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CDC will only sequence post-vaccine COVID cases detected at lower test sensitivities

Directive excludes higher “cycle thresholds” from gene sequence protocol.

May 8, 2021 1:36pm

Updated: May 12, 2021 10:47pm

Instructions from the U.S. Centers for Disease Control and Prevention state that the agency will only undertake gene sequencing of post-vaccinated cases of COVID-19 if the viral samples are detected at notably lower sensitivity levels than are tolerated for positive COVID-19 tests overall.

The directive, posted on the CDC's website, concerns the study of "breakthrough" cases of COVID-19, or positive test results in the fully vaccinated. Numerous such cases have been reported, albeit out of millions and millions of vaccinations. 

Some of those cases, the CDC says, "will have SARS-CoV-2 sequencing performed at a clinical, public health, or commercial reference laboratory." Yet the CDC directs labs to only submit such tests for sequencing if they "have an RT-PCR Ct value ≤28."

In layman's terms, the directive says that positive COVID results detected by the widely used polymerase chain reaction (PCR) test should have a cycle threshold (Ct) of less than 28.

PCR tests work by amplifying the genetic material of a viral sample until it can be detected by the testing machine. Each amplification cycle is known as a "cycle threshold." The more Cts a test has to undergo, the smaller the viral load from the original sample. The higher the cycle threshold, in other words, the lower the amount of virus a patient is carrying. 

Scientists are aware of the risks of interpreting "positive" viral results with high Cts. White House coronavirus adviser Anthony Fauci admitted last year that positive test results with Cts of 35 or greater are likely just "dead nucleotides" rather than living viruses. Nevertheless, many manufacturers of PCR tests recommend much higher Ct cutoff rates of 40

Each new level of Ct doubles the amount of viral DNA in the sample, meaning the difference between 36 and 40 is an exponential increase rather than a merely logarithmic one.

The agency set the lower Ct bar "because sequencing is not feasible with higher Ct values," CDC spokesman Tom Skinner confirmed via email. "At higher Ct values, there is less RNA present and it becomes more difficult or is not possible to sequence the RNA." 

Skinner said that "in general, CDC uses the same CT value cutoff for submitting other SARS-CoV-2 surveillance specimens for sequencing." He did not respond to a followup query asking specifically if the CDC has been sequencing SARS-Cov-2 viral samples only at Ct levels below 28 for the past year.

Still, the CDC's cutoff of 28 Ct for viral sequencing stands in stark contrast to the positive COVID-19 tests drawn from far higher cycle thresholds, which experts have acknowledged are not necessarily a reliable indicator of true infection and/or infectiousness.

Michael Osterholm, the director of the Center for Infectious Disease Research and Policy and a member of President Joe Biden's transitional COVID-19 advisory board last year, said interpreting positive test results with high cycle thresholds "depends upon which side of the curve you’re on." 

"At the very earliest days of infection you can have high CTs that are indicative of infection," he said in a phone interview. "If you're on the front side, you may have high Cts while you're just starting to put out substantial amounts of the virus. If you're on the backside, or the recovery phase, you may have persistent PCR positvity without having infection."

Osterholm admitted that it is difficult to determine which side of the infection a positive test represents, and that it is not readily known what percentage of high-Ct tests fall on one side or the other. 

Other public health officials, on the other hand, have expressly warned of the potential of noninfectious positive results from tests with high Cts. The World Health Organization earlier this year warned of false positive tests associated with high cycle thresholds, stating that the "probability that a person who has a positive result ... is truly infected with SARS-CoV-2 decreases as [viral] prevalence decreases."

Some critics and commentators have expressed concern over the past year that COVID-19 tests that rely on high Ct levels are counting arguably healthy and non-infectious individuals as positive "cases," thereby exaggerating the scope and severity of the global outbreak.

A review by the New York Times last year found that in data sets from three states where Ct levels were recorded "up to 90 percent of people testing positive carried barely any virus."

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