There are two things I don’t understand.
In TSA airport lines, what is the security benefit of spending 5 minutes doing random “enhanced screening” on Grandma, a ninety-year-old woman with a walker who took 5 minutes to advance through the metal detector? We’ve all seen it. I suppose a terrorist organization could equip Grandma with explosives. And we want random checks to be perceived as fair. Still, I don’t get it.
Next, I hear people on TV barking all day about increasing testing and doing contact tracing for COVID-19. Efficient testing – yep, great idea. Contact tracing? How does one do that with 50,000 to 70,000 cases reported a day? Transmission occurs mostly via asymptomatic or pre-symptomatic patients, well before any presumed test would be read. Some tests are taking up to 8 days to be read. Even if all Americans downloaded an app on their phones to send 24/7 geolocation information to contact tracers, I don’t see how public health would improve.
I also don’t understand some of the paradoxes of quantum physics, but that’s a story for another day.
Onward to discussing a brilliant suggestion I heard on This Week in Virology (“the podcast about viruses, the kind that make you sick” – its bona fide tagline). Michael Mina, a public health expert at Harvard, explained why a daily rapid home-based test for SARS-CoV-2 could tame the pandemic.
Our current testing regimen is clinical-grade. It’s designed to be extremely sensitive. Mina co-authored a paper arguing that test sensitivity only needs to be surveillance-grade. When testing at the population level, we are mostly interested in whether one person will transmit an infection to another person.
After infection, individuals undergo a period of incubation during which viral titers are usually too low to detect, followed by an exponential growth of virus, leading to a peak viral load and infectiousness, and ending with declining viral levels and clearance…. These results demonstrate that effective surveillance, including time to first detection and outbreak control, depends largely on frequency of testing and the speed of reporting, and is only marginally improved by high test sensitivity. We therefore conclude that surveillance should prioritize accessibility, frequency, and sample-to-answer time; analytical limits of detection should be secondary.
More on that shortly.
Patients infected with SARS-CoV-2 take a while to develop clinical symptoms, if they ever do. The virus multiplies. Once it reaches a critical threshold of virus concentration, that patient can transmit the infection to another. The “gold standard” for clinical testing is quantitative real-time polymerase chain reaction (qPCR). qPCR remains expensive, and even in the best of situations, has a sample to result time of 24-48 hours. These assays have analytical limits of detection that are usually within around 103 viral RNA copies per ml (cp/ml). qPCR typically uses a primer to bind to the nucleic acid (in this case RNA). Binding is associated with a fluorescent signal. The exercise is repeated (amplified) multiple times (cycles). An important term is Ct which is known as “cycle threshold.”
The Ct (cycle threshold) is defined as the number of cycles required for the fluorescent signal to cross a threshold (i.e. exceeds background level). Ct levels are inversely proportional to the amount of target nucleic acid in the sample (i.e. the lower the Ct level the greater the amount of target nucleic acid in the sample).
Ct < 29 is a strong positive reaction – indicative of abundant target nucleic acid in the sample.
Ct of 30-37 is also a positive reaction – indicative of moderate amount of target nucleic acid.
Ct of 38-40 is a weak reaction – indicative of minimal amounts of target nucleic acid which could represent an infection state or environmental contamination.
In other words, the more cycles PCR needs to detect a threshold fluorescent signal, the lower the RNA concentration in the initial sample. This sample is less infectious.
And vice versa. The fewer cycles needed to detect a threshold fluorescent signal, the higher the RNA concentration in the initial sample. This sample is more infectious and of greater interest for surveillance.
Golf provides a helpful, if strained, analogy. A low golf score is a positive test of you being a good golfer. A low Ct is evidence the initial RNA concentration of the sample is high and more infectious.
As I stated before, 103 viral RNA copies per ml (cp/ml) is the limit of detection with clinical-grade qPCR.
There are cheaper and faster assays with higher thresholds of detection (i.e., around 105 cp/ml) such as point-of-care nucleic acid LAMP [loop-mediated isothermal amplification] and rapid antigen tests.
Patients with low virus concentrations are presumed to not be contagious.
Since filtered samples collected from patients displaying less than 106 cp/ml contain minimal or no measurable infectious virus, either [of the cheaper and faster assays] should detect individuals who are currently infectious. The absence of infectious particles at viral RNA concentrations < 106 cp/ml is likely due to (i) … abundant subgenomic mRNAs, leading to overestimation of the number of actual viral genomes by 100-1000X, (ii) technical artifacts of RT-PCR at Ct values > 35 due to limited template, and (iii) the production of non-infectious viral particles as is commonly seen with a variety of RNA viruses.
In other words, if you use a less sensitive test, (one with a lower target Ct) you will still be able to answer the question, is this patient infectious. What if on the day you test a patient, the result is negative but (had it been measured by qPCR), you would have found some copies of viral RNA? It should not matter. If the patient is getting “worse”, and you are testing daily with your $1/day test, the virus will multiply and you’ll pick it up tomorrow, before or while they are contagious. At the population level, that is the important question you want to answer. If the patient is getting “better”, then the viral kinetics are trending favorably. The patient will still test negative on your $1/day test. The patient will still not transmit the disease.
