CT value: How low is too high?
From the discovery of Covid-19, there has been a battle among scientists and public health specialists over how to test people for the virus, and the standards that should be used to classify test results as positive, negative or inconclusive.
Since then, several debates have been ongoing over the issue of the cycle threshold (CT) value.
Standard tests identify Covid-19 infection by isolating and amplifying viral RNA using a procedure known as the polymerase chain reaction, which relies on multiple cycles of amplification to produce a detectable amount of RNA. The CT value is the number of cycles needed to spot the virus, when the PCR machine stops running.
It is commonly agreed among experts in this field that if the virus is not detected after 37 to 40 cycles, the test result is negative.
On the other hand, a test that registers a positive result after 12 cycles, is a clear and definite result, as the sample contains more than 10 million times as much viral genetic material as a sample with a CT value of 35.
Classification over the lower limits of the CT is more complex, when samples can test positive with very different amounts of virus present. In this kind of situation, some of them may fall in the gap between what is agreed to be a positive, as opposed to a week negative.
The matter is addressed in a discussion published by the Yale School of Medicine by Marie L. Landry, a director of the Clinical Virology Laboratory of Yale New Haven Hospital.
In the discussion following an article published in the New York Times, Landry discussed the matter from a hospital laboratory perspective.
In the NYT story, it was said that samples with a CT value higher than 33 in which the virus does not grow in culture are “likely not to be contagious.”
For this reason, the authors argued that to standardize a positive test result at a CT of higher than 35 would be “too sensitive,” and could result in many false-positive results, particularly for people already recovered from the virus.
The authors proposed that a more reasonable cut-off would be CT 30-35 or even CT <30.
In consideration of the criteria previously proposed, Landry’s conclusions led to a different interpretation. The director proposed an additional set of standards to be used to assist interpretation: Low Positive: positive tests with a CT 30-34.9; Very Low Positive: sample positive with a Ct >35-39.9; and Borderline Positive: positive sample with a CT >40-44.9.
Landry also noted that “high sensitivity tests are essential for acutely ill hospitalized patients as virus titers in the upper airway may be low (CT>30 or CT >35). However, recovering patients [who are] now non-infectious, may also have a very low positive PCR result.”
The virologist also added that in community testing, “not reporting positive results with CT >30 would be a disservice to these patients,” as the quality of the sample might suffer some changes due to transportation and time between collection and testing, among other factors.
In a more revealing conclusion, Landry concluded that “reporting CT values alone can be misleading, especially since CT values can vary significantly between various tests and labs.”
Different standards,
different policies
In the international community there is a general consensus that a CT value of ≥35 indicates a positive result in community testing. Dr. Landry noted, however, that situations where patients are already hospitalized and/or being treated in isolation might prompt health authorities to decide to slightly reduce the CT value (never below 30), classifying some test results as “negative or very low positive” even if the CT value falls in the gap commonly considered positive.
In August last year, the health authorities of the neighboring region of Hong Kong announced a recommendation on the criteria for releasing confirmed Covid-19 patients from isolation.
This medical criterion establishes that to be released from isolation, symptomatic patients must show an improvement in their clinical condition including the absence of fever, in addition to fulfilling one of two other criteria.
Firstly, the patient should have passed 10 days since the onset of illness. Also, two clinical specimens of the same type taken at least 24 hours apart should test negative for nucleic acid by PCR; or three clinical specimens of the same type taken at least 24 hours apart should have PCR test results with a consistent CT value of 33 or above.
For patients not developing any Covid-19 symptoms, only the PCR result criteria must be met, following the same standard of CT value ≥33.
This decision from the HK authorities was said to be based on prevailing scientific understanding of Covid-19, and was made by recommendation of the Scientific Committee on Vaccine Preventable Diseases and the Scientific Committee on Emerging & Zoonotic Diseases under the Center for Health Protection, joined by the Chief Executive’s expert advisory panel.
The Macau
evidence-based study
In Macau, according to a study published by the Centre for Evidence-Based Medicine, the criteria in use establish that a positive result was defined for a CT value less than or equal to 35, while a negative test result is registered if the CT value is more than 38. Results falling in between these two figures, defined as a CT value of 36 to 38, “require confirmation by re-testing and are reported as inconclusive.”
Last week, the National Health Commission of the PRC issued new standards for diagnosis, treatment, and isolation of patients with Covid-19.
The ninth version of these regulations outlines isolation management and treatment venues according to the condition of the disease, stating that mild infections do not need to be admitted to hospital. There is also a relaxation of the standards for release from isolation and discharge from hospital.
The new criteria for lifting isolation and discharge includes two consecutive nucleic acid tests with a sampling interval of over 24 hours for ORF1ab and N genes in which the CT value is equal to or higher than 35; a fluorescence quantitative PCR test with a value above 40 or two fluorescence quantitative PCR test with a value equal or above 35.
In addition, the new rules also enforce changes on the previous 14 days health management in isolation after discharge, to a seven day home health monitoring after hospitalization.
Commenting on the new rules to Chinese media sources, Zhang Wenhong, Director of Department of Infectious Diseases, Huashan Hospital of Fudan University, said that mild cases of infection will no longer require treatment in hospital since “the proportion of mild cases progressing to severe cases is very low.”
Zhang added, “Our positive nucleic acid criteria have been synchronized with the international standards from [previously] stricter criteria, and the criteria for hospitalization time [in isolation] has also been reduced. This means that more patients can be discharged early, which will greatly ease the pressure on our medical resources.”
Chen Zhengming, professor of epidemiology at Oxford University, told Reuters news agency that the coming weeks have great importance in determining whether the policies can effectively curb the growth of infections and achieve the zero-infections goal.
“Regardless of the [economic] cost, the old method is very effective in preventing the epidemic, which is the biggest political task [at the moment in China],” Chen said, adding, “If [abrupt] changes are made [to these measures], the public may misunderstand it as [the government] giving up.”
Should the CT value
be displayed?
Another heated discussion is around whether the CT value should be displayed and presented to the patient when a test result is positive.
Advocates of this idea point to new research indicating that CT values could help doctors to flag patients at high risk for serious disease, Michael Mina, a physician and epidemiologist at Harvard University’s T.H. Chan School of Public Health said, in a report published by Science, an academic journal from the American Association for the Advancement of Science.
Mina said that recent findings also suggest the displaying of the CT value numbers next to the test result could help officials determine who is infectious and should therefore be isolated and have their contacts traced.
“CT value is an imperfect measure. But whether to add it to test results is one of the most pressing questions out there,” Mina added.
Marta Gaglia, a virologist at Tufts University, also agrees on the imperfection of the value saying, “The same sample can give different CT values on different testing machines, and different swabs from the same person can give different results. The CT value isn’t an absolute scale,” she says with Mina adding that such factors make many clinicians wary.
“Clinicians are cautious by nature. They say, ‘If we can’t rely on it, it’s not reliable’,” Mina added.
Nonetheless, both are among a large group of experts who say that knowing whether CT values are high or low can be highly informative and result in a powerful tool in decision-making.
