• A Discussion with Dr. Serena Koenig About the Why, When, and How of Novel Coronavirus Testing

    As cases and deaths from the coronavirus disease 2019 (COVID-19) continue to grow worldwide, attention has turned to testing strategies for the novel coronavirus as a window into the pandemic. Dr. Serena Koenig is an infectious disease specialist, Associate Professor of Medicine at Harvard Medical School, and Associate Physician in the Division of Global Health Equity and the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.

    Over the last eight years, Dr. Koenig also has guided Analysis Group’s extensive pro bono work in support of the GHESKIO Centers in Haiti, most recently addressing the COVID-19 crisis. She has coauthored over a dozen papers and collaborated on National Institutes of Health (NIH) grants with members of Analysis Group.

    In this Q&A with Analysis Group Managing Principal Elyse Swallow, Dr. Koenig covers key topics related to testing for the novel coronavirus that can lead to COVID-19.

    How do you test for the coronavirus that is causing the pandemic and that has led to the spikes in hospitalization to treat the most severe cases of COVID-19?

    Let me start by explaining that we currently rely on two big families of tests for the novel coronavirus, or more specifically, SARS-CoV-2, which is the virus that causes COVID-19: testing for the presence of the virus, and antibody tests.

    Viral tests are used to detect current infection with the SARS-CoV-2 virus, and are primarily done using reverse transcriptase polymerase chain reaction (RT-PCR) tests. Antibody tests detect your body’s response to infection by testing for immunoglobulin G (IgG) and immunoglobulin M (IgM), which are antibodies your body produces when it fights off SARS-CoV-2 infection.

    There is technically a third type of test called the antigen test, but to date these tests are less widely used, so let’s focus on RT-PCR and antibody tests.

    Why is testing so important? What kind of information does testing provide?

    Testing is a crucial tool to understand and fight the pandemic. Accurate information about both current and past infection status helps determine who to treat for the disease, who to trace as potential contacts of infected individuals, who to isolate to prevent transmission to others, and how many people have been infected.

    At an epidemiological level, we could answer questions about the spread of the virus in the population. That will be a great help in informing allocation of medical resources for those who need to be treated for or hospitalized with COVID-19, designing strategies for safely reopening the economy, and assessing progress towards herd immunity, which is driven by the percentage of the target population that tests positive for antibodies.

    What are the biggest challenges you face?

    What is really tricky about these tests is that they are more or less effective depending on how long the patient has been infected. RT-PCR is most sensitive when the patient is newly infected, but its ability to detect the virus diminishes within days. Meanwhile, antibodies only become detectable as the body reacts to the virus, a process that takes time.

    On top of that, testing positive for antibodies does not mean that you are not contagious, because you might still be shedding virus depending on how long ago you were infected. As you can see, the timing of test administration is extremely important and makes false results problematic.

    What do we need to keep in mind when interpreting the test results?

    To diagnose current infection, the RT-PCR test works by amplifying the presence of the genetic material of the virus for better detection. One problem with this test is that you may miss the virus and give a clean bill of health to somebody who is infected. That is called a false negative result. On the other hand, PCR tests rarely give false positive results, since they only return positive results if they actually detect the virus.

    To determine past infection, the antibody test relies on a blood draw as opposed to a nasal swab. These tests identify whether you have antibodies to SARS-CoV-2 in your blood, though they can also yield false positives (meaning that they find antibodies when there are none) and false negatives (meaning that no antibodies were found, but you still have been infected). Remember that if the antibody test is administered too soon after infection, it may fail to detect antibodies in your blood.

    How quickly can we get testing results?

    There are a few defining features of our current testing landscape that impact how quickly and accurately we can get results from both the diagnostic RT-PCR and the antibody tests.

    It typically takes between a couple of hours and a few days to get the results of an RT-PCR or an antibody test. Right now, the issue is less with how long it takes to get results than the lack of test availability. As tests become more widely available, though, lab capacity may become an issue, and the time to get results may change.

    RT-PCR testing also involves multiple steps that require trained technicians, as well as devices and chemical supplies that can be in short supply. This is a particular issue in developing countries such as Haiti, where your Analysis Group teams have done a lot of work with GHESKIO.

    Each of these features plays into the potential delays, higher expense, and slower nature of RT-PCR testing. That’s why researchers are on the hunt for innovative methods that may yield faster results, cheaper.

    The current antibody test landscape has been widely dubbed the “Wild West,” with the rate of innovation rushing ahead of regulatory capacity. This has resulted in some low-quality testing with unreliable results, but I hope that the landscape will improve with time.

    Can you say more about why error matters when it comes to testing?

    Put simply, there are three types of errors we are concerned about. The first is if you are told you have the novel coronavirus and you don’t (false positive); the second is if you are told you do not have the virus but you do (false negative); and the third is if you are told you have antibodies, but you never actually had the virus (another form of false positive). Theoretically, you could also be told you don’t have antibodies when you, in fact, do, but the clinical consequence of that is mild – it only means you will take more precautions than you should need to.

    The issue with the false negative is that you may put other people at risk because you don’t know that you have the disease. You may also put yourself at risk by not seeking treatment when the first symptoms appear.

    The issue with the false positive is that it may completely skew our understanding of the propagation of the disease even if it is quite low.

    What problems can false positives create?

    Say that you live in an area with 100,000 people, and 2,000 of those people have SARS-CoV-2, for a true positive rate of 2 percent. Suppose your test is right 95 percent of the time but has a 5 percent false positive rate.

    This may seem pretty good. However, it means our test may perfectly identify all 2,000 people who are positive (assume no false negatives), but 5 percent of the 98,000 people who do not have the virus will be incorrectly identified as having the SARS-CoV-2 virus. That’s 4,900 people incorrectly identified as having SARS-CoV-2.

    That means that you would believe the population to include 6,900 people who have the virus when only 2,000 do; the estimate from the test is 3.5 times the reality, even though the false positive rate seems pretty low (5 percent).

    To put a finer point on it, if your test comes back positive, this means you have a higher chance of not having SARS-CoV-2 than having it. Are you one of the 2,000 true positives, or one of the 4,900 false positives?

    The error rates of current tests present a significant obstacle to regulatory or policy decisions based on testing results.

    As an infectious disease specialist, what would you recommend as the right testing strategy?

    Testing is an important part of the response to the pandemic. Most public health experts agree that we need to increase the availability and accuracy of tests. That way, we can have the information we need to carefully consider the rules and regulations needed to fight this disease. That includes, but is not limited to, providing guidance on how to safely reopen.

    Testing should be used alongside other mitigation strategies. Testing is necessary, but it is most powerful when used alongside other tools such as contact tracing, responsible distancing, and investing in our public health infrastructure. I know that Partners in Health, with whom I have worked and for whom Analysis Group has provided pro bono services as well, has been very active in contact tracing in Massachusetts. That is an important part of the public health response.

    Testing acts as a pulse check; it tells us how we are doing on infections in a given area, and using that information, we can employ the suite of strategies we need to fight the pandemic.