“We made too many wrong mistakes.” - Yogi Berra
“This time is unlike anything any of us has experienced, just in terms of the bombardment of data.”
- Rommie Amaro, director, National Biomedical Computation Resource, University of California, San Diego
When I first addressed the issue in my March 26 post, it was evident that testing would play a pivotal role in helping control the spread of COVID-19. Sadly, the U.S. dropped the ball and failed to facilitate nation-wide testing early on in this pandemic. Finally, that mistake has been corrected and testing for SARS-CoV-2 is now widely accessible across the U.S. This is good news and especially important at this juncture when the pandemic is surging in many areas of our country. This testing and its accessibility do, however, raise new issues. The goal of this Germ Gem post is to clarify who should be tested for COVID-19 and why and also to provide an overview of the different tests currently available.
Who should be tested? First, anybody who develops an illness with symptoms compatible with the diagnosis of COVID-19 should be tested for an infection by SARS-CoV-2. Symptoms may include: fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhea, a variety of skin manifestations (including “COVID toes”), and two symptoms that recently were added to the list: the new onset of deafness or delirium. Symptoms usually appear 2-14 days after exposure to the virus.
Developing any of the above symptoms may appear to be a simple determinant for getting tested for infection by this virus, but things aren’t necessarily that easy. As we all know, the number of symptoms associated with COVID-19 is constantly growing. Moreover, they overlap with other infections that target the respiratory tract. Nonetheless, if you develop any of the above symptoms, you should get tested.
Second, even if you don’t have any of these symptoms but have been in contact with someone who has tested positive for the virus, whether they are symptomatic or have no symptoms (that is, are asymptomatic) you should get tested. (Your potential exposure to someone with COVID-19 can be provided by your state health department using an App recently developed by Apple and Google in partnership with the nonprofit PathCheck Foundation.) Asymptomatic infections are a major challenge (the ‘Achille’s heel’) of the COVID-19 pandemic because these infected individuals, although not ill themselves, can nonetheless transmit the virus in the air by aerosols or droplets by coughing, sneezing, or even loud singing or shouting. According to recent data from Columbia University and the University of Washington’s Institute for Health Metrics and Evaluation, an estimated 3.6 million Americans are currently infected and between 40% to 50% of these SARS-CoV-2 infections are asymptomatic.
Why get tested? As is true for all laboratory tests, testing should only be carried out if the test results have the potential of impacting decisions regarding clinical management. In the case of COVID-19, these decisions include who should be hospitalized (for those with symptomatic infections) and quarantining (for those with asymptomatic infections).
Tests that tell if you are currently infected. Once the decision has been made (often in consultation with a doctor or public health official) that testing is in order either for the purposes of diagnosing COVID-19 in symptomatic (ill) people or in the context of “contact tracing” (of asymptomatic people with known exposure to a COVID-19 patient), there are two kinds of tests that are readily available for detecting SARS-CoV-2: molecular tests or antigen tests.
Molecular tests detect viral nucleic acid (RNA) using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay, whereas antigen tests detect fragments of the viral spike (S) protein and the nucleocapsid protein. Both kinds of tests are rapid (results are generally known within 2 days), highly sensitive, and specific. By the end of October, the Food and Drug Administration (FDA) had authorized nearly 230 diagnostic tests for COVID-19. While antigen tests carry a greater chance of false negatives because they are not quite as sensitive as molecular tests, they are inherently faster and are currently driving point-of-care testing in schools and nursing homes (test results using the Abbott BinaxNOW test are available in 13 minutes).
Samples for viral detection are usually collected via swabbing the nasopharynx or by collection of saliva. (Testing of saliva is at least as good, if not better, than nasopharyngeal swabs and is certainly less painful.) Through contracts with state health departments, commercial companies provide kits throughout the U.S. (via United Parcel Service) for collecting saliva samples at home with convenient instructions about sample handling given on-line via ZOOM. On November 17, the FDA issued an Emergency Use Authorization for the first COVID-19 diagnostic rapid self-testing at home test (the “Lurica COVID-19 All-in-One Test Kit”) that provides results in 30 minutes or less. This rapid test, however, should only be used on people with symptoms and is currently authorized for prescription use only.
Tests to tell if you had a past SARS-CoV-2 infection. Two kinds of tests can be done to tell whether someone was infected in the past by SARS-CoV-2. Both types of test look for evidence of an immune response to the virus. The more readily available is antibody testing. Antibodies are proteins (called immunoglobulins) that are produced by B lymphocytes that neutralize the virus by binding to structures such as the S protein, thereby preventing viral entry into host cells. Antibodies are assayed in the serum of blood (thus, their designation as serologic assays).
The second kind of immune assay measures T-cell responses to SARS-CoV-2 antigens. A recently developed T-cell test—reported to be the first of its kind—appears to be more effective than commercially available antibody tests in detecting past COVID-19 infections. (An example of this kind of test is the FDA-approved test for tuberculosis called the QuantiFERON test.) Only time will tell if T-cell tests should be used instead of antibody tests for past SARS-CoV-2 infection.
Serologic assays for SARS-CoV-2 infection are an important tool for surveillance and epidemiologic studies for understanding the transmission dynamic of the virus in the general population. Antibody tests help determine whether the individual being tested was previously infected—even if that person never had symptoms. Serologic assays are also used in the testing of vaccines and in determining the level of herd immunity to SARS-CoV-2 in various communities or countries.
What’s on the horizon of COVID-19 testing? Like many aspects of the public health response to COVID-19, including development of vaccines, methods for testing for infection (current or past) have also evolved at warp speed. My guess is that point-of-care tests, including rapid at-home tests, are likely to accelerate the fastest. I also believe that many of the technological advances that have emerged in less than a year’s time of the COVID-19 era, are likely to transform diagnostic, therapeutic, and vaccine development for other infectious diseases.
In an article in Science in November (“Advancing new tools for infectious diseases”), Rajesh Gupta, the Qualcomm Professor in Embedded Microsystems at the University of California, San Diego, provides a sense of the revolutionary nature of technological advances arising out of COVID-19. This is good news not only for managing the COVID-19 pandemic but for many other areas of medicine and public health.