PCR testing can help clarify confusion over Covid-19 rebound and isolation

President Biden’s recent case of Covid-19, its rebound, and his extended isolation offers an opportunity to consider how more precise interpretation of viral load via PCR testing might be used to safely return people to work or school earlier.

Biden tested positive for SARS-CoV-2, the virus that causes Covid-19, on July 21, after beginning to experience a runny nose, dry cough, and fatigue the night before. He took the antiviral Paxlovid for five days, as prescribed. He felt well, and serial testing indicated that his body had cleared the virus on July 26. He returned to work on July 27, consistent with guidelines set by the Centers for Disease Control and Prevention. Yet on July 30, the president tested positive again, and was “forced to resume strict isolation procedures” despite feeling fine, according to a memo from his physician, Kevin C. O’Connor.

This decision, well within current norms for care, was nonetheless consequential: The president was forced to cancel a trip to advocate for legislation in support of the domestic semiconductor industry, despite feeling fine. It wasn’t until Aug. 7 that he returned to “public engagement and presidential travel.”

The re-emergence of the SARS-CoV-2 virus after treatment — also known as Paxlovid rebound — is increasingly recognized by clinicians. It may happen when a reservoir of virus is suppressed by antiviral therapy but not eradicated by it. This rebound suggests that new strategies, such as increasing treatment time from 5 to 10 days, should be evaluated, since the virus can apparently linger in individuals who have no symptoms, with or without treatment.

This raises a key question: Do such individuals harbor enough virus to be contagious to others?

Current recommendations for returning to school or work (which the Washington Post and others have called confusing) rely on empiric observations: symptoms and the timing and results of Covid tests, usually the rapid antigen tests such as the at-home tests provided by the federal government. The imprecision of such guidance leaves uncertainty for both individuals and public health officials grasping for more actionable data.

This is where “gold standard” testing — PCR-based tests — have added value. PCR tests measure SARS-CoV-2 in a different way than antigen tests. They are highly precise, allowing them not only to detect infection before symptoms start, when rapid antigen tests are often negative, but also give quantitative results throughout the course of infection. The drawback is that samples collected for PCR testing need to be sent to a lab for analysis, so they don’t provide an instant readout of infectivity.

Modeling suggests that this ability of PCR tests to quantitate viral loads can be translated into the risk of transmitting SARS-CoV-2 to others. Serial positive PCR results, either in the course of an infection or following Paxlovid rebound, offer the possibility of interpreting — objectively and quantitatively — how practically significant the positive results are. If viral load is high, individuals should continue to take precautions for themselves and to prevent infecting others; if low, they can be confident they do not carry enough virus to be infectious to others, and can return to work (but with mask wearing until virus is fully cleared or 10 days have passed).

The quantitative details of Biden’s PCR tests haven’t been made public. But the information could have been used by his physicians to determine if he had a greater or lesser need to isolate, stringently wear high-grade masks (for example KN95) when around others or, particularly with no symptoms, suggest little to no further risk to his health or that of those around him.

While translating viral test data into clinical decision-making needs greater attention, a variety studies have begun to consider transmissibility and viral load. This was perhaps most clearly analyzed by Ruian Ke and colleagues, who examined viral transmission among serially tested NBA players and nine individuals in the first cluster of Covid-19 infections in Germany (both pre-Omicron). Their modeling indicated that transmission is high early after infection, when viral loads are at or below the limit of what rapid antigen tests can reliably detect, but that transmission risk can persist, typically up to 10 days, rarely longer. It is plausible that transmission risk, particularly early after exposure, is even greater with current variants.

Such studies have not, however, translated into Covid management recommendations, in part because they yield a range of risk probabilities, which is useful for health care policymakers but less so for infected individuals and their clinicians. Nonetheless, the current emphasis on rapid tests that do not yield quantitative information can be supplemented (or improved) by the use of quantitative PCR testing.

The Covid-19 clinical testing laboratory at the Rockefeller University, where I work, has implemented an easy-to-use, sensitive, inexpensive serial PCR saliva testing program that has helped keep the university’s pre-K program children, staff, and families safe and the program open during the pandemic.

Individuals who test positive for SARS-CoV-2 by PCR or rapid antigen test and are asymptomatic can be tested again and, if a repeat PCR test is negative, return to school or work as early as three to five days. Those who experience Paxlovid rebound or persistent positive PCR or rapid antigen tests can be triaged according to their symptoms and viral load. Individuals who feel well but are PCR positive with a low viral load that is unlikely to make them a transmission risk (Rockefeller’s current guidance defines that as a viral load under about 1,000 copies of the virus per milliliter of saliva) can return to school or work but must wear a KN95 mask until testing shows the virus has been cleared or 10 days have passed.

Rockefeller and other clinical laboratories in New York City, such as the Pandemic Response Lab, are pushing to turn around PCR test results in under 24 hours — 99% of Rockefeller’s test results are returned the same day of submission — making them even more clinically actionable.

Making decisions on return to work is a clinical one that can now be supplemented by hard numeric data. If widely implemented, attention to viral load — hence risk of transmission — could inform management for everyone.

Robert B. Darnell is a senior attending physician and professor of molecular neuro-oncology at The Rockefeller University, an investigator with the Howard Hughes Medical Institute, a senior visiting fellow at MITRE, and the founding director and CEO emeritus of the New York Genome Center.