BY ALEX RODRIGUEZ AND JENNIFER CABRERA
The CDC has updated their testing guidance to say the asymptomatic “do not need a test,” a change that has, according to the New York Times, “prompted confusion and alarm from experts.”
The CDC’s document on testing guidance now includes the following information:
Current PCR tests provide evidence of the presence of viral RNA but no information about whether the individual is infectious
The Spectator’s “Could mass testing for Covid-19 do more harm than good?” explains how PCR testing works:
“Detection of viruses using Polymerase Chain Reaction (PCR) is helpful so long as its accuracy can be understood: it offers the capacity to detect RNA in minute quantities, but whether that RNA represents infectious virus is another matter. RT-PCR uses enzymes called reverse transcriptase to change a specific piece of genetic material called RNA into a matching piece of genetic DNA. The test then amplifies this DNA exponentially; millions of copies of DNA can be made from a single viral RNA strand.
“A fluorescent signal is attached to the DNA copies, and when the fluorescent signal reaches a certain threshold, the test is deemed positive. The number of cycles required before the fluorescence threshold is reached gives an estimate of how much virus is present in the sample. This measure is called the cycle threshold (Ct). The higher the cycle number, the less RNA there is in the sample; the lower the level, the greater the amount in the initial sample.”
The article goes on to say that a Canadian study found that live virus was only detected when the cycle threshold was less than 24. One patient in the study who tested positive had been PCR-positive three months earlier and was also antibody positive. Inactivated RNA degrades slowly and can be detected weeks after the patient is no longer infectious. “In one case, RT-PCR continued to pick up fragments of RNA until the 63rd day after symptom onset. The duration of faecal shedding of viral RNA in one patient was up to 47 days from symptom onset.”
In a French study on the duration of infectiousness, scientists cultured samples from PCR tests and found that the culture positivity rate (a measure of the viability of the virus) decreased with the number of cycles that it took to detect that virus. No culture was obtained from samples that required more than 34 cycles.
A recent New York Times article presented evidence that specimens detected in 27 to 34 cycles rarely show any live virus, and specimens detected above 34 cycles never show any live virus. “It’s just kind of mind-blowing to me that people are not recording the Ct values from all these tests — that they’re just returning a positive or a negative,” said Angela Rasmussen, a virologist at Columbia University in New York.
The New York Times article said, “The standard tests are diagnosing huge numbers of people who may be carrying relatively insignificant amounts of the virus” and that identifying these non-contagious people “may contribute to bottlenecks that prevent those who are contagious from being found in time.”
In a review of data from three labs, the New York Times found that “up to 90 percent of people testing positive carried barely any virus,” meaning that only about 10% of people who test positive may actually need to isolate and submit to contact tracing. The recommended solution was to reduce the threshold to 33 cycles, based on CDC calculations.
A literature review of studies on infectiousness based on PCR testing found two studies showing that the odds of live virus culture reduced by 33% for every one unit increase in cycle threshold and that thresholds over 30 cycles were associated with non-infectious samples.
The FDA’s Instructions for Use for the CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel currently recommends a threshold of 40 cycles for a specimen to be considered positive, well above the recommendations of the studies cited above.
The bottom line is that 70%-90% of positive results from COVID-19 PCR tests are currently inaccurate because they detect virus at levels that are either too small to transmit to others or simply a remnant of recent exposure.
Cases vs. positive tests
The decision to equate a positive PCR test with a “case” in the COVID-19 pandemic is not aligned with recommendations from the test manufacturers or with definitions of cases for other viruses.
The fact sheet for the Quest Diagnostics SARS-CoV-2 rRT-PCR test states, “This test is to be performed only using respiratory specimens collected from individuals suspected of COVID-19 by their healthcare provider.”
The fact sheet goes on to explain what it means if a specimen tests positive: “A positive test result for COVID-19 indicates that RNA from SARS-CoV-2 was detected, and the patient is infected with the virus and presumed to be contagious. Laboratory test results should always be considered in the context of clinical observations and epidemiological data in making a final diagnosis and patient management decisions.”
