CLICK TO EXPAND // Updates as of May 19, 2020
Now weeks into a national lockdown, we have all likely seen reports regarding the challenges in obtaining and performing testing for patients with a suspected COVID-19 infection. Given the inadequate number of testing kits that were available as the number of known cases was increasing, many individuals who were experiencing mild to moderate symptoms that could have been related to COVID-19 were unable to obtain appropriate testing or testing on an appropriate timeline. With the wealth of information (often conflicting) that exists about testing and the number of changes that have taken place in the past few weeks, I wanted to provide you all with a brief summary about my current understanding of testing and how things will continue to evolve over the coming weeks.
Note: The topics explored in this blog are incredibly fluid with updates and changes happening daily. The material as originally presented is up to date as of Tuesday April, 21st, 2020. We will seek to provide updates to this blog after the date of publication as important information or changes arise.
Test History: Polymerase Chain Reaction (PCR) Testing
Initial testing policies and continued testing efforts for those with moderate to severe symptoms has involved the collection of human cells using a naso-pharyngeal swab (swab up the nose) or occasionally an oro-pharyngeal swab (swab in the throat). After the collection of these cells and their mixture into the testing medium, the lab would then perform a test known as a PCR (Polymerase Chain Reaction) to essentially look for evidence of the virus’ genetic material (it has RNA instead of our DNA) in the collected set of cells. As the virus replicates predominantly in tissues of the respiratory tract, finding evidence of its genetic material from cells in the respiratory tract in someone with symptoms most consistent with the best known symptom pattern of COVID-19 is arguably the best method of identifying someone who is sick with an active infection of COVID-19. While this type of testing has been and will remain critical for identifying those with active infections as well as those with more severe infections in hospital settings, for those who have had mild symptoms and have now recovered or who continue to have major challenges in accessing PCR testing, we must look to newer alternatives.
Overview of Antibody Testing
Another type of emerging test outside of the PCR (genetic) test is known as an antibody test. As part of our own immune response to external pathogens including intracellular pathogens such as a virus, we may develop antibodies to various aspects of the pathogen. Antibodies are essentially specialized proteins with two functional components. One portion of the antibody is tasked with recognizing and binding to various protein patterns such as those of a virus while the second portion is tasked with binding to our own immune cells in order to further communicate what it has recognized on the pathogen portion. Over the course of an infection, we will utilize different types of antibodies that have specialized structures and thus specialized functions, with some antibodies being more helpful and critical for the earlier stages of an infection and others being more helpful in later stages and after the infection has resolved.
Role of COVID-19 Antibody Testing
As you can likely start to see, testing individuals for antibodies to COVID-19 would be a great way to determine who is having or has had an immune response to the virus. While there is still much that we do not know about individuals who test positive on such antibody tests (for example, a) Do they have lifelong immunity? b) Are they still actively shedding the virus in a way that makes them contagious? c) Is the antibody test actually showing evidence of an immune response to COVID-19 and not just another type of more benign coronavirus?) the information antibody testing can provide will help us more quickly return to a degree of normalcy and better understand the extent of the virus’ spread. While it may feel like we should immediately begin testing everyone with antibody tests, we need to make sure we understand the information the test is actually telling us, the reliability of the information it is providing, and the clinical picture of the person we are testing in the first place.
Below I have outlined the primary scenarios where antibody testing would be the most helpful starting with the best candidates and ending with the less optimal scenarios.
1. Previously symptomatic individuals with symptoms that could have been attributed to COVID-19 with no previous PCR testing who have now recovered.
Individuals who are no longer symptomatic but previously showed symptoms such as fever, shortness of breath, chest tightness and loss of sense of smell at least 5-7 days prior to considering antibody testing are ideal candidates for antibody testing. Depending on the timeline from the first onset of potential COVID-19 symptoms, PCR testing in a “recovered” and asymptomatic individual could result in a negative test and the perception that one never had the virus. Testing for antibodies at least 5 days after the first onset of symptoms, however, can potentially identify the nature of any immune response to the virus and thus help us to discern whether one’s previous symptoms were actually related to COVID-19 or to some other cause.
2. Mildly symptomatic individuals who are unable to obtain PCR testing and have had symptoms for at least 5 days.
These individuals have been the most under-represented with most current PCR testing policies. Getting them access to a test that can be performed and resulted in a 48 hour period would be greatly helpful for determining one’s individual course of treatment and for our greater efforts at understanding infection rates.
3. Asymptomatic individuals with known (positive PCR test) close contacts who exhibited symptoms at least 2 weeks prior.
There are hundreds of thousands of individuals who are currently asymptomatic in various versions of quarantine given a known and not just theoretical exposure to someone with COVID-19. It would be helpful to understand which of these individuals indeed actually contracted the virus and have developed an immune response- antibodies to the virus. Interpreting testing results in this group does become a little more challenging, however, when one lacks symptoms, and therefore lacks a theoretical timeline for when we would normally expect to see antibodies. For asymptomatic individuals with known COVID-19 exposures, I would suggest waiting at least 10 days to 2 weeks after the date of known exposure to the positive close contact before pursuing the antibody testing. Even with this timeline, however, one could still test negative for antibodies even though one is currently in an evolving state of infection, but in a state that is too early for detecting antibodies.
