“Unlocking” COVID-19: the use and misuse of tests

By the end of March, Spanish authorities found that the first quick antigen tests for COVID-19 they had bought did not exactly work : when exposed to an infected sample, they failed to detect it most of the times. In mid-April, the UK passed through the same ordeal: tests worth millions of euros resulted to be far less sensitive than expected.

David Heymann, Professor of infectious disease epidemiology at the London School of Hygiene & Tropical Medicine, head of the WHO response during the SARS1 epidemic: “Countries need a system able to identify both people infected in the past […] and those acutely ill.” – Read David Heymann’s full interview

The minefield of testing

Over 500 brands of tests have flooded the market, according to FIND (the Foundation for Innovative New Discoveries, a Swiss-based non-profit that is checking the performance of tens of COVID-19 tests), and not all of them are of good quality.

In the first place, not all COVID-19 tests are born equal. The gold standard is the famous Polymerase Chain Reaction (PCR) test, that diagnoses an active infection by detecting the RNA (Ribonucleic Acid) of the virus in nasopharyngeal swabs. This is a highly reliable test, but it requires the processing of the sample in a laboratory, and takes several hours to yield results.

Cassandra Kelly, director of Emerging Threats at FIND: “PCR is the optimal test for active infections, the most sensitive and specific. The challenge is that it requires a laboratory infrastructure and time. In the case of a new outbreak, this testing strategy would face a new bottleneck.” – Read Cassandra Kelly’s full interview

An alternative to PCR testing is antigen tests: these diagnose an active infection usually by detecting pieces of the virus in nasopharyngeal swabs. A third approach is provided by antibody (or serologic) tests: these diagnose a past infection, by detecting in a blood sample the antibodies generated by the organism in response to infection.
Antigen tests and antibody tests often come in the format of rapid diagnostic tests (RDTs), that yield fast results, without processing the sample in a laboratory, as required by the PCR tests. Some RDTs look like pregnancy tests: a blood sample is placed on a strip that yields a visual outcome.
At the moment, all RDTs – both for antigens and for antibodies – share an unideal feature: their sensitivity is less than satisfactory, and sometimes very low. This means that they yield many false negatives. In other words, a patient may receive a negative response to the test, while actually having an active infection or having been previously infected.
To avoid that, one could send all patients with a negative result to have a PCR test. “But in a low-prevalence scenario, like the one we are in, [i.e. one in which the actual number of cases is low in many European countries] you would have an enormous number of negatives, and you would need to funnel all of them to PCR”, Kelly points out.
The specificity of these tests (i.e. the proportion of healthy people who are correctly identified as not having the condition), on the other hand, can be fairly good, according to preliminary analyses. However, the specificity is challenged in a low-prevalence situation. “We want to make sure that a positive is actually a positive. Otherwise, we could burden the healthcare system by treating false positives”, says Kelly.

The use and interpretation of tests

There is a set of common misunderstandings on the use of tests, according to Kelly and Heymann.
• First, antibody tests are sometimes misused to track active infections, instead of past ones. In fact, these tests work in a specific time-window after the infection (between 8 and 25 days at most). Before and after that, their sensitivity drops dramatically.
• Second, a positive antibody test is sometimes interpreted as a sign of having developed immunity to the virus. “But nobody understands whether those antibodies provide protection and for how long”, Heymann points out.
• Third, quick tests are used as a diagnosis of infection. A negative result leads sometimes to the misbelief that certain symptoms come from a disease other than COVID-19, like an allergy. “That misuse is extremely impactful for sustaining active transmission of the virus. It’s critical that it does not happen”, says Kelly.

According to Heymann, PCR testing should be the main tool for detecting infected patients and tracing the infection in their contacts. Antibody tests, on the other hand, should have an exclusively epidemiologic purpose: drawing a map of where the infection have been stronger in the past and getting an idea of the level of potential immunity in the population.
Kelly warns that using quick tests makes sense only if they are coupled with a strong PCR and ELISA (Enzyme-linked Immunosorbent Assay) infrastructure, to compensate for the limitation of the tests.

Test technology is evolving quickly and testing strategies may greatly improve if a breakthrough appears. For example, a research group supported by the EU-funded HG nCoV19 test project has recently announced successful results of a rapid diagnostic test of active infection.
However, while findings like these don’t hit the street, both Kelly and Heymann agree that hygiene, social distancing and isolating active cases still remain essential elements to keep the pandemic at bay.

Useful link
• Coronavirus testing: information on test devices and methods in a single place