Testing For COVID Infectiousness Fine-Tuned

"If  you have to zoom a lot, then the thing [the initial SARS-CoV-2 virus load] was small to start with. [Whereas if a modest number of zoom-ins are required to detect the presence of COVID-19, the load was large.]"

"We have to stop thinking of people as positive or negative, and ask 'How positive'?"

Dr.Michael Mina, physician, epidemiologist, Harvard University

Credit...Johnny Milano for The New York Times

"I think a lot of the discussion is, do we need a test that is so sensitive, and what is the meaning of these tests at the very end threshold? Are they people we need to isolate?"

"Although such low counts could imply either an early- or a late-stage infection, the long duration of the RNA-positive tail suggest that most infected people are being identified after the infectious period has passed."

"Crucially for the economy, it also means that thousands of people are being sent into 10-day quarantines after positive RNA tests, despite having already passed the transmissible stage of infection." 

"If there is a signal of genetic material of the virus, we can't ignore that. [There would be no recommendation that those people shouldn't isolate], unless, let's say, they go back and find out their symptoms started three weeks ago."

Dr.Vanessa Allen, chief of medical microbiology, Public Health Ontario

 

"We were able to grow the virus at higher than 25 when they were earlier in their disease course, and that's a good representation of someone who has a low viral load early in disease, and we're just catching him or her very early."

Guillaume Poliquin, acting head, National Microbiology Laboratory, Canada

 

"Is it accurate to say that if you have somebody who has a CT value higher than 25 that they are less likely to be infectious? Yeah, that is accurate."

"These people may have had the disease for two weeks or more, in which case, well, are we overcalling it? No, because they still were a case -- we still have to track down all their contacts from when they had the disease."

Dr.Jared Bullard, associate director, Cadham Provincial Laboratory

“It’s just kind of mind-blowing to me that people are not recording the C.T. values from all these tests, that they’re just returning a positive or a negative,” one virologist said.  Credit...Erin Schaff/The New York Times

The most scientifically accurate of the tests used in the detection of the virus causing COVID-19 is discovered by searching for the presence of minuscule bits of viral genes from cells and mucus swabbed from the nose, where, should a trace amount be detected, it is amplified (copied) over and over, millions of times in cycle following cycle, each doubling the material detected to isolate the target. Similar to zooming in on a computer screen. 

Critics of the criteria are now enquiring how many such rounds or cycles are too many for the purpose of the target? When should "zoom in" pull back in searching for virus presence? Given that the likelihood of the person remaining infectious can diminish with increased cycles since the test -- reverse transcription polymerase chain reaction (RT-PCR) -- is capable of detecting debris from an old infection. Even once someone has cleared the live organism, in other words, the test can be positive.

What concerns the doubters is that there are people being ordered to isolate when they are no longer a threat to public health since they are no longer infectious. And given that provinces encourage mass testing with the use of a  hypersensitive test to turn out daily case numbers it is implied that a detected case is viewed as a source of infection. Most labs in Canada set cycle limits of RNA detection between 35 and 40 cycles. According to Dr.Mina of Harvard, the cut-off should be closer to 30 (representing the number of cycles required to detect RNA, known as the cycle threshhold (CT-value).

Should it take over 25 cycles to isolate the presence of the virus, according to some researchers, those people may not be contagious. A study in Clinical Infectious Diseases, reported in Science magazine saw researchers examining, 3790 samples testing positive for the SARS-CoV-2 virus causing COVID. 70 percent of samples with a cycle threshold of 25 or lower could be lab grown -- live, viable viruses -- the people likely infectious. Three percent of cases with cycle thresholds above 35 only, could be cultured.

While the finding appears to validate that high cycle thresholds where more 'enhancing' is required equals lower viral loads, the researchers cautioned this should not alter public health policy. A Canadian collaboration between the University of Manitoba and the Canadian national microbiology laboratory saw researchers taking samples from 90 Manitobans who tested COVID-19 positive in the spring wave. The researchers discovered an inability to grow live virus from samples taken from people following over 8 days since they began showing symptoms -- and which took over 24 cycles to detect.

In Massachusetts and New York, over half of infections identified by PCR testing had cycle threshold values in the mid-to-upper 30s indicating low viral counts, according to a recent investigation by the New York Times. A virus detected beyond 25 cycles is likely leftover genetic material from dead virus, points out Dr.Bullard, "But that doesn't mean it's a false positive, or that it's not important to find people, still". In the face of a global pandemic, it becomes vital that every signal be understood.

On the other hand, borderline cases do occur, resulting in debate over whether COVID tests should reflect the cycle threshold value instead of simply negative or positive. A cycle threshold above 35 as "low level positivity" is beginning to be reported in some laboratory networks. Dr. Allan is in agreement with Dr.Mina of Harvard that more inexact instruments such as antigen tests which operate similarly to pregnancy tests -- cheaper, allowing people to test multiple times weekly, with fast turnaround times -- are required to enable the identification of people at a time when they're more likely to be infectious.

Health-care workers test a resident of Mumbai, India, for coronavirus infection using a rapid antigen assay.   Credit: Anshuman Poyrekar/Hindustan Times via Getty