4. Asymptomatic individuals with theoretical exposure to the virus.
As you likely realize, this group of individuals is both the largest, most variable and thus the most challenging to accurately assess with an antibody test. Many can make arguments for expanding and offering testing to these groups, which we will likely be doing in the coming weeks and months, but I list this group and the testing scenario at the bottom as there are just so many variables for individuals in this bucket that could alter the timing and interpretation of antibody testing. In my opinion, testing such a population should start with the most ubiquitously exposed groups- our essential workers. While many of the essential workers fall into one of the other scenarios described previously, many more are still living in a world wondering have I been directly exposed to an actively infected individual in a state of susceptibility? It makes sense to me then, for certain corporations and large companies employing individuals in areas of essential need to strongly explore these tests for their employees in order to better understand their current level of exposure and identify who may be better candidates for continuing to work in these exposed roles.
How Reliable is COVID-19 Antibody Testing?
In the last week alone there has been a huge surge of companies offering various versions of COVID-19 antibody testing kits. As you can likely imagine, there is some money to be made by companies- while not entirely unjustly, and the current FDA approval process for such tests is essentially non-existent at least in how it was formally designed outside of emergency proceedings, leading many like myself to be quite cautious in assessing the available testing landscape. At the time of writing (April 21st), there have only been 4 antibody tests that have received an officially emergency use authorization – not the same thing as a full approval, so that it can be offered in various clinical laboratories. Of the 100 or so other lab companies that have submitted testing registration information to the FDA and/or are currently marketing their antibody tests, the only requirements set down by the FDA are essentially that the test must be reliable and accurate and that the lab company cannot advertise that its test is actually diagnosing a COVID-19 infection (1).
Excerpt from an FDA Statement on April 7th
“In March, the FDA issued a policy to allow developers of certain serological tests to begin to market or use their tests once they have performed the appropriate evaluation to determine that their tests are accurate and reliable. This includes allowing developers to market their tests without prior FDA review if certain conditions outlined in the guidance document are met. The FDA issued this policy to allow early patient access to certain serological tests with the understanding that the FDA has not reviewed and authorized them.”
With all of this in mind, we must be open, but careful in the next phase of testing implementation with the various types of antibody tests that will be administered. While the antibody tests themselves are all similar in nature, the specific viral proteins to which the antibodies are developed (amidst many other testing characteristics) are quite different and their individual ability to detect the presence of COVID-19 antibodies and ability to correctly indicate when they are not present is going to be quite variable.
Given that we will not have any formally approved FDA tests during this emergency period, we will primarily have to rely on data presented by the lab technology companies and the testing labs themselves about the usefulness of specific antibody tests. While it would be easy to think that the first test that received an FDA emergency use authorization — an antibody test from the lab Cellex — is the best antibody test for patients, this would be making a logical fallacy as the Cellex test is simply the first of what will be many more tests getting the emergency use authorization moniker.
From what is published from the FDA regarding the Cellex test, it appears to have around a 93% sensitivity (ability to detect the antibodies in a sick individual) and around 96% specificity (ability to correctly determine who is not sick) . As you can see, the test is still not perfect, and will occasionally not detect antibodies when someone actually has them and can even indicate that someone has the antibodies when in fact they actually do not, arguably the more problematic issue. After looking at some of the other published data from other antibody tests, most tests appear to have sensitivities around 85-95% and specificities around 93-100%
While it is impossible to get fully comprehensive data regarding all the newly marketed antibody tests, Johns Hopkins has provided a nice centralization of tests that have received FDA emergency use authorizations or tests that have been approved by similar FDA organizations in other countries (3). It should be noted that many of the tests that have been used in other countries such as China and that are listed on the Johns Hopkins site are the tests themselves than many of the lab testing companies seeking emergency use authorizations are using through specified partnerships. In addition, the FDA continues to regularly post updates about new tests, both PCR and antibody tests that are receiving emergency use authorizations that you can find from the cited reference (4).
Obtaining COVID-19 Antibody Testing
Now you may be asking: How do I get an antibody test and what will it cost? The answers to these questions will indeed be incredibly variable, but the first place to start is to contact your primary care provider or primary physician providing services for you. At this juncture with the antibody tests being so new, many practices may or may not have access to the tests themselves and/or the ability to draw your blood to perform the tests. As of the writing of this article, only one of the major clinical laboratories, Quest Diagnostics, has started to offer an IgG antibody test, however, I have not been able to see any of the test’s methodology or statistics including its sensitivity or specificity, making it very challenging to recommend as of yet. Another large clinical Labcorp does not appear to be currently performing any antibody testing, however they have just received an emergency use authorization for one of its PCR tests to be performed at home instead of at a health care provider’s office. While the testing landscape will invariably change over the coming weeks, there appears to be some initial challenges for patients and physicians to obtain reliable and authorized antibody tests.
