Testing Could Help End the Pandemic, if Only We Had Tests

In the heady days following December 2020, when efficacy data showed that the mRNA vaccines reduced the risk for infection by SARS-CoV-2 by more than 10-fold, public health experts spoke with a unified voice: Vaccination was the path to ending the coronavirus pandemic. In a world where vaccines nearly eliminate the risk of infection, the messaging made sense. It may even have been correct — had we been able to vaccinate enough people, both at home and abroad, in a short enough time frame. But for reasons ranging from the logistical to the political, we were not able to meet that challenge. To date, 62% of Americans are fully vaccinated against the virus, according to The New York Times, well short of the 90% or more that experts estimate we'll need to achieve herd immunity.

Meanwhile, case rates are soaring, thanks largely to the advent of the Omicron variant and its ability to evade antibodies. Although infection with Omicron appears to be milder than that with Delta or the original strain of SARS-CoV-2, its lethality (for the unvaccinated) is still dramatically higher than for other respiratory infections. The weekly average of COVID-19 deaths has surged to nearly 1700, roughly nine times the figure from 6 months ago.

The Biden administration seems to have acknowledged that its efforts to push vaccines as a solution to the pandemic have not succeeded. Instead, the White House recently announced a plan to deliver 500 million rapid tests for free to US households, and it has worked out a deal to require insurers to cover home kits. Those moves suggest an acceptance of the fact that COVID-19 is here to stay.

To be clear, vaccinations continue to play a critical role in public health by preventing our hospitals being overrun by severely ill patients with COVID. But with vaccination rates only inching higher, testing clearly has become the new focus for public health experts. Will it work? Can we test our way out of this pandemic?

Why Test?

COVID-associated interventions can be interpreted in the light of their benefit to the individual and society. At the individual level, COVID testing entails both risks and benefits. The primary individual benefit of testing is to obtain proof of COVID such that, if necessary, appropriate therapeutics such as nirmatrelvir/ritonavir can be administered. Of course, having proof of a negative COVID test is useful too, as a prerequisite for international travel, for instance. But we must acknowledge that for otherwise healthy, adequately immunized people, testing has some risk at the individual level — namely, being forced into isolation for a period of time (although that period has been changing rapidly of late, to the chagrin of many experts).

The chief benefits of COVID testing, therefore, do not accrue to the individual being tested, but rather to those around them — their noninfected contacts and the public at large. By isolating positive cases, we reduce the total amount of virus circulating in public, which should reduce the spread of disease.

Of course, the benefits of testing depend on the reliability of the tests themselves, the timing and indications for testing, and, critically, their availability. In the face of the Omicron variant, data surrounding the diagnostic performance of COVID tests are rapidly evolving. This is the state of play.

Nucleic-Acid Amplification Tests

From the beginning of the pandemic, nucleic acid amplification (NAAT) — sometimes called polymerase chain reaction, PCR, or molecular tests — have been the gold standard for diagnosing a COVID-19 infection. NAAT tests work by identifying and amplifying a specific nucleic acid sequence. Amplification is the key to their high level of sensitivity. In iterative cycles, nucleic acid sequences that correspond to SARS-CoV-2 are doubled, and doubled, and doubled again, increasing the signal-to-noise ratio which will allow for the detection of the virus. While not reported by clinical labs, research labs frequently use the "cycle threshold" as a proxy for viral load, with lower cycle thresholds implying higher viral loads, because less amplification was necessary to detect the virus.

NAATs have high sensitivity and specificity, estimated at 90% and 99%, respectively. In fact, they may even be overly sensitive, identifying individuals as infected who are no longer infectious. NAATs may continue to be positive for SARS-CoV-2 months after the initial infection, which has led the CDC to recommend against repeating these tests after the initial test is positive.

NAATs are further compromised by their turnaround time, which can range from as short as 2 hours to as long as a week if testing volume outstrips lab bandwidth. This lag severely limits the public health benefit of these tests. While the CDC recommends that those with symptoms consistent with COVID isolate while waiting for their NAAT result, the ability to enforce this recommendation is nonexistent. As a result, before they have a test result in hand, many people may be willing to rationalize their symptoms as something other than COVID and thus continue public activities.

