ohsu · ohsu. 23 actt-1 prelim report • hospitalized adults with evidence of lower respiratory...
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Sept. 25, 2020 El l ie Sukerman, MD
COVID-19 UpdatesOHSU
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Objectives
• Differentiate testing strategies
• Describe testing technologies and performance
• Discuss current treatment guidelinesOHSU
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Diagnostic vs. Screening Testing
• Diagnostic– Patients with signs/sxs consistent with COVID-19 or– Asymptomatic but with known or suspected exposure
• Screening– Identify infected, asymptomatic cases without known
or suspected exposure
https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html. Accessed 8/22/20.
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Testing TechnologiesMolecular Tests Antigen Tests Antibody Tests
AKA: • Diagnostic tests
• Viral tests
• Nucleic acid
amplification (NAAT)
• RT-PCR
• LAMP
• Rapid
diagnostic test
• Note, some
molecular tests
are also rapid
tests
• Serology
testing
Site of
collection
• NP, nasal, throat swab
• Saliva
• NP or nasal
swab
• Finger stick or
blood draw
Time to
results
• ~1h for rapid tests
• 1+ days for “slow” tests
• 1h or less • Point of care up
to a few days
https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html. Accessed 9/20/20.
https://www.fda.gov/consumers/consumer-updates/coronavirus-testing-basics. Accessed 8/25/20.
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NAAT Testing
• Sn likely 70-98% -> false negatives up to ~30%
• Factors affecting false negative rate include timing of sample collection and quality of sampling
• Sp high (~98-99%)
Arevalo-Rodriguez, et al. False-negative results of initial RT-PCR assays for COVID-19: a systematic review. medrxiv.org. 4/21/20.
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Testing Interpretation
• Take into account test characteristics and pre-test probability
• A ”positive” PCR test has more weight than a negative test due to
the test’s high Sp but moderate Sn
• If high clinical suspicion for COVID-19 but the initial test is
negative -> repeat testing
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The persistent positive PCR
Gombar S, Chang M, Hogan CA, et al. J Clin Virol. 2020;129:104477.
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Viral shedding vs. infectious virus
Van Kampen, et al. (Preprint) Medrxiv. 2020.
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Persistent Positive PCR
• Test-based strategy for discontinuation of transmission-based precautions or isolation no longer recommended
• Resulted in prolonged isolation or delayed return to work for those who continue to shed virus but are no longer infectious
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Duration of Isolation and Precautions
• COVID-19, isolation and precautions can generally be discontinued when:– 10d after symptom onset*– Resolution of fever for at least 24h without fever-reducing
medications– Symptom improvement
• For those with asymptomatic infection, isolation and precautions can be discontinued 10d after the date of the 1st
positive PCR test
*consider extending duration of isolation and precautions up to 20d after symptom onset
https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html. Accessed 9/20/20.
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Antigen Tests
NAAT/PCR
Tests
Antigen Tests
Sensitivity High Moderate
Specificity High High
Time to results ≤1h to days Minutes
Cost Moderate Low
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Potential Role of Antigen Tests• Diagnostic testing
– Early in course of infection when viral loads high and people are most infectious
– Persons with known exposure
• Screening testing– High-risk congregate settings where repeat testing
could quickly identify infection leading to rapid infection prevention and control intervention
https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html Accessed 8/23/20.
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Availability of Antigen Tests
• 4 assays with FDA EUA as of 9/20/20
• Use of these tests for diagnostic or screening testing requires FDA EUA
https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-
devices/vitro-diagnostics-euas#individual-antigen. Accessed 9/20/20.
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Antibody (Ab) Testing
• Not recommended for dx or exclusion of infection
• Should not be used to determine immunity or inform decisions to discontinue physical distancing or PPE
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Timing of Ab Testing
Sethuraman, N., et al. (2020). "Interpreting Diagnostic Tests for SARS-CoV-2." JAMA.
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Timing of Ab Testing
• Consider IgG testing if high clinical suspicion with repeatedly negative PCR results BUT…
• Best sensitivity at 3-4 weeks after sx onset
https://www.idsociety.org/practice-guideline/covid-19-guideline-serology/. Accessed 8/23/20.
