The Science of SARS-CoV-2 Testing: What

Tests Are Available and What This May

Mean for You

Guest post by Clem McDonald, MD, Chief Health Data Standards Officer at the National
Library of Medicine

COVID-19 testing equips individuals with the information they need to protect themselves and
others, and arms public health professionals with data that can inform response efforts.

Recently, leadership across NIH articulated why widespread testing is necessary, important, and
achievable. Equally important is understanding the different types of testing available. As a
leader and pioneer in the development of clinical data standards, NLM supports the electronic
exchange of clinical health information data, including those related to COVID-19 testing, for
approved purposes and with appropriate privacy protections.

Three types of testing are available to identify COVID-19 (the disease caused by the SARS-
CoV-2 virus).

1) Nucleic acid amplification tests (NAAT), also called molecular tests, detect the virus’s
genetic material;

2) Antigen tests detect parts of specific proteins produced by the virus; and

3) Antibody tests detect COVID-19 antibodies in the blood (serum) that infected people develop
to fight off the virus.

NAAT tests are dependent upon a method used to multiply the relatively few copies of viral
nucleic acid that might be present in a specimen into a very large number of copies — making it
much easier detect the virus. At present, most NAAT tests use an amplification method called
polymerase chain reaction (PCR).
PCR uses small segments of DNA, called primers, to pick out the DNA that it needs to multiply.
The PCR instruments process the sample in repeated cycles of heating and cooling. During each
cycle, the number of copies of the targeted nucleic acid doubles. From a few original copies, it
can generate up to a billion new copies to make the virus easier to see in the final detection step.

The FDA recently authorized a different NAAT test method called loop-mediated isothermal
amplification (LAMP). This test method warms the sample to a constant temperature and uses
six different primers to drive the replication of different segments of the novel coronavirus’s
genome. It does not require multiple cycles of heating and cooling. By many accounts, this
method is faster and easier to use than real-time PCR. Other methods of COVID-19 detection are
under development.  

Different SARS-CoV-2 NAAT testing products target different parts of the virus, use different
primers to start the PCR reaction, apply to different specimens, and differ in the ability to detect
the virus.

The primary methods for collecting a sample are through nasal, throat, and saliva (spit).
Nasopharyngeal (NP) samples are believed to be the most sensitive for detecting the virus, but
pushing the swab through the nostril into the nasopharynx at the base of the skull can be
uncomfortable. The collection of other samples from nasal swabs and saliva can be easier on the
person being tested and are becoming increasingly accessible.

The spread of SARS-CoV-2 is particularly challenging to manage because people can be

contagious and spread the infection to others, even before they begin to show symptoms. NAAT
tests can sometimes detect the virus in early stages before symptoms appear, but not always, and
do not necessarily turn positive immediately with the onset of symptoms.

One strategy with NAAT tests involves the use of pooled samples. Pooled sampling involves
mixing several samples together in a batch, or pooled sample, then analyzing the pooled sample
with a diagnostic test. If the test on the pooled specimen is negative, then all the individuals who
contributed to the pool are considered negative for COVID-19. If the pooled sample is positive,
the lab must run separate tests on each of the samples to determine who is positive and who is
negative. When the prevalence of COVID-19 in a population is low (in the 1-2% range), the total
number of tests needed is reduced, and an organization’s testing capacity increases.

Antigen tests for COVID-19 detect the presence of a protein that is part of the SARS-CoV-2
virus. Today, the NP and mid-nasal samples are the primary sampling methods used for antigen
testing, but the development of antigen tests for saliva are underway.

Antigen tests are relatively inexpensive and provide results almost immediately. These tests
perform best in the early days after an infection begins. While they are not as sensitive as NAAT
tests, some have suggested that repeated testing with a fast, although less sensitive test, may do
more to help end the epidemic more quickly than perfect tests done infrequently.

Antibody SARS-CoV-2 tests detect the antibodies, or the “virus fighting proteins”, that a
person’s immune system produces to fight infection. Antibody testing is generally done on the
serum component of a blood sample. Antibodies may appear just a week or so after symptoms of
SARS-CoV-2 infection appear. Antibody tests are not used to diagnose an active COVID-19
infection; however, they are useful for detecting whether someone has had a past infection.

Two different kinds of antibodies can be measured: IgM (immunoglobulin M) and IgG
(immunoglobulin G). IgM antibodies appear early after infection (usually after the first week or
so). Somewhat later, IgG antibodies, a more durable antibody, is produced. Today, there is no
clear advantage of IGM or IgG antibody testing and not everyone will develop antibodies after a
known COVID-19 infection. Importantly, scientists do not know how well or for how long
antibody levels might protect someone against a future infection.

If you’re trying to
picture antibodies, here’s some help. Imagine these helping to fight off disease.

All three types of tests can be evaluated locally with a point-of-care (POC) machine or sent to
laboratory for processing (in-lab testing). POC tests are carried out in close proximity to a patient
and typically take 5-15 minutes, but only one or a handful of samples can be processed at a time.
Not all POC machines have the capability to communicate electronically to public health and
other reporting systems. In-lab testing machines can process hundreds of samples at time and,
with the right safeguards, can deliver results electronically to patients, providers and public
health reporting systems. However, in-lab testing has built-in delays due to its batch testing
nature and the time it can take to deliver samples to laboratories.

There are many opportunities for innovation in testing methods to improve upon the efficiency,
specificity, and scalability of currently available tests. Having a good set of well performing tests
for SARS-CoV-2 is very important, but we also need to be able to deliver the results of such tests
accurately and quickly (electronically) to the responsible care providers and to public health
authorities.

To facilitate electronic delivery of such content, NLM has long supported the development of
formal health care terminologies including LOINC (Logical Observation Identifiers Names and
Codes), RxNorm, along with SNOMED CT, and more recently, communication structures such
as HL7 FHIR(R). These capabilities are especially important during this time of COVID-19. In the last
six months, the FDA has authorized more than 80 SARS-CoV-2 test products for emergency use,
the CDC has defined a COVID-19 Case Report Form, and the Centers for Medicare & Medicaid
Services has specified content that should accompany every SARS-CoV-2 test. NLM-supported
LOINC codes have been defined for all of this content, as well as SNOMED CT codes for coded
test values. The FDA, CDC, and industry have produced a compendium of the all SARS-CoV-2
tests and their standard codes. The use of standardized test codes for test results is essential to
smooth delivery of test results into electronic health records and for the aggregation of test
results for research and public health purposes.
Testing for COVID-19 is important, safe, and easy. Getting tested early and often and following
best practices, such as wearing a mask, washing hands often, and limiting social contact will help
get us back to normal.

Did you learn something new about testing methods? How else can NLM help support testing
activities?

Clem McDonald, MD, is the Chief Health Data Standards Officer at NLM. In this role, he
coordinates standards efforts across NLM and NIH, including the FHIR interoperability
standard and vocabularies specific to clinical care (LOINC, SNOMED CT, and RxNorm). Dr.
McDonald developed one of the nation’s first electronic medical record systems and the first
community-wide clinical data repository, the Indiana Network for Patient Care. Dr. McDonald
previously served 12 years as Director of the Lister Hill National Center for Biomedical
Communications and as scientific director of its intramural research program.