September 7th, 2020

Relieving the COVID-19 Testing Logjam by Separating the Symptomatic from Asymptomatic

As the days grow shorter and we celebrate Labor Day here in the United States, the end of summer looms awfully near. With that will soon come colder temperatures, more time spent indoors, kids back in school, and the inevitable respiratory virus season.

How we address these “viral URIs” in the midst of the COVID-19 pandemic presents a major challenge for clinicians, patients, healthcare systems, and — the focus of this piece — diagnostic laboratories.

Because while certain symptoms might suggest rhinovirus or influenza or RSV or adenovirus or metapneumovirus more than SARS-CoV-2, there is no single clinical sign or symptom that would reliably separate one from the other.

Which means that essentially everyone with a viral respiratory tract infection is eligible for — and arguably needs — COVID-19 testing. This adds considerable volume to an already overburdened testing system that, in this well-argued piece by Atul Gawande in The New Yorker, is “as messed up as a pile of coat hangers.”

What I would propose is that we start by separating out symptomatic from asymptomatic testing. Let’s use a quick and less expensive antigen test for asymptomatic testing, and save the PCRs only for people with symptoms.

We have to do something. The demand for asymptomatic COVID-19 testing is already off the charts, increasing all the time.

One of my colleagues mentioned to me that testing people without symptoms is at least 40% of our hospital’s testing volume. Most of these tests are for admissions (all get tested) and for pre-procedure tests, but increasingly also for travelers re-entering Massachusetts or visiting Maine, people who want to see elderly family or friends, as part of school entry requirements, or just someone worried about a recent potential exposure.

But, you note, aren’t these antigen tests notoriously inaccurate? Won’t they miss cases because they aren’t as sensitive as PCR? Indeed, something of a backlash on rapid home testing appeared recently in a New York Times piece (one I happen to disagree with, for the record), and this lack of sensitivity was highlighted:

Experts also noted that antigen tests aren’t great at sussing out small amounts of the coronavirus, which means they’re far more likely to miss a case that a technique like PCR would catch.

For testing of asymptomatic individuals, it’s worth addressing this concern head-on. Because over the last week, I’ve been asked several times to explain why tests for COVID-19 could be different in symptomatic versus asymptomatic people.

Once it was to a group of research scientists.

Once it was to a local news reporter.

Once it was to a gastroenterologist.

Once it was to a bunch of friends in our backyard, during a socially distanced gathering.

All were worried about lower sensitivity of non-PCR testing.

From this diverse group of people, we can conclude that the concept of accepting a less-sensitive test for testing people without symptoms deserves further clarification — it’s a tough one to master, employing the scary-sounding concepts of Bayes’ Theorem.

So let’s get out our #2 pencils, or our handy Bowmar Brain, and do the math. And, following up on a presentation I made this past week on the topic, and a piece co-authored last month with my colleague Dr. Jeffrey Schnipper, we’re going to consider a very simple case.

(The nice editors at STAT wouldn’t let us publish the full math, except in a linked appendix. Since this is my blog, I can write what I want, so am including it here.)

Here’s the case:

August 2020, Boston.
41-year-old woman planning her summer vacation.
Business consultant; has been working remotely since mid-March.
Lives with husband and 2 children, ages 13 and 9.
Completely asymptomatic; everyone in the household well.
Needs testing for COVID-19 before entering the state of Maine.

What are the chances this woman has a contagious infection with SARS-CoV-2? (She has no symptoms, so that’s the “disease” we are testing for.) We’ll call this estimate our pre-test probability — it’s the likelihood a disease is present even before we do any testing.

In asymptomatic people in Boston currently, the pre-test probability is at most 1%. This is the positive test rate at our hospital now among people without symptoms. Now that we have that estimate, it’s math time!

  • For 1000 people like this currently, 10 (1% of 1000) will have COVID-19, and 990 would have nothing.
  • A test with 80% sensitivity will be positive in 80% of these 10 — or 8, missing 2 cases.
  • The test will be negative in 992 people, which includes the 990 without COVID-19, plus the 2 with the infection we missed.
  • The negative predictive value — which is how often the test correctly calls someone negative — is 990/992, or 99.8%.

The chance of missing an infectious case with antigen testing is only 2/1000 — and potentially lower since those who are most infectious have the highest amounts of virus, making false-negative results less likely. This 99.8% negative predictive value is plenty high enough for routine use in asymptomatic people, where the goal is detecting people who might be contagious without knowing it.

In fact, the big worry for testing asymptomatic people is the opposite — a false-positive result. Since false positives are so much more likely in a low prevalence population, all positive results will need confirmation by PCR.

But the take-home message from going through this exercise is that we should not hesitate to deploy “good enough” testing for screening low-risk people without symptoms. The pre-test probability is key to defining the trustworthiness of a test result.

And now you can cue the Jim Gaffigan-esque self-criticizing, high-voice stage whisperDid he just to write about COVID-19 testing again? Can’t he write about anything else?

Hey, last week I wrote about reinfection!

Take it away, Jim — we need you now more than ever!

7 Responses to “Relieving the COVID-19 Testing Logjam by Separating the Symptomatic from Asymptomatic”

  1. Ramesh A Bharadwaj says:

    I agree that antigen testing is an important part of the solution of our current COVID 19 testing shortcomings.
    I would however suggest that antigen testing are best suited for symptomatic patients. At our institution we switched to antigen testing by the BD Veritor system for employees with exposure and symptoms with reflex to PCR for those who test negative by antigen. We started this as a trial run and after 200 tests and 20 positive tests, we found that the antigen tests performed remarkably well. We had only 4 of the 180 who tested negative by the antigen test, test positive by the PCR. Even those 4 had a positive antigen test when we retested them 3 days later.

    When we tried using the BD veritor antigen for asymptomatic patients, we had 8 of 50 patients who tested positive by PCR but negative by the BD veritor ( this was at the peak of SC transmission with positivity rates of 22%).

    If we use antigen testing for asymptomatic patients, I propose it be used as part of serial testing algorithm.

    Ramesh Bharadwaj, MD FIDSA
    McLeod Health,
    Florence, SC

    • Paul Sax says:

      Interesting experience, thank you for sharing it! These data highlight that we have to be flexible about what tests we use, and how to interpret them. The message of “PCR or nothing” has to be retired.


    • Santiago says:

      This is very important. Many think because a patient test is negative that he will remain negative… However it would be extremely difficult to test people every day of course.

  2. Josep M Llibre says:

    Regarding hospitalized patients, what about adding SARS-CoV-2 into the Multiplex PCR we routinely perform in our patients?. We routinelly screen in a single PCR test for: influenza (A, B and H1), RSV, adenovirus, coronavirus 229E and NL63 and OC43, parainfluenza 1-4, rhinovirus, enterovirus, metapneumovirus and bocavirus. So, why not including SARS-CoV-2 in to the mutiplex test?

    • Paul Sax says:

      The major manufacturers of multiplex PCR systems plan to do this, but at least in the USA, they are not yet widely available.


  3. George Turabelidze says:

    Even though I agree with the logic of the proposal, the antigen test sensitivity in asymptomatic people is not well known, and could be way less than 80%. Is any good data available ? The manufactures only recommend those tests for symptomatic people within 7 days of symptom onset. Testing asymptomatic people is essentially “off label” use for those tests. It seems that things are lot more complicated at this stage.

  4. Petrick says:

    What about false positive pcr ? as a low prevalence population- will be a low prvalence poulation regardless antigen or pcr testing …

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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