Is Adding IgM Antibody to Polymerase Chain Reaction Testing Useful for COVID-19 Travel Screening?

Since November 8, 2020, international travelers entering China have been required to present a negative nucleic acid test (NAT) and a negative serum severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin M (IgM) antibody test, known as the “double-negative test,” taken within 48 hours prior to departure. The new requirement for an additional IgM antibody test by the Chinese Embassy for international travelers has sparked discussions among both Chinese and international media, as well as debate within the scientific community on the usefulness of an added IgM test. What is the scientific rationale for a “double-negative test? ” Does it improve the overall sensitivity in screening individuals infected by SARS-CoV-2? Proof of a negative NAT upon arrival or within 72 hours prior to departure is not a new requirement for international travelers in the current coronavirus disease 2019 (COVID-19) pandemic. Many countries have imposed similar travel policies to minimize the risk of cross-infection during travel and thereby preserve the epidemic containment within their borders. These measures are particularly important for countries that are popular for international tourism and business. For instance, over the past Thanksgiving holiday, Hawaii required all travelers to provide a negative COVID-19 test result prior to departure. The US Centers for Disease Control and Prevention (CDC) also recently updated its Testing and International Air Travel recommendations for passengers to obtain COVID-19 testing both 1 to 3 days before and 3 to 5 days after air travel. Furthermore, given that many countries are currently facing yet another new COVID-19 surge, strict travel policies will continue to be imposed. Regardless of the context of travel, as with all testing, who, what, when, and how to test matter significantly, in addition to the test performance itself. Since the start of the pandemic, NAT for SARSCoV-2 has been regarded as the gold standard test for COVID-19, as it is overall the most sensitive approach to detect viral presence during the first week after symptom onset. However, not all NATs perform equally. Among the more than 200 molecular diagnostic tests that received Emergency Use Authorization (EUA) by the US Food and Drug Administration (FDA), many are based on traditional reverse transcription polymerase chain reaction (RT-PCR), while others use less conventional methods such as droplet digital PCR, isothermal amplification, matrix-assisted laser desorption ionization–time-of-flight mass spectrometry, or clustered regularly interspaced short palindromic repeats technology. The limit of detection (LOD) of these tests significantly affects the detection sensitivity of SARS-CoV-2 and has been shown to vary over 3,000-fold. Each 10-fold increase in LOD is expected to increase the false-negative rate by 13%, and thus the NAT with the highest LOD may have a false-negative rate as high as 70%. There is no specification regarding which NAT travelers should use under any current travel policy. In the hospital setting, RT-PCR and nasopharyngeal (NP) swabs, being the most sensitive method and sample type, are most commonly used. However, NP swabbing needs to be performed by trained health care personnel, and inadequate collection can compromise test sensitivity. As testing demands remain high, NAT performed in laboratories on asymptomatic individuals might not be applyparastyle "fig//caption/p[1]" parastyle "FigCapt"