A literature review and pooled analysis reviewed seven previously published studies providing data on RT-PCR performance by time since symptom onset or SARS-CoV-2 exposure using samples from the upper respiratory tract from 1330 patients. Over the 4 days of infection before the typical time of symptom onset (day 5), the probability of a false-negative result in an infected person decreases from 100% (95% CI, 100% to 100%) on day 1 to 67% (CI, 27% to 94%) on day 4. On the day of symptom onset, the median false-negative rate was 38% (CI, 18% to 65%). This review and pooled analysis showed that care must be taken when interpreting RT-PCR tests for SARS-CoV-2 infection. 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. [1]
A review detailed the problems with false-negatives from RT-PCR tests. One study from Wuhan, China by Yang et al. (Feb 2020), consisting of 213 patients hospitalized for COVID-19, showed that 11% of sputum, 27% of nasal, and 40% of throat samples were deemed falsely negative. Another preprint systematic review (March 2020) of five other studies involving 957 patients had false negatives ranging from 2% to 29% (certainty of evidence was considered very low). Diagnostic testing can help in safely opening countries, but only if the tests are highly sensitive and validated under realistic conditions against a clinically meaningful reference standard. The FDA should ensure that manufacturers provide details of tests’ clinical sensitivity and specificity at the time of market authorization and assuring the test sensitivity in asymptomatic people is an urgent priority. Negative results, even on a highly sensitive test, cannot rule out infection if the pretest probability is high, so clinicians should not trust unexpected negative results. Thresholds for ruling out infection need to be developed for a variety of clinical situations. [2]
A systematic review of the accuracy of COVID-19 tests reported false-negative rates of between 2% and 29% based on negative RT-PCR tests which were positive on repeat testing. The lack of a gold-standard is a challenge for evaluating COVID-19 tests. Clinical adjudication may be the best available “gold standard,” based on repeat swabs, history, and contact with patients known to have COVID-19, chest radiographs, and computed tomography scans. Interpretation of a test result depends not only on the characteristics of the test itself such as sensitivity, specificity, positive likelihood ratios, and negative likelihood ratio, but also on the pre-test probability of disease based on their learned mental shortcut. A single negative test result may not be informative if the pre-test probability is high, especially when facing new and unfamiliar diseases such as COVID-19. Factors that increase pre-test probability include signs, symptoms, history of exposure, and local rates of COVID-19 infection. The likelihood of an alternative diagnosis decreases pre-test probability. [3], [4]
A case report and literature review compiled reports that display false-negative results of COVID-19 testing. Most studies compared RT-PCR to CT scans to verify the diagnosis. The incidence of false-negative results ranged from 17% to 63% for nasopharyngeal RT-PCR for SARS-CoV-2. [5]
A meta-analysis was performed to describe the accuracy of available tests to detect COVID-19 in Brazil. Sixteen tests were included and sensitivity (Se), specificity (Sp), true positive (TP), false positive (FP), true negative (TN), false negative (FN), positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) were described for each test. The pooled diagnostic accuracy of tests in Brazil was satisfactory; however, the rate of false-negative results from tests which detect SARS-CoV-2 IgM antibodies ranged from 10 to 44%. [6]
An editorial warns about the possibility of false-positive results with SARS-COV-2 antibody tests. Cellex, the first antibody test approved by the U.S. Food and Drug Administration for the virus, has a reported sensitivity of 94% and specificity of 96%. When compared to a hypothetical SARS-COV-2 antibody test that is 90% sensitive and 99% specific, the false-positive incidences are much higher when the prevalence of SARS-COV-2 is low. Additionally, many of the other tests with provisional approval by the U.S. Food and Drug Administration have not been appropriately evaluated for accuracy. [7]