With the increase in positive COVID tests, physicians, contact tracers, and hospitals in our town are very busy. I would imagine the same can be said for your community. With this time of year being normally very high for hospital usage, a strain in the healthcare industry has come to all regions from all angles.
Might there be a better way we can use our resources wisely? Knowing COVID patients’ cycle threshold (Ct) values could benefit patients, physicians, and their community.
Many patients test positive for COVID without any symptoms. What does that mean? Medical tests need to be taken in context. Patients question whom they might have gotten it from, whom they might have given it to, and why their spouses — whom they have lived with in close contact — do not have it. Some become deniers of proper restrictions and proper healthcare, only making everyone more vulnerable.
For certain patients, knowing the Ct value is not useful. In the first few days when a patient may be early in their infection and not exhibiting any symptoms, the viral load may not have risen high enough to cause a useful Ct value. In these situations, antigen tests done sequentially may be more useful.
As the viral load increases, however, knowing Ct values becomes more helpful. These can be another piece of data that a physician can use to manage a patient’s care.
Patients with symptoms who come to the hospital and have a high Ct number (meaning less viral load) and few comorbidities might be best triaged to outpatient treatments. Home oxygen saturation monitoring, daily contact with home health nurses to determine extent of new symptoms, or, if indicated, some of the new outpatient monoclonal antibodies or remdesivir, might be best given outpatient. This would save valuable resources for those symptomatic patients with comorbidities with lower Ct values (indicating higher viral loads) who need more elaborate inpatient treatment and monitoring.
Not all tests used today give us this information. Qualitative PCR testing only indicates a simple positive or negative based on the internal cut-off point at which the machine shuts off. Quantitative testing where you actually know the cycle threshold value is becoming more available. Each have their benefits and limitations.
The FDA has given lab manufacturers a wide latitude in determining the cycle threshold cut-off number of their qualitative tests to determine positive versus negative. These tests were approved under Emergency Use Authorization and have not been subjected to typical FDA scrutiny. With this in mind, the state of Florida has required all laboratories doing COVID testing to report the cycle threshold numbers used in qualitative and quantitative tests.
So how does a qualitative RT-PCR test work? Basically, the manufacturer sets the test to turn off the cycling or amplification process when a certain number is hit. For a qualitative test set at 40, after 40 amplification cycles, if any viral material is detected, it turns off and is reported as positive. If none is detected, it would be reported as negative. If the number of amplification cycles was really 15 or 25, it would still run until it gets to 40 and be reported as positive.
With these type of tests, it’s critical to use an agreed-upon cycle threshold value such as 33 (CDC) or 35 (Dr. Fauci) rather than setting it at a potentially misleading 40 or 45. Many of the current tests in use are preset by the manufacturer to these higher numbers.
The World Health Organization issued a notice last week telling the labs “the cut-off should be manually adjusted to ensure that specimens with high Ct values are not incorrectly assigned SARS-CoV-2 detected due to background noise.” Could this be a reason why many people test positive but remain asymptomatic? In that same memo, WHO said all labs should report the cycle threshold value to treating physicians.
A quantitative test is designed to come up with the actual cycle threshold value as the cycling process turns off when detecting any virus. There is not a preset value, so a quantitative measure is obtained. A test that registers a positive result after 12 rounds of amplification for a Ct value of 12 starts out with 10 million times as much viral genetic material as a sample with a Ct value of 35. Above that level, Fauci has said the test is just finding destroyed nucleotides, not virus capable of replicating.
It’s not only physicians who can use this information. Contact tracers who know Ct values can direct their attention to those with the lowest numbers. “If 100 files land on my desk as a contact tracer, I will prioritize the highest viral loads first because they are the most infectious,” Michael Mina, MD, PhD, an epidemiologist at Harvard, has said.
The CDC has been less supportive of reporting Ct values to help guide the treatment of patients. The agency rightly points out that Ct values are not indicated to determine when a person is no longer infectious. That information is just not known. Moreover, the CDC does not agree that Ct thresholds measure viral load in an individual patient.
Still, CDC guidance does acknowledge that “serial Ct values may be useful in the context of the entire body of information available when assessing recovery and resolution of infection.” I am not suggesting using Ct values to determine when one’s infectivity is over, but certainly when used appropriately and serially it can only help in predicting severity in the management of patients.
Knowing a patient’s Ct value is not the panacea for all ills. Ct numbers are not perfect and vary from machine to machine, but at this point they are all we have. Viral cultures are near impossible to obtain and take much too long. Ct values are an important piece of data, especially if it is routinely reported accurately so that skilled physicians can incorporate it in their decision-making process. I suspect some physicians are already finding ways to access this information. It is of utmost importance that labs use correct reference values that give healthcare workers a chance at directing care effectively.
Simply knowing a yes or no answer is no longer enough. For a qualitative test, at the minimum a positive or negative result AND reporting the lab-cut off Ct value is essential. Ideally knowing the absolute number from a quantitative test is best. I would make an analogy to a hemoglobin and hematocrit test simply being reported as normal or abnormal — none of us in healthcare would accept that.
There are nuances in medicine that we need to know to best treat our patients-cycle threshold levels are one of those. So if you will, push your labs to tell you your patient’s Ct value. It will make triaging and “predicting the future,” which we all are being asked to do, much more accurate. After all, is this not a patient care issue?
Robert Hagen, MD, is recently retired from Lafayette Orthopaedic Clinic in Indiana. He’s an adjunct professor at Indiana University, a past president and board member of the Indiana Orthopaedic Society, and a past member of the Board of Councilors for the American Academy of Orthopaedic Surgeons.
Last Updated January 04, 2021