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IDSA Ab Testing Guidelines
• For pediatric pts with multisystem inflammatory syndrome, suggest using IgG and PCR to provide evidence of current or past COVID-19 infection
• Suggest against IgG/IgM combination tests to detect evidence of past infection
https://www.idsociety.org/practice-guideline/covid-19-guideline-serology/. Accessed 8/23/20.
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Ab Test Performance
• False positives possible, PPV ranging 50-100%*– With low seroprevalence, PPV decreases so a
false positive may be more likely than a true positive
• False negatives may occur if testing is performed early in illness*assumes 5% seroprevalence
https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/eua-authorized-serology-
test-performance. Accessed 8/25/20.
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Re-infection Risk
• Lots of uncertainties
– Are patients with antibodies protected against reinfection?
– If so, what antibody concentration is needed to provide protection?
– Durability of protection?
• No confirmed reports of reinfection within 3mos of initial infection
https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html. Accessed 9/20/20.
To KK, Hung IF, Ip JD, et al. Clin Infect Dis. 2020.
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Credit: davegranlund.com
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Treatment
• Remdesivir
• Steroids
• Convalescent plasma
• In the pipelineOHSU
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Remdesivir• IDSA Guidelines (as of 9/15)
– In hospitalized patients with severe* COVID-19, remdesivir is suggested over no antiviral treatment
• NIH Guidelines (last updated 7/24)– Recommend prioritizing remdesivir for use in
hospitalized pts requiring supplemental O2 but not high-flow, noninvasive or invasive ventilation or ECMO
*severe defined as: SpO2 ≤94% on room air, and those who require supplemental O2, mechanical
ventilation or ECMO
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-8. Accessed 9/15/20.
https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf. Accessed 9/20/20.
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ACTT-1 Prelim Report
• Hospitalized adults with evidence of lower respiratory tract infection
• Shorter time to recovery in remdesivir group (median 11 vs. 15d)
Time to Recovery by Subgroup*
Beigel JH, Tomashek KM, Dodd LE, et al. N Engl J Med. 2020.
*CIs not adjusted for multiplicityOHSU
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ACCT-1 PrelimEstimates of cumulative recoveries
Overall Patients Receiving O2
Mechanical Ventilation/ECMOHigh-Flow or NIPPV
Beigel JH, Tomashek KM, Dodd LE, et al. N Engl J Med. 2020.
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SIMPLE Trial
• No significant difference of 5 vs. 10d in patients with severe COVID not on mechanical ventilation/ECMO for primary endpoint of clinical status at day 14
• No placebo group
Goldman JD, Lye DCB, Hui DS, et al. N Engl J Med. 2020.
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Remdesivir in Moderate COVID-19• Statistically significant difference in clinical status at day 11 for 5d group but not
10d group vs. SOC; difference of uncertain clinical significance
Spinner CD, Gottlieb RL, Criner GJ, et al. JAMA. 2020;324(11):1048-1057.
Change in Clinical Status Over TimeOHSU
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Steroids• RECOVERY Trial Prelim report showed decreased mortality
and increased likelihood of hospital discharge for dexamethasone vs usual care
• Guidelines recommend dexamethasone 6mg daily for up to 10d for hospitalized pts with hypoxia requiring supplemental O2
• May substitute alternative glucocorticoids if dex not available
Group, R. C., et al. (2020). "Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report." N Engl J Med.
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Convalescent Plasma
• IDSA Guidelines (as of 9/4) – Recommended only in the context of a clinical
trial
• NIH Guidelines (as of 7/17)– Insufficient data to recommend for or against use
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-8. Accessed 9/15/20.
https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf. Accessed 9/20/20.
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Convalescent Plasma (CP)
• PLACID Trial– Adults with moderate illness randomized to
CP plus standard of care (SOC) vs SOC alone
– No difference in primary outcome of progression to severe disease or all-cause mortality at 28d
Mukherjee, et al. (Preprint). medRxiv. 2020.
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Stay tuned
• ACTT-2
• Randomized, double-blind, placebo-controlled phase investigating
efficacy and safety of baricitinib + remdesivir vs. remdesivir in
hospitalized pts
• BLAZE-1
• Randomized, double-blind, placebo-controlled phase 2 evaluating
LY-CoV555 neutralizing Ab for outpatients with symptomatic
COVID-19
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Thank YouOHSU