Like a home pregnancy test, surveillance quality SARS-CoV-2 testing would be frequent, cheap, and could be performed anywhere. Instead of ramming a swab into the middle turbinate, you could rely on anterior nares sampling or even saliva. Before sending kids off to school, spit in a tube and test. Before walking in to work, spit in a tube and test. Want to get into a restaurant or bar? Get the test done by the maître d or the bouncer.
Is a $1 day home-based test a pipe dream? Michael Mina suggests it’s doable with off-the-shelf technology today. He argues the federal government could apply the Defense Production Act to manufacture and distribute such tests. It would be far faster and easier than the research and development required for therapeutics and vaccines.
As a resident, I scrubbed in on a meningioma resection. For hours, the attending surgeon meticulously dissected and removed the tumor. We were almost done. The attending wanted to get it all out. This meant dissecting the remaining strands from the sagittal sinus. The sagittal sinus is a large high-flow draining vein for the brain. You do not want to injure that vessel. If you do, the operative field turns into a bloody mess. Potentially a lethal bloody mess. Well, in our zeal to do a total resection, we got into the sagittal sinus. Several hours later, all was well. A happy ending. But, remember, the tumor was a slow-growing mass. It wasn’t clear this patient would have ever benefited from the additional resection. But once we committed to the plan, the risk went up. The attending concluded with words I’ve never forgotten. “The enemy of good is better.” Sometimes good enough is just fine.
A $1 a day, at home SARS-CoV-2 test may be good enough. Thoughts? Anyone? Anyone? Ferris? Anyone? Comment below.
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Frequent inexpensive testing is a lot like frequent blood sugar testing–it tells you where you stand at any given time, and whether what you’ve been doing (diet-wise for sugar, antisocial distancing for infections, etc.) has been effective. Can’t see a single thing wrong with it, except that 1) most people won’t do it and 2) most of those who will won’t have the slightest idea what they’re actually doing and what the results mean. For it to be effective, there will ave to be a native English speaking help line. We’ll see where that goes.
As far as your understanding quantum physics goes, don’t worry. Here’s a shortcut for understanding the math: each time you do a PCR, you’re approximately doubling the number of particles you’re trying to detect. That means that after n cycles, you will have 2 to the n (2^n) particles for each one you began with. Handy dandy rule to thumb: 2^10 is very close to 1000. Therefore, 2^20 is very close to 1,000,000. For every 10 cycles, add three more zeroes. Assume you need 10^15 particles. If you began with a single particle, after 40 cycles, you’d have 10 ^ (4×3) = 10 ^ 12 particles. Ten more and you’re there: you now have ~10^15.
You’re welcome.
If such a test is required to go to school, work, restaurant, or a bar, I think most people WILL take such a test. And how hard can it be? Spit on a stick. Is there a blue stripe or not? Akin to the home pregnancy test. Those tests are based on rising levels of HCG. They are negative until you hit a threshold value. Most people figure it out. Once they get a result, they can decide what additional information they need. They can even, heaven forbid, call a doctor. And there are plenty of tests that deliver a result without a doctor. In most states, a consumer can log onto requestatest.com (or any number of equivalent sites) and order a HIV test, chladymia-gonorhea-trich panel, or CBC. At Quest, a consumer can order a COVID-19 antibody test.
BTW, I do like the rule of thumb converting powers of 2 to more familiar log 10 scale. 🙂
Analysis Spot-On
The idea of containing this virus with 50-70,000 new cases per day is impossible. Containment was lost at the beginning.
Healthcare workers get N95 masks, but the public gets paper or cloth masks. Why is that?
Because N95 masks are more effective. But if they are more effective, why are we not using them nationwide?
We keep hearing death rates. Most of those dying are in the 70s 80s and 90s. We don’t hear that from media.
Why don’t we protect the people that need protecting?
Why are doctors– “experts” so ignorant of the economic impact of what they recommend. Suicides are up dramatically because of the social isolation and economic catastrophe.
Drug overdoses are up dramatically as well, but we do not hear about that.
We also do not hear about the over reporting of deaths due to Covid, even when the person died of an automobile accident, and had Covid months earlier. BTW we also are not hearing about the number of car accident deaths or other forms of death that are occurring every day in the US.
This has been overblown for political reasons to try to affect the US election. Shame on the politicians and the party members that are perpetuating fear in order to keep panic gowing.
so retired, Covid 19 is all a hoax? I suppose when a vaccine is available you’ll decline since the infection is not nearly as dangerous as the media reports. Do you wear a mask? After all, it’s all hype in your opinion. You should have the right to breathe freely and decide for the rest of us how much risk there truly is since mask protect from spreading the virus more so than infection. BTW are you a retired physician? What specialty if I may ask?