COVID-19, SARS CoV-2

by Editorial Board last updated 2020-06-01 20:40:27.265625-04:00 © Antimicrobial Therapy, Inc.
Coronavirus, SARS CoV-2, COVID-19

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:
  • 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
    • Frequent handwashing (alcohol-based sanitizer and/or soap and water)
    • Sanitize common surfaces
    • Social distancing (at least 6 feet / 1.8 meter)
      • 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)
    • 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.

Testing / Diagnostics

  • Testing Priorities for nucleic acid amplification or antigen tests (see below and https://www.cdc.gov/coronavirus/2019-nCov/hcp/clinical-criteria.html)
    • High Priority
      • Patients with symptoms requiring hospitalization
      • Healthcare facility workers, workers in congregate living settings, and first responders with symptoms
      • Residents in long-term care facilities or other congregate living settings, including prisons and shelters with symptoms
      • Workers exposed to an active case in high-risk facilities such as meat processing plants
    • Priority
      • Persons with symptoms of potential COVID-19 infection, including: fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat
      • Persons without symptoms who are prioritized by health departments or clinicians, for any reason, including, but limited to: public health monitoring, sentinel surveillance, or screening or other asymptomatic individuals according to state and local plans
  • 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. 

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
    • 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. 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: bacterial co-infections (Lancet Microbe online 24 Apr 2020); recognition and management of respiratory co-infection and bacterial pneumonia (Cleve Clin J Med online May 2020)

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.
  • 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)
    • 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.
    • A large multinational registry study (Lancet,  published online May 22, 2020) of 96,032 patients, 14,888 of whom were treated with chloroquine or hydroxychloroquine + a macrolide and 81,144 control patients who were not treated with these drugs found significantly higher in-hospital mortality in treated (16.4% to 23.8%) versus control patients (9.3%) after adjustment for potential confounders. Hydroxychloroquine regimens were independently associated with an increased risk of ventricular arrhythmia (6.1% to 8.1%%) compared with the control group (0·3%). Note: The statistical analysis and data integrity have come under question since publication of the study, see open letter (28 May 20).
    • 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).
  • 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:
    • Lopinavir/ritonavir
      • RCT showed no benefit and no antiviral effect vs. standard care (N Engl J Med doi: 10.1056/NEJMoa2001282)(03/18/20). Due to the high risk of adverse drug-drug interactions (see University of Liverpool compilation: https://www.covid19-druginteractions.org/) in critically ill patients, further trial data are needed before lopinavir/ritonavir can be recommended for treatment of COVID-19.
      • 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-hiv-treatments-for-coronavirus)
  • Updates on COVID-19 research here.
  • Other therapeutic options under evaluation:
  • Other Comments: