Sanford Guide 25/06/20 17:22

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WEB EDITION
COVID-19, SARS CoV-2
last updated Jun 22, 2020 10:14 AM © Antimicrobial Therapy, Inc.

Coronavirus, SARS CoV-2, COVID-19, MIS-C

Clinical Setting Clinical Setting

Transmission
SARS-CoV-2 (2019-nCoV) is a respiratory coronavirus that causes Prevention
the disease COVID-19. Clinical Manifestations
Origins of the virus: SARS-CoV-2 emerged in late 2019 from live Testing / Diagnostics
animal markets in Wuhan, China. Bats are the reservoir species Treatment
and an animal intermediate host is thought to have transmitted the Primary Regimens
virus to humans Alternative Regimens
([Link] Critical Care
Considerations
Comments
Transmission
Transmission is highly efficient:
Droplet is the primary mode of transmission from speaking, yelling, singing, coughing, sneezing
Contact is possible but is a minor mode of transmission
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 contact and and within households (Clin Infect Dis
ahead of print 04/17/20) but in most cases the exposure responsible for transmission is
unknown (Science 10.1126/science.abb3221 (2020)).
Peak 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)

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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:
Median duration of RT-PCR postivity: 17 days (range 12-21 days) (Int J Infect Dis online, 17 May
2020).
Asymptomatic and minimally symptomatic persons also shed virus.

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

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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/[Link].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
Severe disease: age, diabetes, cardiovascular disease, chronic lung disease, obesity,
cancer. At any age if underlying condition (MMWR ahead of print, 03/31/20)
Poor prognosis: older age (> 65 years), high SOFA score & d-dimer >1mcg/mL
(retrospective cohort study, Lancet online ahead of print, 03/11/20)
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:

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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
Testing Recommendations (updated June 13, 2020): nucleic acid amplification or antigen tests (see
below and [Link] 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
For diagnosis of active COVID-19 infection (See IDSA Guidelines at
[Link] excellent review of
current state of diagnostic testing in Ann Intern Med 2020;172:726;
Specimen: upper respiratory nasopharyngeal (NP) swab preferred (see CDC interim guidelines
(above) and JAMA 2020 Mar 11. doi: 10.1001/jama.2020.3786 for yields of different specimen
types).
Test kits: The U.S. FDA has issued Emergency Use Application (EUA) letters for a growing list of
SARS CoV-2 / COVID-19 diagnostic tests. Accuracy and/or reliability remains highly variable.
See FDA for current details: [Link]
medical-devices/emergency-use-authorizations
Antigen tests
The FDA issued the first emergency use authorization (EUA) to Quidel Corporation for the Sofia

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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

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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 (see Comments).
Enrollment in a randomized clinical trial, if available, is strongly encouraged
IDSA Guidelines on Treatment and Management of Patients with COVID-19
NIH COVID-19 Treatment Guidelines.
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):
Bacterial pneumonia, see ventilator-associated pneumonia (VAP)
Concomitant influenza, see influenza
Fungal, especially in advanced illness, but data sparse; aspergillus (anecdotal)
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)

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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
Severe COVID-19 management: N Engl J Med. 2020 May 15. doi: 10.1056/NEJMcp2009575.
Online ahead of print.

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
Preliminary top-line results of an open-label trial announced by RECOVERY (NCT04381936)
investigators (not peer-reviewed) here: 2104 patients were randomized to dexamethasone 6 mg
once per day, po or IV x 10 days and 4321 patients were randomized to usual care alone.
Among the patients who received usual care alone, 28-day mortality was 41% in those who
required ventilation, 25% in those patients who required oxygen only, and 13% in those who did
not require any respiratory intervention. Dexamethasone reduced deaths by one-third in
ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one
fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no
benefit among those patients who did not require respiratory intervention (1.22 [0.86 to 1.75];
p=0.14).
Caveats: Preliminary recommendation based on press release from study PIs of unpublished

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data which has not been peer-reviewed. Important information lacking includes details of usual
care and use of other therapies in either controls or treatment groups.
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).
A 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

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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).

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: [Link]
[Link]/) 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 ([Link]

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of-evidence-to-support-darunavir-based-hiv-treatments-for-coronavirus)
Updates on COVID-19 research here.
Other therapeutic options under evaluation:
See CDC Guidance on therapeutic options: [Link]
ncov/hcp/[Link]. See Summary table of on-going trials compiled by the
American Society of Health-Systems Pharmacists. Review of treatment options being explored:
April 13, 2020 AMA Network
See [Link] (search term = COVID-19) for current status of trials.
Other Comments:
Insights and concise summary of the situation as of late February published on 28 Feb 2020 in
JAMA. Detailed clinical and epidemiologic description of the first 425 cases reported in Wuhan
(N Engl J Med 2020 Jan 29 [Epub ahead of print]) with an associated editorial from Fauci et al
(N Engl J Med 2020 Feb 28 [Epub ahead of print]).
Avoid cruise ships, including river cruises: CDC HAN No. 430 (03/15/20):
[Link]
US hospitalization rates and patient characteristics (CDC, MMWR, April 8, 2020)
CDC Guidance (3/8/20): HAN No. 429: [Link]
and WHO guidance: [Link]
2019/technical-guidance

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