False Negative: Testing’s Catch-22


In a physician WhatsApp group, a doctor posted he had fever of 101° F and muscle ache, gently confessing that it felt like his typical “man flu” which heals with rest and scotch. Nevertheless, he worried that he had coronavirus. When the reverse transcription polymerase chain reaction (RT-PCR) for the virus on his nasal swab came back negative, he jubilantly announced his relief. 

Like Twitter, in WhatsApp emotions quickly outstrip facts. After he received a flurry of cheerful emojis, I ruined the party, advising that despite the negative test he assume he’s infected and quarantine for two weeks, with a bottle of scotch. 

It’s conventional wisdom that the secret sauce to fighting the pandemic is testing for the virus. To gauge the breadth of the response against the pandemic we must know who and how many are infected. The depth of the response will be different if 25% of the population is infected than 1%. Testing is the third way, rejecting the false choice between death and economic depression. Without testing, strategy is faith-based. 

Our reliance on testing has clinical precedence – scarcely any decision in medicine is made without laboratory tests or imaging. Testing is as ingrained in medicine as the GPS is in driving. We use it even when we know our way home. But tests impose a question – what’ll you do differently if the test is negative? 

That depends on the test’s performance and the consequences of being wrong. Though coronavirus damages the lungs with reckless abandon, it’s oddly a shy virus. In many patients, it takes three to four swabs to get a positive RT-PCR. The Chinese ophthalmologist, Li Wenliang, who originally sounded the alarm about coronavirus, had several negative tests. He died from the infection.

In one Chinese study, the sensitivity of RT-PCR – that’s the proportion of the infected who test positive – was around 70%. To put this in perspective, 1000 people infected with coronavirus: 700 will test positive but 300 will test negative. 

Is this good enough?

300 “false negative” people may believe they’re not contagious because they got a clean chit and could infect others. False negatives could undo the hard work of containment. 

Surely, better an imperfect test than no test. Isn’t flying with partially accurate weather information safer than no information? Here, aviation analogies aren’t helpful. Better to think of a forest fire. 

Imagine only 80% of a burning forest is doused because it’s mistakenly believed that 20% of the forest isn’t burning because we can’t see it burning. It must be extinguished before it relights the whole forest, but to douse it you must know it’s burning – a catch-22. That “20% of the forest” is a false negative – it’s burning but you think it’s not burning. 

Because coronavirus isn’t planning to leave in a hurry and long-term lockdown has grave economic consequences, testing may enable precision quarantining of people, communities, and cities. Rather than applying a one-size-fits-all lockdown on the whole nation, testing could tell us who can work and who should stay home. Why should Austin, if it has a low prevalence of infection, shut shop just because of New York City’s high prevalence? 

Testing enables us to think globally but act locally. But it’s the asymptomatic people who drive the epidemic. To emphasize – asymptomatics are yet to have symptoms such as cough and fever. They’re feeling well and don’t know they’ve been colonized by the virus. Theoretically, if we test en masse we can find asymptomatics. If only those who test positive are quarantined, the rest can have some breathing space. Will this approach work?

RT-PCR’s sensitivity, which is low in early illness, is even lower in asymptomatics, likely because of lower viral load, which means even more false negatives. The virus’s average incubation time of five days is enough time for false negative asymptomatics — remember they resemble the uninfected — to visit Disney World and infect another four. 

Whether false negatives behave like tinder or a controllable fire will determine the testing strategy’s success. The net contagiousness of false negatives depends how many there are, which depends on how many are infected. To know how many are infected we need to test. Or, to know whether to believe a negative test in any person we must test widely – another catch-22. 

Maybe we need a bigger test.

Chest CT is an alternative. It’s rapid – takes less than an hour whereas RT-PCR can take over a day to report. In one study CT had a sensitivity of 97 % in symptomatic patients and was often positive before RT-PCR. But there are caveats. 

