One in five infected people may test negative for coronavirus before symptoms show, finds study

The concern is that a negative result may initially give people a false sense of security in the days leading up to symptom onset, say experts.


                            One in five infected people may test negative for coronavirus before symptoms show, finds study
(Getty Images)
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The chance of a false negative Covid-19 result — when a virus is not detected in a person who is, or recently has been, infected — is greater than one in five people and at times higher, according to researchers. The study by experts from the Johns Hopkins Bloomberg School of Public Health says that even up to the day before symptoms start, the probability of a false-negative result is 67%. On the day a person starts experiencing symptoms, the probability of a false-negative result is 38%, shows analysis. 

One of the most commonly used diagnostic tools, particularly during the Covid-19 pandemic, is the reverse transcriptase-polymerase chain reaction test (RT-PCR). It uses a person’s respiratory sample to detect viral particles and determine if the person may have been exposed to a virus. According to the research team, tests for the new coronavirus based on reverse transcriptase-polymerase chain reaction are being used across the US and globally to "rule out" coronavirus infection among high-risk people, such as exposed in-patients and health care workers, but studies suggest that test sensitivity may be low. Accordingly, the team estimated the false-negative rate by day since exposure to infection. They did so by pooling and modeling data from previously published studies on RT-PCR sensitivity of upper respiratory tract samples of people who were ultimately confirmed to have Covid-19.

The researchers found that over the four days of infection before the typical time of symptom onset (day five), the probability of a false-negative result in an infected person decreases from 100% on day 1 to 67% on day 4, although there is considerable uncertainty in these numbers. The false-negative rate decreased to 20% on day eight, three days after a person begins experiencing symptoms. The analysis also shows that on the day a person started experiencing actual symptoms of illness, the average false-negative rate was 38%. Additionally, the false-negative rate began to increase again from 21% on day nine to 66% on day 21. 

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One of the most commonly used diagnostic tools  is the reverse transcriptase-polymerase chain reaction test (RT-PCR), which uses a person’s respiratory sample to detect viral particles (Getty Images)

The study adds to evidence that caution should be used in the interpretation of negative test results, particularly for individuals likely to have been exposed or who have symptoms consistent with Covid-19. Researchers warn that the predictive value of these tests may not always yield accurate results, and the timing of the test seems to matter greatly in the accuracy. "Care must be taken in interpreting RT-PCR tests for SARS-CoV-2 infection — particularly early in the course of infection — when using these results as a basis for removing precautions intended to prevent onward transmission. If clinical suspicion is high, infection should not be ruled out on the basis of RT-PCR alone, and the clinical and epidemiologic situation should be carefully considered," recommends the team in their findings published in the journal Annals of Internal Medicine. 

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Dr Abraar Karan, internal medicine doctor at Brigham and Women's Hospital and Harvard Medical School, who has been studying epidemic response and emerging infectious diseases, said the findings matter because SARS-CoV-2 (the virus that causes Covid-19) viral load has been shown to peak on the day of symptom onset. "Presymptomatic transmission is estimated to account for nearly half of the transmission burden. The concern is that using PCR to detect asymptomatic exposures (through contact tracing programs) that subsequently return negative initially may give folks a false sense of security in the days leading up to symptom onset. To me, this is the most dangerous window. Because you think you’re fine; you are likely interacting with your family in close quarters without a mask on. And you very well could be transmitting virus without knowing it, as viral load is growing/peaking in the upper respiratory tract," he said.

The study comes even as new reports on the number of asymptomatic people with the coronavirus suggest that such patients are much more prevalent than previously estimated. One study analyzed 78 patients confirmed with Covid-19, of which a total of 33 patients (42.3%) were asymptomatic while 45 (57.7%) were symptomatic. The symptoms and signs such as fever, fatigue and dry cough were monitored every day. The prevalence of asymptomatic cases, based on mathematical modeling, is estimated at 35% by the US Centers for Disease Control and Prevention (CDC).

"Since patients with asymptomatic Covid-19 were relatively concealed, the fact of viral shedding detected via nasopharyngeal swabs must not be ignored. Therefore, identifying and isolating patients with asymptomatic Covid-19 as early as possible is critical to control the transmission of Covid-19. Close contacts of patients with Covid-19 should be closely monitored to avoid secondary transmission," says the study published in JAMA Network Open. 

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The concern is that a negative result may initially give people a false sense of security in the days leading up to symptom onset, say experts (Getty Images)

According to another report, 81% of the passengers and crew infected with coronavirus on an expedition cruise ship did not show any symptoms, raising questions about the true prevalence of "silent" infections. "Of the 217 passengers and crew on board, 128 tested positive for Covid-19 on reverse transcription – PCR (59%). Of the Covid-19-positive patients, 19% (24) were symptomatic; 6.2% (8) required medical evacuation; 3.1% (4) were intubated and ventilated; and the mortality was 0.8%. The majority of Covid-19-positive patients were asymptomatic (81%, 104 patients). We conclude that the prevalence of Covid-19 on affected cruise ships is likely to be significantly underestimated, and strategies are needed to assess and monitor all passengers to prevent community transmission after disembarkation," says the study published in Thorax.

According to an editorial in the Thorax, it is difficult to find a reliable estimate of the number of Covid-19 positive patients who have no symptoms. "In early March, the WHO (World Health Organization) suggested the figure might be only 1% – very different from the 81% figure found on the cruise ship. As countries progress out of lockdown, a high proportion of infected but asymptomatic individuals may mean that a much higher percentage of the population than expected may have been infected with Covid-19. These individuals may have immunity to Covid-19. This demonstrates the urgent need for accurate seroprevalence studies to estimate the overall population infection rate across the globe," says Alan Smyth, joint editor-in-chief of Thorax. 

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