Students and their parents need to get off the Cts of their pants and demand these data for each “positive” test
Recently, I demonstrated that actual hospitalizations for covid-19 illness are exceedingly—and mercifully—rare, among U.S. college students returning to campuses since August. When these students test “positive” for the virus by the gold-standard method of reverse transcriptase polymerase chain reaction (rtPCR), only 1 hospitalization occurs for each 6,054 positive tests. Moreover, despite two unconfirmed lay press reports (here; here), there have been no confirmed deaths within this national student cohort, from August till now, where covid-19 was the medically adjudicated and publicly declared, primary cause of death.
At one level, such reassuring phenomena confirm the burgeoning evidence that covid-19, in the overwhelming preponderance of cases, is a rather benign disease in the young, certainly relative to influenza, including seasonal influenza. Conversely, these covid-19 data should raise fundamental questions, both methodologic and interpretative, about the rtPCR “positive” test results dictating draconian campus restrictions imposed upon U.S. college students across the country.
The rtPCR test method amplifies genetic sequences (i.e., nucleic acids from the virus’ core RNA [ribonucleic acid]) obtained in samples, typically, from nasopharyngeal swabs, or saliva. This amplification of viral nucleic acid sequences is measured in cycle thresholds (Ct), a proxy for the total amount of live virus present, or “viral load.” An rtPCR covid-19 assay system developed at the Harvard University/Massachusetts Institute of Technology Broad Institute, currently determining covid-19 “positivity” at 108 northeastern universities, described this exponential relationship:
“…the Ct values correlated strongly with the logarithm of (covid-19) RNA concentration (R-squared > 0.99; indicating a very strong correlation), with the observed range from Ct =12 cycles to Ct = 38 cycles corresponding to viral loads ranging from ~1.9 billion copies/mL to (a mere!) 8 copies/mL, respectively (i.e., an ~250 million-fold difference!).”
Findings I will summarize, below, reveal a strong correlation between Ct values from upper respiratory samples (nasopharyngeal and saliva specimens), symptom onset in relation to test date (STT), and the ability to culture live virus. Lower Cts—meaning less amplification is required—and shorter STTs, indicate a patient’s infectious potential is greater. Additional validating clinical data suggest lower Cts—and hence larger viral loads—are associated with higher covid-19 mortality when patients are hospitalized for symptomatic covid-19 pneumonia, and/or other manifestations of being heavily infected by the virus.
—Dr. Carl Heneghan and colleagues of Oxford University pooled data from 14 studies designed to quantify the relationship between Ct and the ability to culture live virus, concluded: “A cut-off rtPCR Ct > 30 was associated with non-infectious samples.” These investigators added, “Infectivity declines after day 8 even among cases with ongoing high viral loads. A very small proportion of people re-testing positive after hospital discharge or with high Ct are likely to be infectious.”
—Dr. Jared Bullard and colleagues from The University of Manitoba assessed the infectivity of 90 rtPCR covid-19 “positive” samples. They observed infectivity (i.e., the ability to infect cultured cells) only among 26 samples (29%), and none in those with a Ct >24 or STT > 8 days, concluding: “Infectivity of patients with Ct >24 and duration of symptoms >8 days may be low.”
—Broad Institute investigators performed covid-19 rtPCR testing on nasopharyngeal swabs from 32,480 residents and staff in 366 Massachusetts skilled nursing facilities. They calculated that fully 99.99% of the cumulative population covid-19 viral load/“burden” was contained within those whose test Cts were ≤ 26.
—Montefiore Medical Center investigators studied 1,044 patients admitted to their Bronx, New York hospital, with a positive covid-19 nasopharyngeal swab rtPCR test upon admission between 3/26/20 and 8/5/20. Lower rtPCR Cts predicted increased inpatient mortality (n=270 deaths). Cts <22.9, multivariable-adjusted for age, sex, body-mass index, hypertension, and diabetes, were associated with ~4-fold higher covid-19 mortality risk vs. Cts >32.4, and a ~3-fold greater risk vs. Cts between 27.4-32.8.
A 9/6/20 Times of India report “Covid-19 test reports must also state cycle threshold value: Doctors,” described the efforts of Indian pulmonary and pathology laboratory medicine MDs to promote the use of Ct data for patient clinical management:
“If the value is between 20 and 25, home isolation can be advised, but the patient must be monitored through online consultations. Hospital admission is a must in cases where the value is less than 20. This is particularly necessary for patients aged 50 or more who have comorbidity”
No clinical guidelines were provided for Cts >25, which clearly suggested Cts in this range might indicate less acuity. Perhaps most notably the report highlighted this admonition from the Indian doctors to patients:
“Many doctors are now telling patients that their covid-19 test reports should mention the cycle threshold and not just the positive or negative outcome”
As a physician-epidemiologist, I wish to echo and expand upon this clarion call from my Indian colleagues: U.S. university students and their parents should demand all covid-19 “positive” tests include their corresponding Ct values (Note: the Broad Institute, and other major commercial testing platforms throughout the U.S., produce and record Ct data). It is well past time these Ct data were provided so rational distinctions can be made for triage. Those students with Ct >30 rtPCR “positive tests” who are asymptomatic, or mildly symptomatic (i.e., mild upper respiratory symptoms, but without fever, shortness of breath, or sudden, significant loss of taste or smell), must be distinguished from students with positive tests at Cts ≤25, accompanied by any major symptoms (fever, malaise, any shortness of breath, abrupt and profound smell or taste dysfunction). There is no tenable evidence asymptomatic students with “positive” covid-19 rtPCR tests at Cts >30 are at risk themselves, nor that they pose a serious risk of infectious spread to others. On the other hand, symptomatic students who test positive at Cts ≤25, do merit higher-risk triage, including isolation, and assiduous observation by medical staff.
Hope against hope, Ct transparency on campuses will have a ripple effect and encompass all public covid-19 testing, particularly mass, asymptomatic testing, whose Ct-blinded results are wreaking unnecessary havoc upon our lives.