The emergence of the Omicron variant has had little impact on the sensitivity or specificity of NAATs. It is notable, though, that one target sequence (the S-gene sequence) is mutated enough in Omicron to lead to S-gene target failure (SGTF) of the NAATs. This failure does not lead to a negative test, as NAATs typically target several sequences. Rather, SGTF has become a useful early indicator of a likely Omicron infection, as Delta infections do not manifest SGTF on NAATs.

Clinically, then, NAATs are best used as an initial test to identify a new COVID infection in someone without documentation of prior disease and are of little use in documenting resolution of infection.

Antigen-Based Tests

Once the RNA from SARS-CoV-2 enters a host cell, it hijacks cell components to synthesize the proteins necessary to create new SARS-CoV-2 virions. Those proteins can be directly detected by antigen tests, which are superior to PCR tests in terms of speed and convenience, though inferior in terms of sensitivity. Antigen tests can be used in clinical settings, but really shine in the home setting because they are simple enough that untrained individuals can run them.

Most COVID antigen tests use the lateral flow technique. Briefly, a testing strip is impregnated with an antibody attached to a detector compound. In most cases, these antibodies are directed against the nucleocapsid (N) protein of SARS-CoV-2. Notably, there are multiple mutations in the N protein of the Omicron variant. The sample is applied, usually in a buffer, to one end of the test strip, and antigen, if present, is dragged by solvent flow through the detector antibodies. If the antibody binds antigen, a display compound will change color, indicating a positive test. A control compound will change color regardless to indicate that the test was completed successfully.

Antigen tests are susceptible to both false-negative and false-positive results, although the former are much more common. False-negative results can occur due to inadequate ascertainment of the sample, misuse of the test, or situations where the viral load is not high. New data suggest that antigen tests may be negative in the early days of an Omicron infection, which may limit their usefulness as a public health measure. Many antigen tests are, in fact, indicated to be used sequentially (24 or 48 hours apart) to increase sensitivity. Still, the reduced sensitivity of antigen tests in the face of low viral loads may prove to be useful in assessing infectiousness. For this reason, many experts have argued that a negative antigen test be a pre-requisite for ending isolation of positive COVID cases. That the CDC has not adopted this policy may speak more to the difficulty of equitably obtaining antigen tests than the validity of this clinical approach.

False-positive results from antigen tests are quite rare. A recent study of 903,408 antigen tests given as part of a repeated workplace screening program found that 278 (0.05%) led to a false-positive result. The majority of these false positives were traced to a single batch of antigen tests, suggesting that manufacturer error, rather than user error, was to blame. The positive predictive value of an antigen test, like all diagnostic tests, is dependent on the prevalence of disease in the community. Under current conditions, it is safe to assume that a positive antigen test indicates active COVID infection.

When to Test

CDC guidance regarding testing is complicated. The following flowchart summarizes the recommendations, which differ on the basis of likelihood of COVID exposure, the presence of symptoms, the adequacy of vaccination, and the likelihood of exposing vulnerable populations.

Figure. COVID Testing Flowchart

The utility of screening tests in asymptomatic people remains a source of substantial debate. Again, the individual benefit to those so screened is limited, as by definition they are not sick enough to warrant antiviral therapy. The benefit to the public health may be significant, however, if newly infected individuals could be isolated to limit further spread.

Given the concerns in regard to antigen testing in the Omicron era, NAATs would be the natural choice for an asymptomatic screening program but would only be effective if results could be returned quickly. While some private businesses and universities have the capacity to engage in screening and surveillance for COVID, the nation as a whole lacks the infrastructure to accommodate such a testing program. Whether it could have been created in the early days of the pandemic is a moot point. Whether such a system should be erected to address future pandemics is worthy of serious consideration.

The Real Testing Challenge

Testing is successful only when tests are available. Shortages of both NAATs and antigen tests have led people to turn to unorthodox methods — like using the emergency room — to secure needed testing. While those who are seriously ill from COVID will be identified when hospitalized, the much larger population of individuals with mild infection will be missed if they are unable to secure a test easily and cheaply. And it is those with mild or asymptomatic infection who, if undiagnosed, will continue to circulate in society and increase the spread of the disease. Data suggesting that testing is least accessible to those in disadvantaged socioeconomic circumstances implies that the lack of adequate testing infrastructure may exacerbate existing healthcare disparities.

The early recognition of vaccination as the number-one public health goal of the coronavirus pandemic led to what has been a real public health success: the rapid development of effective vaccines, made ubiquitously and cheaply available. That testing has been relegated to the back burner for so long may be our number-one public health failure.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com.

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