by Barbara Cáceres
Health experts now say that
PCR testing for SARS-CoV-2, the virus
associated with the illness COVID-19, is too sensitive and needs to
be adjusted to rule out people who have insignificant amounts of the
virus in their system. 1
The test's threshold is so high
that it detects people with the live virus as well as those with a
few genetic fragments left over from a past infection that no longer
poses a risk.
It's like finding a hair in a room after a person left
it, says Michael Mina, MD, an epidemiologist at the Harvard
Chan School of Public Health. 2
In three sets of testing data that include cycle thresholds compiled
by officials in Massachusetts, New York and Nevada, up to 90 percent
of people testing positive carried barely any virus, a review by
New York Times found. 3
Manufacturers and Labs Set Criteria for Positive COVID-19 Test
The reverse transcriptase quantitative polymerase chain reaction (RT-qPCR)
test used to identify those people infected with the SARS-CoV-2
virus uses a nasal swab to collect RNA from deep within the nasal
cavity of the individual being tested.
The RNA is reverse
transcribed into DNA and amplified through 40 or more cycles, or
until virus is detected. 4
The result is reported as
a simple "yes" or "no" answer to the question of whether someone is
The U.S. Food and Drug Administration (FDA) officials state they do
not specify the cycle threshold ranges used to determine who is
positive, and that commercial manufacturers and laboratories set
their own threshold ranges. 5
PCR Test Threshold for COVID-19 Positivity Is Too Sensitive
Any test with a cycle threshold (CT) above 35 is too sensitive, says
Juliet Morrison, PhD, a virologist at the University of California,
"I'm shocked that
people would think that 40 [cycles] could represent a positive."
A more reasonable cutoff would be 30 to
35, she added.
Dr. Mina said,
he would set the figure at
30, or even
Those changes would mean the amount of genetic material in a
patient's sample would have to be 100-fold to 1,000-fold that of the
current standard for the test to return a positive result worth
acting on. 6
The CDC's own calculations suggest that it is extremely difficult to
detect any live virus in a sample above a threshold of 33 cycles.
"We've been using one type of data for everything, and that is just
plus or minus - that's all," Dr. Mina said.
"We're using that for
clinical diagnostics, for public health, for policy
But "yes" or "no" isn't good enough, he added.
It's the amount of virus that should dictate the infected patient's
"It's really irresponsible, I think, to forgo the
recognition that this is a quantitative issue," Dr. Mina said. 8
The number of people with positive results who aren't infectious is
particularly concerning, said Scott Becker, executive director of
the Association of Public Health Laboratories.
"That worries me a
lot, just because it's so high," he said. 9
SARS-CoV-2 Positive Case Numbers Drop When Cycle Threshold is
Adjusted, Removing Need for Contact Tracing
Officials at the Wadsworth Center, New York's state lab, have access
to CT values from tests they have processed, and analyzed their
numbers at The Times's request.
In July, the lab identified 872
positive tests, based on a threshold of 40 cycles.
With a cutoff of
35 cycles, about 43 percent of those tests would no longer qualify
About 63 percent would no longer be judged positive if
the cycles were limited to 30.
In Massachusetts, from 85 to 90 percent of people who tested
positive in July with a cycle threshold of 40 would have been deemed
negative if the threshold were 30 cycles, Dr. Mina said.
say that none of those people should be contact-traced, not one," he
"I'm really shocked that it could be that high
- the proportion of
people with high CT value results," said Ashish Jha, MD, director of
the Harvard Global Health Institute.
"Boy, does it really
change the way we need to be thinking about testing." 10
"Gold Standard" PCR Tests Leave Many Unanswered Questions Due to
A positive PCR test does not tell doctors whether the person is
currently ill or will become ill in the future,
whether they are
infectious or will become infectious
whether they are recovered or
recovering from COVID
whether the PCR test identified a viral
fragment from another coronavirus infection in the past...
reports that a person who has recovered from COVID-19 may have low
levels of virus in their bodies for up to three months after
diagnosis and may test positive, even though they are not spreading
CT Value Adds Context to PCR Results, Personalizes Care
cycle threshold (CT) is not reported on PCR tests, new
evidence suggests the CT value could help to better inform clinical
decisions, particularly when testing in the absence of symptoms for
When SARS-CoV-2 virus is detected after fewer
amplification cycles, that indicates a higher viral load and a
higher likelihood of being contagious, while virus detected after
more amplifications indicates a lower viral load.
