i.e., healthcare workers, first responders
    • To determine resolution of SARS CoV-2 infection for purposes of ending isolation or work exclusion
    • Public health surveillance
  • Nucleic acid amplification tests
  • Antigen tests
    • The FDA issued the first emergency use authorization (EUA) to Quidel Corporation for the Sofia 2 SARS Antigen FIA for diagnosis of active COVID-19 infection.  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
      • 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 (see Comments)
      • 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 
      • 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).
    • Enrollment in a randomized clinical trial, if available, is strongly encouraged 
  • Patients without hypoxia
    • Supportive care
  • MIS-C in children
    • No definitive data
    • IVIG 2 gm/kg
    • Methylprednisolone
    • Refractory cases: Consider anakinra or infliximab

Alternative Regimens

  • None

Critical Care Considerations

  • Critical illness, hospitalized in ICU, on mechanical ventilation. Suggested interventions (NIH COVID-19 Treatment Guidelines; Surviving Sepsis Campaign Guidelines, Intens Care Med 46:854, 2020):
    • Fluids: balanced crystaloids
    • Pressors: norepi > vasopression/epi; cardiogenic shock - dobutamine; not dopamine
    • Steroids:
      • Refractory shock: low dose hydrocortisone
      • No ARDS: no steroids
      • ARDS: steroids controversial 
    • Anti-inflammatory: acetaminophen and/or ibuprofen
    • Antiviral therapy for SARS CoV-2: Remdesivir (See Primary Regimens, above)
    • Co-infection. Empiric antimicrobial therapy (data insufficient, but reasonable to consider; if initiated, re-evaluate at 2-3 days and adjust or discontinue antimicrobials, as appropriate, based on clinical status and microbiology):
  • Co-infection: Important to differentiate quickly between viral and bacterial systemic inflammation. Diagnostics should include multiplex PCR for respiratory pathogens other than SARS CoV-2, e.g., bacterial pneumonia (S. aureus, S. pneumoniae, gram negative bacilli), influenza. Use rapid test panels if possible due to potential for rapid progression of pneumonia in severely ill COVID-19 patients.
  • Immune-based and antithrombotic therapy guidance, see NIH Guidelines (rapidly evolving area)
  • References:

Comments

  • Remdesivir
    • 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.
  • Dexamethasone
    • The RECOVERY trial (pre-print, not peer reviewed), 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 (21.6%) compared to usual care (24.6%) (age adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001).  Dexamethasone reduced deaths in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), and in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002).  Dexamethasone did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Dexamethasone was associated with fewer hospital days than usual care (median 12 days vs. 13 days) and a greater probability of discharge within 28 days (rate ratio 1.11 [95% CI 1.04 to 1.19]; p=0.002); the effect was greatest for those receiving mechanical ventilation at baseline (test for trend p=0.002). For patients not on mechanical ventilation at baseline, fewer patients progressed to the pre-specified composite secondary outcome of invasive mechanical ventilation or death (risk ratio 0.91 [95% CI 0.82 to 1.00]; p=0.049); the effect was greater for patients receiving oxygen at randomization (test for trend p=0.008).

  • Convalescent plasma
    • 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).
    • case-control study (pre-print, not peer reviewed) of 39 patients with severe COVID-19 treated with 2 units of convalescent plasma matched to 156 untreated control patients found improvements in 14-day oxygenation status (82.0% vs. 75.7%; p=0.028) at 14 days and a lower mortality at 30 days (12.8% vs. 24.4%; p=0.039). In an adjusted sub-group analysis plasma-treated non-intubated patients had lower mortality (hazard ratio=0.19 [95%CI, 0.05-0.72]), whereas plasma-treated intubated patients did not (hazard ratio = 1.24 [95%CI, 0.33-4.67]).

    • A case series (pre-print, not peer reviewed) 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%.

  • Chloroquine or Hydroxychloroquine ± Azithromycin
    • Not recommended due to lack of data supporting efficacy and risk of serious, potentially fatal cardiac arrhythmia. See FDA Drug Safety Communication (04/24/2020)
    • FDA Emergency Use Authorization (EUA) revoked on June 15, 2020.
    • Double-blind randomized placebo controlled trial of hydroxychloroquine (N Engl J Med.2020 Jun 3. doi: 10.1056/NEJMoa2016638) showed lack of efficacy of hydroxychloroquine as post-exposure prophylaxis administered within 4 days of moderate or high risk exposure (87.6% of all exposures) in preventing COVID-confirmed (11/414 hydroxychloroquine treated versus 9/407 placebo, p=0.82) or COVID-compatiable illness (48/414 versus 55/407, p=0.46).  See accompanying editorial for discussion of results and limitations.
    • Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial (NCT04381936), 1,542 patients randomized to hydroxychloroquine and 3,132 patients randomized to usual care alone, stopped enrollment in the hydroxychloroquine arm 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 evidence of beneficial effects on hospital stay duration or other outcomes. 
    • Retrospective study (pre-print, not peer reviewed) of 368 male patients with confirmed COVID-19 at US Veterans Health Administration medical centers reported a higher risk of death from any cause in the hydroxychloroquine group (n=97) (adjusted HR, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the hydroxychloroquine + azithromycin group (n=113) (adjusted HR, 1.14; 95% CI, 0.56 to 2.32; P=0.72) compared to the no hydroxychloroquine group. There was no significant difference in risk of ventilation in either the hydroxychloroquine group (adjusted HR, 1.43; 95% CI, 0.53 to 3.79; P=0.48) or the hydroxychloroquine + azithromycin group (adjusted HR, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no hydroxychloroquine group.
    • Retrospective study of 1,376 hospitalized patients from one medical center in New York study, 811 of whom were treated with hydroxychloroquine and 565 were not: Hydroxychloroquine treatment was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death in either unadjusted or propensity weighted analyses.
    • Study from Brazil (JAMA Netw Open. 2020 Apr 24;3(4.23):e208857) comparing 2 dosage regimens of chloroquine diphosphate, 450 mg bid on day one then 450 mg once daily x 5 days (2.7 gm total dose) compared to 600 mg bid x 10 days (12 gm) for 81 patients with severe COVID-19 illness was terminated early due to toxicity, principally in the higher dose arm: ventricular tachycardia in 2 patients (both higher dose arm), 15% with QTc prolongation > 500 msec (11% in the lower dose group, 18% in the higher dose group).