False negative: COVID-19 testing’s catch-22

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In a physician WhatsApp group, a doctor posted he had a fever of 101 degrees Fahrenheit and muscle ache, gently confessing that it felt like his typical “man flu” which heals with rest and scotch. 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 assumes he’s infected and quarantine for two weeks, with a bottle of scotch.

It’s believed that the secret sauce to fighting the pandemic is testing for the virus. The depth of the response will be different if 25% of the population is infected than 1%. Testing is the third way, rejecting the choice between death and economic depression. Without testing, strategy is faith-based. But 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. The Chinese ophthalmologist, Li Wenliang, who originally sounded the alarm about coronavirus, had several negative tests. He died from the infection.

In one study, RT-PCR’s sensitivity – that’s the percentage of infected testing positive – was 70% – 1000 with coronavirus: 700 test positive but 300 test negative.

Good enough?

300 “false negative” may believe they’re not contagious and could infect others, undoing 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. 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.

Testing may enable precision quarantining, enabling us to think globally but act locally. But it’s the asymptomatics who drive the epidemic. To emphasize – asymptomatics haven’t yet developed symptoms such as cough and fever. Theoretically, if we mass test, 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 incubation time of five days is enough time for false negatives – 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 on 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.

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 that 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.

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 also depends 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 groceries. Not all false negatives are equal. False-negative doctors could infect not just their patients but their colleagues, leaving fewer firefighters to fight fires.

Saurabh Jha is a radiologist and can be reached on Twitter @RogueRad.  

Image credit: Shutterstock.com

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