False negatives: how accurate are PCR tests for COVID-19?

Written by Jenny Straiton

New research calls into question the accuracy of SARS-CoV-2 RT-PCR tests as the chance of receiving a false negative COVID-19 test could be greater than 1 in 5.

As the COVID-19 pandemic spread and the importance of testing was proven, attention was on PCR as institutions all over the world developed new diagnostic tests for detecting SARS-CoV-2. Researchers and clinicians around the globe have been using the RT-PCR technique to find out whether a person has been infected. These tests have played a vital role in many countries’ response to the disease by allowing epidemiologists to better track the spread and determine infection rates in given areas.

However, new research from Johns Hopkins University (MD, USA) has found that the chance of these tests giving a false negative – stating no infection when the individual actually is infected – is greater than 1 in 5, at times being far higher. The study, which analyzed seven previously published studies that evaluated RT-PCR performance, calls into question the accuracy of the predictive value of such tests.

Publishing their results in the Annals of Internal Medicine, the researchers stress the need for caution in interpreting any negative results of RT-PCR diagnostic tests, as many other factors, such as the timing of the test, appear to play a role in the accuracy of the results. The probability of a false negative COVID-19 test decreased from 100% on Day 1 of the infection to 67% on Day 4. This further decreased to 20% on Day 8, 3 days after a patient would first start to experience COVID-19 symptoms.

Day 8 appeared to be the optimal time for testing, as after this the probability of a false negative once again began to increase. A 21% probability on Day 9 increased to 66% if testing occurred on Day 21 of infection.

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There are likely various reasons for the false negative results. In an interview with the Huffington Post UK, James Gill (University of Warwick, UK) stated he believed that sampling errors may play a part, and some testing centers may be swabbing incorrectly; “It’s a swab that requires some  experience to do well, certainly without being uncomfortable,” Gill explained.

As shown in the recent study, timing is also a major factor as the virus moves around the body throughout the course of the infection. “The longer you have the condition, the virus migrates and it goes down into your lungs,” commented Gill. “So even though you’re coughing, you’ve got the fever, we might not be able to get the swab because it might not be there anymore. It might’ve gone down to the lungs. That’s one reason we can miss it.”

A similar study, published earlier this month in the BMJ, also highlighted the inaccuracies of PCR-based testing. Noting that a positive test should hold more weight than a negative one due to the test’s high specificity yet moderate sensitivity. The authors suggested that a single negative test should not be used to rule out infection – particularly in patients displaying symptoms of COVID-19.

Perceived secrecy over false negative COVID-19 tests has caused frustration among many healthcare workers as many frontline workers have continued to work after being declared virus-free. The relatively high rate of false negative results, combined with the ‘silent spread’ from asymptomatic individuals, has likely led to the high number of patients contracting the virus in a hospital setting.

Testing remains vital for controlling the spread of the pandemic, and the chance of false negatives should not be a deterrent for taking a test. The aforementioned studies only comment on the accuracy of PCR-based tests and alternative testing methods are available. Antibody tests are able to determine whether an individual has had the virus by detecting the presence of antibodies against SARS-CoV-2 in a blood sample. Different tests do vary in accuracy and tests relying on blood samples drawn by healthcare professionals have been shown to be more accurate than those that use finger prick samples, with research suggesting unvalidated samples may give unreliable results.

In order to reduce the impact of false negative COVID-19 results, clinicians should be aware of the pitfalls in the test’s accuracy and share with patients that a negative result does not necessarily mean no infection; if experiencing symptoms an individual should self-isolate, regardless of test result.