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Rapid Diagnostic Tests for COVID-19: What You and Your Patients Need to Know
2/22/22
YUKA MANABE, MD
Professor of Medicine, Associate Director of Global Health Research and Innovation
Division of Infectious Diseases, Johns Hopkins School of Medicine
ANDREW PEKOSZ, PhD
Professor of Public Health
W. Harry Feinstone Department of Molecular Microbiology and Immunology
Johns Hopkins Bloomberg School of Public Health
Session Outline
• By the end of this sessions, participants will be able to
• Describe what a lateral flow test is
• Discuss the sensitivity and specificity of COVID-19 lateral flow tests compared to PCR
• Describe clinical scenarios where COVID-19 lateral flow tests are most useful
• Describe methods for assessing the presence of infectious virus in a COVID-19 clinical
specimen
• Demonstrate correlations between COVID-19 rapid antigen tests, PCR-based tests
and the presence of replication competent virus
• Understand the limitations of infectious virus detection and COVID-19 rapid antigen
tests on predicting transmission
Clinical Case I
• An immunocompetent 36-year-old woman who works as a server at a
restaurant has mild COVID-19. In anticipation of return to work, she
performed a rapid antigen test on day six of her symptoms, and the result is
positive. She is amenable to wearing an N95 respirator or comparable mask
at work.
How should she think her return to work in the context of this
result?
Clinical Case II • An immunocompetent 32-year-old man has returned to in-person work and has developed mild headache without fever. He wishes to pursue testing for SARS-CoV-2 and asks whether he should pursue a PCR-based test or an at-home lateral flow assay. What variables contribute to your answer to his question?
Disclosures Dr. Manabe receives salary support from NIH funded Rapid Acceleration of Diagnostics (RADx) program (U54EB007958-12, 3U54HL143541-02S2) and has received research grant support to Johns Hopkins University from Hologic, Ceres, Cepheid, Roche, ChemBio, Becton Dickinson, miDiagnostics, and Yukon, and has provided consultative support to Abbott.
What is a lateral flow test?
• ~15 minutes
• Qualitative detection of SARS-CoV-2
nucleocapsid protein antigen in
• Needs buffer to release N protein
• Nasopharyngeal or nasal swabs directly
• Do not distinguish between SARS-CoV,
SARS-CoV-2
• Clinical sensitivity 80%-97% compared
to EUA molecular assay
• Usually detects Ct values
17 FDA Emergency Use Authorized Home Antigen Assays (13 companies; 2/11/21-2/9/22)
Antigen tests are insensitive compared to RT-PCR
Pickering S Lancet Microbe 2021;2:e461-71
Viral Load and Host Responses
Host Inflammatory phase
Viral response phase
Pulmonary period Convalescence/Inflammation
Sethuraman, Jeremiah, Ryo JAMA
How are they authorized to be used? • Symptomatic • Asymptomatic – 2 tests 24-36 hours apart • Aysmptomatic single use – only 2 tests • Bilateral nasal swab (blow nose first)
etection of Infection Detection of Infection Detection of Infection Detection before or
Nasal Saliva
0.6 Antigen
RTqPCR RTqPCR
Serial testing can increase the sensitivity of rapid antigen
1.0
0.4
tests
0.8
Protocol SensitivityProtocol Sensitivity
0.2
Nasal Saliva
Antigen
0.6 RTqPCR RTqPCR
0.0
1.0
0.4 Enrolment
0.8
while viral culture positive
0.2
Detection before or
0.6
0.0
1.0
0.4
0.8 Daily sampling of individuals over 14 consecutive days
while viral culture positive
Protocol Sensitivity
0.2
Heterogeneity in dynamics of viral RNA shedding
0.6
0.0
Daily Every Every Every Every Every Weekly
1.0
0.4 Other Third Fourth Fifth Sixth
Day Day Day Day Day
0.8
while vira
0.2
Detec
Smith RL et al. JID 2021Antigen tests are insensitive early after exposure
(contacts of RT-PCR-confirmed COVID-19 cases)
• Study of 235 contacts of
confirmed COVID-19 positives
• 140 asymptomatic
• 95 symptomatic
• First 99 had antigen testing
• Antigen testing most reliable in the
first 5 days of symptoms
• False negative RT-PCR tests in the
pre-symptomatic phase
• Saliva antigen testing insensitive
Robinson ML medRxiv doi: https://doi.org/10.1101/2022.02.05.22270481How do the tests perform? Are some better than
others?
• All home tests are visual detection
BD Veritor
• Those with red line may 2678 individuals
disadvantage color-blind
• Reader can increase sensitivity
(POC, CLIA-waived)
• Sensitivity generally similar
Biosensor
• Two tests were authorized for
single testing in (asymptomatic
screening) rather than 2 test serial
format 1596 individuals
Schuit E BMJ 2021; 374:n1676Does the variant matter?
Bekliz M medRxiv https://doi.org/10.1101/2021.12.18.21268018Delta vs Omicron: Test Us At Home Study
Soni A medRxivShould I swab my throat?
