The Law of Holes, PCR Cycle Thresholds, and the Hotel California

Hindsight is 20/15, and in hindsight America’s response to the pandemic could have been better. What matters now is what we can change for the better now. The First Law of Holes, aka The Law of Holes, is this: “If you find yourself in a hole, stop digging.” The United States of America is in a hole, and, as Walt Kelly’s Pogo might observe, “we have met the enemy and he is us.”

Polymerase chain reaction (PCR) is the “gold standard” of diagnostic testing, “since it can theoretically identify and detect a target with a single copy in the sample.”[1] PCR “is a quick, easy way to create unlimited copies of DNA from just one original strand.”[2] Said another way, PCR allows scientists to take something that is infinitesimally small and make it large enough to study:

Sometimes called "molecular photocopying," the polymerase chain reaction (PCR) is a fast and inexpensive technique used to "amplify" - copy - small segments of DNA. Because significant amounts of a sample of DNA are necessary for molecular and genetic analyses, studies of isolated pieces of DNA are nearly impossible without PCR amplification.[3]

The process of amplification is exponential and is measured by cycle thresholds (Ct), so one Ct produces two copies, and two Ct produce four copies, and so on. As a general principle, the lower number of Ct required for a positive test, the higher the viral load of that patient, which a study from New York – Presbyterian Hospital/Weill Cornell Medical Center suggests is predictive of outcome.[4]

The CDC has established that Ct = 40 is the measure of a positive test for SARS-CoV-2.[5] As everyone remembers from high school algebra,

240 = 1,099,511,627,776

So, according to the CDC, it is clinically appropriate to provide a binary result – positive or negative – based on amplifying a DNA strand up to one trillion times. There is increasing evidence that a more appropriate Ct value would be 37, or 35, or even 33, since the presence of the virus at those levels is likely dead, and therefore not infectious.[6],[7],[8],[9],[10] In fact, in this interview with This Week in Virology, Anthony Fauci, M.D. states this:

"What is now sort of evolving into a bit of a standard that if you get a cycle threshold of 35 or more that the chances of it being replication-confident are minuscule...It's very frustrating for the patients as well as for the physicians. Somebody comes in, and they repeat their PCR, and it's like 37 cycle threshold, but you never, almost never can culture virus from a 37 threshold cycle. So, I think if somebody does come in with 37, 38, even 36, you got to say, you know, it's just dead nucleotides, period."

Moreover, Dr. Fauci noted this:

"When someone comes in and it's positive, they don't give them the threshold until you go back and ask for it.”

And he said this in July.

There are many, many reasons that America is in a hole today, and it is high time we stop digging. PCR testing is the gold standard in some cases, but in the pandemic, PCR testing has become a hammer and every American a nail. Or, even worse, a shovel being used as a hammer.

America cannot get out of the hole without addressing the long tail from the long-known issue with PCR Ct values. Virtually all of the media, and too many elected officials and regulators, appear to believe that the difference between a PCR Ct of 35 and 40 = 5, when in fact it is a multiple of 32. Ironically, in a moment tailor-made for personalized medicine based upon what is known about SARS-CoV-2, perhaps nothing reveals the fallacy of personalized medicine as the way in which PCR testing is currently being utilized. To produce a binary answer – positive or negative – for a DNA strand that may have been magnified as many as 1,000,000,000,000 times is a lot of things, but it isn’t precise or personalized or consumer-friendly. In no other part of medicine, especially a system of personalized medicine, would a difference of 32x be considered acceptable, particularly when that difference reveals whether someone is infectious.

What is the result of using an extraordinarily sensitive test to produce a binary answer? Record earnings for the manufacturers of laboratory equipment and assays, one example of which was Quest Diagnostic’s 164% growth in earnings per share last quarter, and a Gordian knot for everyone else, with a dose of a self-inflicted crisis.[11]

How? As of October 6, 2020, HHS has instructed hospitals to treat observation patients even suspected of being positive for SARS-CoV-2 as “hospitalized” for reporting purposes, in express contravention of the “Two-Midnight Rule”, leading to “record” hospitalizations.[12] At the same time, 10 states – including California, Florida, Michigan, New York and Pennsylvania – representing over 35% of the U.S. population, have incorporated PCR testing (i.e., a “negative“ test result) in some form or fashion into the discharge criteria for COVID-19 patients to long term care facilities, contrary to CDC guidelines.[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23] The Law of Holes meets the Hotel California: we are programmed to receive, but you might never leave.