The real sensitivity of CT is likely much lower than 97% because the study has biases which inflate performance. CT, like RT-PCR, has a low sensitivity in early illness and even lower sensitivity in asymptomatic carriers for the same reason – lower viral load. Furthermore, CT has to be disinfected to prevent spread, which limits its access for other patients.

Coronavirus’s signature on CT – white patches in lungs, known as ground glass opacities – doesn’t have the uniqueness of the Mark of Zorro, and looks like lung injury from other rogue actors, which means we can mistake other serious conditions for coronavirus. Imagine hyenas in wolf’s clothing. 

No test is perfect. We still use imaging despite its imperfections. But, let’s ask: what’d you do differently if the test is negative and you have mild symptoms of cough and fever? Should you not self-isolate? What if you’re falsely negative and still contagious? If the advice dispensed whether the test is positive or negative is the same – i.e. quarantine for 2 weeks – what’s the test’s value? 

Perhaps people will more likely comply with voluntary quarantine if they know they’re infected. Information can nudge behavior. But the logical corollary is that to comply with social distancing you need to be tested. People flocking to CT scans to affirm they’re not infected could infect those hitherto uninfected. A pandemic is no time to test nudge theories.

Does that mean testing has no value? Testing is valuable in managing populations. To individuals, the results must be framed wisely, such as by advising those who test positive to quarantine because “you’re infected” and those who test negative to keep social distancing because “you could still be infected.” 

Even when policy goals are uniform, messaging can be oppositional. “Get yourself tested now” contradicts “you must hunker down now.” When messages contradict, one must choose which message to amplify. 

The calculus of testing can change with new tests such as antibodies. The value of testing depends also on what isolation entails. A couple of weeks watching Netflix on your couch isn’t a big ask. If quarantine means being detained in an isolation center fenced by barbed wires, the cost of frivolous quarantining is higher and testing becomes more valuable. 

I knew the doctor with the negative RT-PCR well. He’s heroically nonchalant about his wellbeing, an endearing quality that’s a liability in a contagion. In no time he’d be back in the hospital; or helping his elderly parents with grocery. Not all false negatives are equal. False negative doctors could infect not just their patients but their colleagues, leaving fewer firefighters to fight fires. 

It is better to mistake the man flu for coronavirus than coronavirus for the man flu. All he has to do is hunker down, which is what we should all be doing as much as we can. 

Saurabh Jha is a contributing editor to THCB. He can be reached @RogueRad.

4 replies »

  1. Hello,

    The information about RT-PCR test is very useful to detect corona affected people
    The statement “NO TEST IS PERFECT” is a bit of extra stress to the people.

    Thank you.

  2. There are millions of people with deep dry coughs and fevers and sore throats and loss of smell and taste and fatigue. Some of these get Covid-19. Some if these people are minimally symptomatic or asymptomatic. Some get unequivocal corona infections and are tested positive and then proceed to try certain drugs, vitamins, supplements, treatments like inhaling steam or medicated vapor, or try eating thousands of different foods. Thus, there are billions of anecdotes generating all over the world. Fortunately or unfortunately we are mostly connected with Google, Facebook, Twitter, et al. Software can search all our connections. What we are looking for is people who had robust evidence of Covid-19 and then tried Something, anything documentable, like eating lots of zinc or selenium or vitamin C or arginine, or even hydroxychloroquine, whatever, and then had the symptoms go away. These boundaries and conditions can be filtered into place looking at billions of bits of social media. We thus do experiments on zillions of anecdotes and our results become, voila, data.

  3. This is a well-timed article. My son recently got a negative test result after several weeks of coughing & low grade fever, and I was worried about a false negative myself. The fact that he’s now stayed home for 2+ weeks anyway means he’s probably no longer contagious. I will say this, though – the difference in behavior for people with a negative corona result lies not in what they do, but what their quarantine buddies do. Example: while he was sick, I would of course never have sent my son to the grocery store. But, I also self-quarantined with him, while we were waiting for his test results, even though I was not sick, just in case. Now that he has a negative result, and I’m not sick, I feel comfortable doing essential errands again. It’s also nice to be able to share the TV remote without disinfecting it every time.