CDC director’s COVID returns as study finds such rebounds shockingly common

A woman adjusts her face mask while sitting in front of a microphone.
Enlarge / Rochelle Walensky, director of the US Centers for Disease Control and Prevention (CDC), adjusts her protective mask during a Senate Health, Education, Labor, and Pensions Committee hearing in Washington, DC.

Rochelle Walensky, director of the Centers for Disease Control and Prevention, has experienced a COVID-19 rebound—a return of mild symptoms and positive tests after completing a course of the antiviral drug Paxlovid and testing negative—the CDC announced today.

Walensky first tested positive on October 21 and experienced mild symptoms. She completed a five-day course of Paxlovid, recovered, and tested negative. But on Sunday, October 30, her mild symptoms returned, and she once again tested positive, the agency reported.

Walensky now joins the ever-growing ranks of people reporting rebounds after Paxlovid, including high-profile rebounders such as President Biden and top infectious disease expert Anthony Fauci. But, according to a small study published in JAMA Network Open last week, rebounds may be surprisingly common in all COVID-19 cases—even those not treated with Paxlovid.

The study looked more closely at daily symptom data from 158 untreated people with COVID-19, who acted as a placebo group in a drug trial. They were followed for 28 days after their COVID-19 cases began. In that time frame, 108 of the 158 people—68 percent—reported a recovery in which their symptoms fully resolved for at least two days. But, of those 108 people, 48 people—44 percent—reported a return of symptoms before the end of the 28-day follow-up period.

Common recurrence

The rebounds were generally mild. Of the 48 rebounders, 41 only reported mild symptoms during their rebound, seven reported moderate symptoms, and none reported severe outcomes. The most common rebound symptoms were cough, fatigue, and headache.

Overall, the authors—led by researchers at the University of California San Diego—concluded that “the natural history of untreated COVID-19 was variable and undulating,” which “may explain some of the rebound of symptoms after treatment for COVID-19, like in cases of what has been described as Paxlovid rebound.”

The study had limitations, as all do. It didn’t confirm rebounds with rapid test results. It also occurred while alpha was the dominant SARS-CoV-2 variant, so it’s unclear if rebound rates are the same now as omicron subvariants dominate and people generally have higher levels of immunity from vaccination and previous infections.

But, it adds more data to a puzzling phenomenon. Scientists still aren’t clear why rebounds occur, who is at risk, or how common it is. Some have speculated that it could be due to rebounding viral replication or faltering immune responses. Some preliminary data from the National Institutes of Health, however, suggested that rebounds may be due to immune responses flaring as the body clears debris from a quashed infection.

In clinical trials for Paxlovid, Pfizer researchers noted that about 1 percent to 2 percent of both treated and placebo groups had rebounds, suggesting it’s equally likely to occur with or without treatment. But, as the use of Paxlovid has become more common, anecdotal reports of rebounds after a course of the treatment piled up, making it seem like the percentage of affected people is much higher than just 1 or 2 percent. The new study supports that anecdotal conclusion—but not just for those taking the antiviral.


Biden tests negative for COVID twice, leaves isolation

US President Joe Biden waves from his isolation following a virtual meeting on July 26, 2022.
Enlarge / US President Joe Biden waves from his isolation following a virtual meeting on July 26, 2022.

President Joe Biden has now tested negative for SARS-CoV-2 on two separate rapid antigen tests, and he is ending his “strict isolation measures.”

The president tested negative Tuesday evening and then again on Wednesday morning, the president’s physician, Kevin O’Connor, wrote in his daily update letter of the president’s SARS-CoV-2 infection.

Biden, 79, first tested positive Thursday morning while experiencing mild symptoms of a runny nose, fatigue, and a dry cough.

After the diagnosis, he immediately went into isolation and began a five-day course of the antiviral Paxlovid. He completed that course 36 hours ago, O’Connor wrote. The president is fever-free, and the rest of his symptoms are improving and are “almost completely resolved.”