• Not how they are
authorized to be used
• No data on the ability of
different sample types to
flow over the nitrocellulose
• Biologic plausibility that
there may be differential
detection in different
compartments based on
the variant
Marais medRxiv doi:
https://doi.org/10.1101/2021.12.22.21268246
Ke R medRxiv https://doi.org/10.1101/2021.07.12.21260208PROS CONS • Fast turnaround time • Doesn’t work well with contacts • Over-the-counter and easy to especially early after contact perform • May need 2 tests used serially • Familiar format (pregnancy test) • False positives – depends on COVID • Relatively inexpensive (should prevalence, pre-test probability be even cheaper) • Doesn’t contribute to public health • Acceptable sensitivity surveillance (often not reported) particularly with symptomatic • Supply chain dependent disease • No human control –’air swab’
Individual and Public Health Testing Considerations
INDIVIDUAL PUBLIC HEALTH
• Interrupt household/ workplace • Remove those most likely to have
transmission transmissible disease (triage)
• Knowing one’s status • Surveillance – case numbers, VOC
• Don’t want to infect others
• Availability of test influences Antigen tests have high sensitivity in
decision those with the highest viral burden
Molecular tests high throughput,
Molecular tests highest sensitivity, mandatory reporting, variants
longer turnaround time, insurance
covers
Antigen tests – fast, private
Accessibility vs Sensitivity…
Pekosz A et al Clin Infect Dis 2021Summary • Antigen tests are not as sensitive as molecular tests (Ct value cut-off) • Most sensitive with symptomatic disease (may need to be done serially in asymptomatic screening with risk of false positives) • Can be performed at home, rapidly, easily (if available) • Often do not contribute to public health surveillance
SARS-CoV-2 Rapid Antigen
Tests, Infectivity and
Transmission
Andrew Pekosz, PhD
Department of Molecular Microbiology and Immunology
Johns Hopkins Bloomberg School of Public Health
Johns Hopkins Center of Excellence for Influenza Research and
Surveillance (JH-CEIRS)Disclosures
Dr. Pekosz received support from NIH funded Rapid
Acceleration of Diagnostics (RADx) program
(U54EB007958-12, 3U54HL143541-02S2) and Becton
Dickinson but was not directly involved in diagnostic test
validation or performance assessment.Objectives • Describe methods for assessing the presence of infectious virus in a clinical specimen • Demonstrate correlations between rapid antigen tests, PCR-based tests and the presence of replication competent virus • Understand the limitations of infectious virus detection and rapid antigen tests on predicting transmission
SCV-2 Virus Isolation from Clinical Specimen
• Labor and time intensive process requiring BSL3 containment
• Nonspecific readout validated by virus specific secondary test
• Variant specific kinetics
• Cell type dependent isolation efficiencySCV-2 Virus Isolation and correlation to
antigen and PCR tests
• Presence of infectious
virus correlates well
with rapid antigen
testsSCV-2 Virus Isolation and correlation to
antigen and PCR tests
• Presence of infectious
virus correlates well
with rapid antigen
tests
• Method for detecting
infectious virus can
significantly impact
correlation with rapid
antigen testSCV-2 Virus Isolation and correlation to antigen and PCR tests • When compared to the presence of infectious virus, antigen tests compare quite well with RT- qPCR tests
SCV-2 Virus Isolation and correlation
to antigen and PCR tests
• Cohort of over 60
individuals with daily
nasal swab and saliva
to study acute phase
COVID-19
• Substantial
heterogeneity in
infectious virus
sheddingSCV-2 Virus Isolation and correlation to
antigen and PCR tests
• Cohort of over 60
individuals with daily
nasal swab and saliva
to study acute phase
COVID-19
• Substantial
heterogeneity in
infectious virus
sheddingSCV-2 Virus Isolation and correlation to
antigen tests in a human challenge
• SARS-CoV-2
human challenge
study
• 90% probability of
detecting virus at
100 FFA/mlSCV-2 Virus Isolation and correlation to
antigen tests in a human challenge
• “Lateral flow results were
strongly associated with
viable virus and modelling
showed that twice weekly
rapid tests could diagnose
infection before 70-80% of
viable virus had been
generated.”Pros Cons
- Correlation of RAT with infectious virus - Unclear if the absence of infectious virus
shedding can be significant (>90%) correlates with reduced likelihood of
transmission
- Rapid results and low costs facilitate
multiple tests to confirm positives - Heterogeneity of virus shedding (RNA and
infectious virus) hinders the establishment of
- Identifying potentially infectious
general principles
individuals can have massive impacts on
limiting transmission chains - Correlation of RAT/infectious virus with PCR
positivity is not very goodAcknowledgement Team Virus Isolation Ruifeng Zhou Jaiprasath Sachithanandham Andrew Pekosz Nico Swanson Maggie Li Abigail Conte Anne Jedlicka Amanda Dziedzic
Clinical Case I
• An immunocompetent 36-year-old woman who works as a server at a
restaurant has mild COVID-19. In anticipation of return to work, she
performed a rapid antigen test on day six of her symptoms, and the result is
positive. She is amenable to wearing an N95 respirator or comparable mask
at work.
How should she think her return to work in the context of this
result?Clinical Case II • An immunocompetent 32-year-old man has returned to in-person work and has developed mild headache without fever. He wishes to pursue testing for SARS-CoV-2 and asks whether he should pursue a PCR-based test or an at-home lateral flow assay. What variables contribute to your answer to his question?
Session Outline
• By the end of this sessions, participants will be able to
• Describe what a lateral flow test is
• Discuss the sensitivity and specificity of COVID-19 lateral flow tests compared to PCR
• Describe clinical scenarios where COVID-19 lateral flow tests are most useful
• Describe methods for assessing the presence of infectious virus in a COVID-19 clinical
specimen
• Demonstrate correlations between COVID-19 rapid antigen tests, PCR-based tests and the
presence of replication competent virus
• Understand the limitations of infectious virus detection and COVID-19 rapid antigen tests on
predicting transmissionSLIDES & RECORDINGS
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