For SARS-CoV-1, the CDC and WHO recommended testing only patients “with a high index of suspicion for having SARS-CoV-1 disease” and re-testing positive specimens in a reference laboratory. When a PCR specimen indicated infection, the recommendation was to test a second specimen.
Needless to say, mass testing of asymptomatic individuals does not generally involve an examination by a healthcare provider to determine whether an individual is suspected of COVID-19 or to make a diagnosis from clinical observations.
Early in the pandemic, tests were only available to people who were symptomatic, had been exposed to someone with a positive test, or had traveled to certain areas. During this period, there was a distinct relationship between cases, hospitalizations, and deaths. As testing expanded and people were encouraged to get tested out of curiosity or in order to return to jobs or school, the relationship that had previously existed between “cases” (positive tests), hospitalizations, and deaths changed dramatically.
These two charts demonstrate the relationship between the arrival of cases, ICU census, and fatalities. The ratio between cases and deaths tracked closely from March through May, but starting in June, cases doubled while fatalities were cut in half, changing the ratio by 400%. Hospitalizations never rose to their April levels, meaning there was about a 250%-300% change in ratio.
Tests that are too sensitive have real costs to individuals and their families
As Quest Diagnostics’ PCR Fact Sheet says, “in the event of a false positive result, risks to patients could include the following: a recommendation for isolation of the patient, monitoring of household or other close contacts for symptoms, patient isolation that might limit contact with family or friends and may increase contact with other potentially COVID-19 patients, limits in the ability to work, the delayed diagnosis and treatment for the true infection causing the symptoms, unnecessary prescription of a treatment or therapy, or other unintended adverse effects.”
Not only does a positive test keep the person tested (and often their family) out of work and school, the panic and fear over positive cases in our media has resulted in harassment and shaming of those who test positive.
John McMullen reported in PhillyVoice that after the Detroit Lions’ Matthew Stafford tested positive for COVID (later determined to be a false positive), his wife wrote on Instagram, “Even after we knew it was false positive, our school told us they were not allowed back, I was approached in a grocery store and told I was ‘endangering others,’ my kids were harassed and kicked off a playground, I was told I needed to wait in my car when trying to pick up food, and people closest to us had to get tested just so they could go back to work… and that’s just to name a few things.”
An article in Inside Higher Ed quoted Sherry Pagoto, a professor and director of the UConn Center for mHealth and Social Media at the University of Connecticut: ”I do not think messages to the student body that take a scolding tone to all students are useful and may be counterproductive to the many who are doing the right thing.”
The Los Angeles Times reported on the stigma faced by patients who have recovered from COVID, and the CDC published an article noting that even people with an unrelated cough who live in a group setting or are homeless may be shunned by others who suspect they have the coronavirus. In extreme examples, people stigmatized by a contagious disease may face verbal or physical abuse or be denied housing, education, or employment, the articles said.
The change in testing guidance is a good start, but the cycle threshold guidance also needs to change
The CDC’s new recommendation to only test symptomatic or exposed people is a good start to address the hysteria caused by rising case numbers and the social stigma faced by people with false positive test results. However, an additional change is needed: the FDA recommendation for 40 cycles of amplification in PCR testing is far too sensitive and is leading to alarm about high numbers of “cases” in asymptomatic people, particularly young people like college students, who are often asymptomatic at the time of the positive test, possibly because they have already recovered from a previous mild infection.
The point of testing should be to identify infectious individuals, and the current testing procedures fail in that public health goal. The FDA should update their guidance to recommend no more than 34 cycles, require labs to communicate the number of cycles required to detect the virus for each positive test, and require labs to disclose the cycle threshold for all previous COVID tests (if that data is available) to clean up the inflated statistics (cases, hospitalizations, and deaths) associated with test results that exceeded 34 cycles.