While the testing options at this point may be limited, I am aware of a CLIA certified laboratory known as KBMO Diagnostics that has a FDA registered antibody test with adequate sensitivity and specificity that is currently available for physicians to order and for patients to have performed and resulted in around 48 hours. KBMO’s specific antibody test has been utilized in China in approximately 2 million individuals and has a sensitivity of around 87% and a specificity near 100%. The KBMO Diagnostics team has also arranged for a network of mobile phlebotomists who are able to draw the blood necessary for the test without individuals leaving their homes. The test collection kit can be ordered and drop shipped to the patient or wherever the testing is to be performed. The test itself including the rapid shipping to and from the patient is $150. The mobile phlebotomy services start at $100 per draw, but cost only $50 for subsequent draws at the same location. At the current time, payment for the testing kits must be provided at the time of ordering. While the cost of the test is not inconsequential, there is language in the previously passed CARES Act that indicates that health insurance companies (commercial) will be required to cover COVID-19 testing services including services provided from clinical labs or providers that are out of network. While there are many potential issues that could arise from this seemingly good element of the CARES Act, in the case of the KBMO antibody test, one should theoretically be able to submit paperwork (like a superbill) including testing and diagnostic codes to one’s insurance carrier after paying for and performing the KBMO antibody test even through the KBMO lab is an out of network lab facility.
When it comes to point of care or in-home antibody tests that can be performed using a finger prick to obtain capillary blood, 1 of the 4 antibody tests that have received emergency use authorizations is for an in-home testing kit (5). After reviewing the lab company and affiliates websites as well as the scientific media pieces describing the test kits approval, however, it is still unclear to me how as a provider I can actually get one of these tests ordered for my patients and at what scale these tests are being produced. As you can imagine, this process is both frustrating and evolving and I am confident over the coming days and weeks there will be greater access to authorized tests for both providers and patients.
What Does All of This Mean?
As you can imagine, everyone would love to know exactly how far the virus has spread, who precisely has been affected and do those affected with positive antibody tests now have immunity? We simply do not have answers to these questions, and while we must be tempered in our conclusions, we must be willing to strategically deploy testing to better understand the nature of this pandemic and start to more comprehensively answer these questions. A preliminary study (yet to be formally peer-reviewed) coming out of Stanford appeared to indicate, after utilizing antibody testing for a larger population of individuals within a defined geographic region, that there was evidence of positive antibodies and suspected viral exposure in 2-4% of the population tested, a 50-85 times greater number than current case estimates derived almost exclusively from PCR testing appear to indicate (6). While the hypothesis that a larger percentage of individuals (mainly asymptomatic) have been exposed and developed antibodies to the virus is strongly supported, the statistical calculations and models used in this previously mentioned study and in other similar reports are flawed in a number of ways, mainly do to the limitations in the sensitivity of the antibody tests used, the still relatively low number of cases or prevalence of antibodies and sampling bias related to the selection of participants. It is likely safe to say more people have been infected than current case data shows, with most of these unreported cases coming from asymptomatic individuals, but the exact percentages of cases within certain geography regions remains a mystery.
Testing for COVID-19 is an evolving process with the latest evolutions involving the new access to antibody tests looking for signs of an immune response. Despite the inclination to immediately deploy these types of tests for all Americans, the FDA has currently allowed large scale marketing of unproven antibody tests. It will be critical over the coming weeks, to balance the risks and benefits of utilizing unproven testing with the need to have some form of testing performed across large populations. While I suspect there to be improved oversight by the FDA over the coming weeks, there is currently too much uncertainty about which antibody tests are the most accurate, reliable and readily accessible. For those interested in receiving antibody testing, you should contact your local medical professional and can consider exploring the resources provided below about one of the antibody tests provided by KBMO Diagnostics.
KBMO Diagnostics Testing Information
Test Details: https://kbmodiagnostics.com/
Physician Ordering Form: https://kbmodiagnostics.com/physician-order-form-covid-19-kits/
Detailed Test Description Slides: https://kbmodiagnostics.com/wp-content/uploads/KBMO-Diagnostics-COVID-19-Rapid-Test.pdf
COVID-19 Diagnostic and Procedure Codes
Test Diagnostic Codes (7)
One Step Antibody Tests: 86328 (Ex. KBMO Antibody Test)
Two Step Antibody Tests: 86769
Potential Diagnosis Codes
R06.02: Shortness of breath
R50.9 Fever unspecified
(These codes would be reasonable for people in Scenarios 1/ 2 depending on one’s symptoms)
Z03.818: Encounter for observation for suspected exposure to other biological agents ruled out.
(This code is for those with a THEORETICAL exposure -Scenario 4)
Z20.828: Contact with and (suspected) exposure to other viral communicable diseases
(This code is for those with a KNOWN exposure- Scenario 3)
Expected Reimbursement/Insurance Payment for Testing (8)
U0001 – PCR Testing : $35.91
U0002 – Antibody Testing : $51.31
Note: The rates your commercial insurance will be billed for and will pay for these tests is variable, but they typically use these rates from the CMS (Medicare) in constructing their payment and reimbursement rates
CLICK TO EXPAND // References