"It's just kind of mind-blowing to me that people are not recording
the CT values from all these tests - that they're just returning a
positive or a negative," said Angela Rasmussen, PhD, a virologist at
Columbia University in New York.
"It would be useful information to
know if somebody's positive, whether they have a high viral load or
a low viral load," she added. 12
In a study published in
Clinical Infectious Diseases in May, 2020, 13 the authors suggested that viral load based on CT
cutoff could establish whether inpatients have transmissible disease
or need to be retested.
This would conserve valuable testing
capacity, reagents, and personal protective equipment (PPE), and
determine when a patient could discontinue isolation.
Taking the CT
value into account may also help justify symptom-based strategies
recommended by the CDC.
CT values may enable contact tracers to
focus only on persons most likely to be infectious, which will
become increasingly important as asymptomatic screening expands.
Another study 14 found that patients with positive PCR
tests at a CT above 33-34 are not contagious and can be discharged
from the hospital or strict confinement at home.
Evidence from both viral isolation and contact tracing studies
supports a short, early period of transmissibility.
for the CT value in context, RT-qPCR results can be used in a way
that is personalized, highly sensitive, and more specific. 15
FDA Approves Rapid, Less Sensitive Coronavirus Antigen Test
Highly sensitive PCR tests seemed like the best option for tracking
the coronavirus at the start of the pandemic.
But for the outbreaks
raging now, Dr. Mina said, what's needed are coronavirus tests that
are fast, cheap and abundant enough to frequently test everyone who
needs it - even if the tests are less sensitive.
"It might not catch
every last one of the transmitting people, but it sure will
catch the most transmissible people, including the super
The FDA noted that people may have a low viral load when they are
A test with less sensitivity would miss these
That problem is easily solved, Dr. Mina said:
again, six hours later or 15 hours later or whatever," he said.
rapid test would find these patients quickly, even if it were less
sensitive, because their viral loads would quickly rise.
infected with the virus are most infectious from a day or two before
symptoms appear till about five days after.
But at the current
"you're not going to be doing it frequently enough to
have any chance of really capturing somebody in that window," Dr.
Mina added. 16
When a patient is tested for the coronavirus, doctors typically tell
them to stay home until the results come in.
If a patient tests
positive and faces a two-week quarantine, that means they could
spend a total of three weeks in isolation. That's a long time for
anybody who has bills to pay or kids to care for, and it's
understandable that some people will continue working until the
results come in.
The problem is that anybody who does this with a
serious infection is putting others at risk. 17
Rapid tests can be
helpful in these situations...
In late August, the U.S.
Food and Drug Administration (FDA) approved
the first rapid coronavirus test that doesn't need any special
Made by Abbot Laboratories, the 15-minute test
will sell for U.S. $5 but still requires a nasal swab to be taken by
a health worker. 18
The Abbot test is the
fourth rapid point-of-care test that looks for the presence of
antigens rather than the virus's genetic code as the PCR molecular
tests do. 19
Experts: US CVOID-19 positivity rate high due to ‘too
sensitive' tests. Daily Mail Aug. 30, 2020.
Your Coronavirus Test Is Positive. Maybe It Shouldn't Be.
The New York Times Aug. 29, 2020.
SARS CoV2 Molecular Assay Evaluation: Results.
FINDDX July 3, 2020.
Centers for Disease Control and Prevention.
Duration of Isolation and Precautions for Adults with
COVID-19. Sept 10, 2020.
To Interpret the SARS-CoV-2 Test, Consider the Cycle
Threshold Value Clinical Infectious Diseases
May 21, 2020.
Bideau ML, et al.
Viral RNA load as determined by cell culture as a management
tool for discharge of SARS-CoV-2 patients from infectious
disease wards. European Journal of Clinical
Microbiology and Infectious Diseases Apr. 27, 2020;
Editorial: Questionable Testing Thresholds. The
Northside Sun Sept. 17, 2020.
FDA Approves New Rapid Coronavirus Test. WebMD
Aug. 27, 2020.
Rapid coronavirus tests can give results in 15 minutes, but
they aren't a pass for partying or seeing your parents.
Business Insider Sept. 21, 2020.