Complicating matters even more, recent studies demonstrate that people who were truly positives are infectious for approximately 10 days from symptom onset, but people who have recovered from SARS-CoV-2 can test positive for SARS-CoV-2 as many as 83 days after their initial symptoms.[24],[25],[26]

The laboratories know the actual Ct value for each patient, and Dr. Fauci says that it is available on request. The leading laboratory companies can transmit lab values immediately and electronically to the leading EMRs. Are they sharing it with you? Are you developing strategies with that vital lab value in mind? Are you sharing it with your customers, i.e., the patients?

It is said that insanity is doing the same over and over again but expecting different results…sort of like a country performing as many as 2M PCR tests per day to determine admissions, approve discharges and implement quarantines without knowing the Ct value…which is the most important thing that any of us can know at the moment.

We must do absolutely everything in our power to protect the elderly and other high-risk populations from the effects of SARS-CoV-2. But how can we do that if hospitals cannot discharge patients who are no longer infectious but may test positive for the virus for as long as 83 days? How can we do that if hospitals lack physicians and nurses to care for desperately ill patients because those caregivers are in quarantine because of a “positive” test result from a fragment of DNA that is “dead virus”? How can hospitals survive, much less thrive, if consumers believe that hospitals operating at 85% occupancy are “full” and, as a result, delay elective or even emergent care?

The events of 2020 have reminded us that hospitals are both essential to the health of a community and simultaneously left to fend for themselves in a crisis. Elected officials and regulators and policy wonks and payers and pharmaceutical companies cannot get America out of the hole, and lab companies don’t have any reason to do so. Only hospitals can. If not you, who? If not now, when?


[1] https://diagnostics.roche.com/us/en/roche-blog/what-is-pcr-and-why-is-it-the--gold-standard--in-molecular-diagn.html

[2] Ibid

[3] https://www.genome.gov/about-genomics/fact-sheets/Polymerase-Chain-Reaction-Fact-Sheet

[4] https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa851/5865363

[5] https://www.fda.gov/media/134922/download

[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427302/

[7] https://www.cebm.net/covid-19/infectious-positive-pcr-test-result-covid-19/

[8] https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1491/5912603

[9] https://academic.oup.com/cid/article/71/16/2252/5841456

[10] https://link.springer.com/article/10.1007/s10096-020-03913-9

[11] https://www.fool.com/earnings/call-transcripts/2020/10/22/quest-diagnostics-inc-dgx-q3-2020-earnings-call-tr/

[12] https://www.cms.gov/newsroom/fact-sheets/fact-sheet-two-midnight-rule-0

[13] https://www.nga.org/wp-content/uploads/2020/06/State-Actions-Addressing-COVID-19-in-Long-Term-Care-Facilities.pdf

[14]  https://www.alabamapublichealth.gov/covid19/assets/guidance-transfer-release-hospitals-042820.pdf

[15] https://www.cdph.ca.gov/Programs/CHCQ/LCP/Pages/AFL-20-53.aspx

[16] https://ahca.myflorida.com/docs/AHCA_E-Blast-Emergency_Rule-Hospital_COVID-19_Testing_Requirements_LTC_Facility_Residents.pdf

[17] https://www.michigan.gov/whitmer/0,9309,7-387-90499_90705-529855--,00.html

[18] https://health.ny.gov/professionals/hospital_administrator/letters/2020/docs/dal_20-14_covid_required_testing.pdf

[19] https://ndresponse.gov/sites/www/files/documents/covid-19/Additional%20Resources/Hospitals%20and%20VP3%20FINAL.pdf

[20] https://www.health.pa.gov/topics/disease/coronavirus/Pages/Guidance/Hospital-Guidance.aspx

[21] https://www.dhs.wisconsin.gov/dph/memos/communicable-diseases/2020-20.pdf

[22] https://www.hhs.gov/sites/default/files/covid-19-faqs-hospitals-hospital-laboratory-acute-care-facility-data-reporting.pdf

[23] https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-patients.html

[24] https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(20)30172-5/fulltext

[25] https://www.nature.com/articles/s41586-020-2196-x

[26] https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/10.1001/jamainternmed.2020.7570