Biden will now leave his isolation but will wear a well-fitting mask for 10 days. The decision to end isolation exceeds the standards set by the Centers for Disease Control and Prevention, which does not require negative tests to end isolation. The agency advises that people can end their isolation after five days, without a test, as long as they are fever-free and their symptoms are improving, but they should mask until 10 days after testing positive.

O’Connor ended the letter by noting the possibility that Biden could experience a COVID “rebound” following his course of Paxlovid. It’s unclear why, but some people with COVID-19 experience a resurgence of symptoms and again test positive after an initial but brief recovery. This phenomenon has been particularly reported in patients who take Paxlovid, but the percentage of people who experience a rebound remains unknown.

“The President will increase his testing cadence, both to protect people around him and to assure early detection of any return of viral replication,” O’Connor wrote.


COVID rebounds: Immune responses may be reignited by cleanup of viral scraps

A box of Paxlovid, the Pfizer antiviral drug.
Enlarge / A box of Paxlovid, the Pfizer antiviral drug.

Pfizer’s antiviral pill Paxlovid is among the most treasured tools for hammering COVID-19; it can knock back the relative risk of hospitalization and death by 89 percent in unvaccinated patients at high risk of severe disease. But, as use of the convenient drug has grown in the US, so have troubling reports of rebound cases—people who took the pill early in their infection, began feeling better, and even tested negative but then slid back into symptoms and tested positive again days later.

It’s still unclear just how common the phenomenon is, but it certainly happens in some proportion of Paxlovid-treated patients. In May, the Centers for Disease Control and Prevention even issued a health alert over the rebound reports.

But, amid the rising awareness, it has also become clear that patients who have not been treated with Paxlovid can also rebound. In fact, in Pfizer’s clinical trials of Paxlovid, researchers noted that about 1 percent to 2 percent of both treatment and placebo groups had rebounds.

Together, this has raised a slew of questions: Are the rebounds reignited infections? Are people still infectious? Do they need to resume isolation? Are they again at risk of severe disease? Did their immune systems fail to mount an effective response? Is the virus mutating to become resistant to Paxlovid? Is omicron causing more rebounds than previous variants?

So far, there’s limited data and mostly only anecdotal reports. But a new, small pre-print study led by researchers at the National Institutes of Health offers some encouraging news about COVID rebounds. The study, which included data on seven rebounding patients—six of whom were treated with Paxlovid and one who was not—found no evidence of Paxlovid-resistant mutations, viral replication gone wild, or faltering immune responses.

Intact immune responses

Instead, a detailed look at their immune responses found that rebounds were associated with a surge in antibody and cellular immune responses specific against SARS-CoV-2. At the same time, rebounds were accompanied by downward trends in markers of innate (non-specific) immune responses, as well as levels of SARS-CoV-2 nucleocapsid bits in the blood.

Together, the findings suggest that the rebounds could be partly due to reignited immune response as the body works to clear cellular debris and viral scraps from a quickly smothered infection. Or, as the authors put it: “rebound symptoms may in fact be partially driven by the emerging immune response against residual viral antigens possibly shed from dying infected cells due to cytotoxicity and tissue repair throughout the respiratory tract.”

In further support of this, the authors—co-led by infectious disease experts Brian Epling and Joe Rocco—note that while three of four controls had a recoverable, live virus during their acute infection, only one of the seven rebounding patients had a live virus at the time of their rebound. And that one patient also had underlying immune suppression, which may explain the finding. Further, none of the rebounding patients developed severe disease.

The study is, again, very small and may not be generalizable to all rebound cases. The authors call for rebound studies with larger cohorts. But some elements of the findings are already backed up. For instance, other studies have also failed to identify Paxlovid-resistant mutations. And on Tuesday, the CDC published a study of more than 5,000 Paxlovid-treated patients, finding that less than 1 percent of patients had emergency visits or hospitalizations in the 5-to-15 rebound period after treatment.

For now, the NIH researchers find their new findings “encouraging.” As Epling wrote in a tweet on Tuesday, ” the findings suggest that “an appropriate immune response is developing, so rebound isn’t caused by people not developing an immune response to COVID while on Paxlovid.”