William Miller, MD
With President Biden experiencing a return of COVID symptoms, there has been a flurry of news reports on “COVID rebound”. Let’s look at what this is and why it happens.
First, it might be helpful to remember that continuing to have positive test results for COVID following an infection is common and is not what we are calling COVID rebound. The PCR test (the one we use in hospitals) is expected to continue to detect viral DNA fragments in a person’s nose for up to 90 days after an infection has cleared. This does not mean that the person still has COVID or that they are infectious. Similarly, the antigen tests (the ones you can do yourself at home) can also continue to be intermittently positive for several weeks. To add to the confusion, a person testing negative after clearing COVID can intermittently test positive without this representing a reactivation.
The reason is that these tests are all able to detect both intact virus and fragments of disintegrating virus. In the first 5 to 7 days infection our immune system successfully gets rid of our cells that have been converted by the virus into viral replication factories. Yet, there are still millions of copies of the virus in our nose and throat that still need to be attacked and destroyed by our immune system. Thus, it is not surprising that there will be fragments of virus still hanging around for a long time that may be detected. We believe that the number of active viruses usually drops low enough by day 14 of the infection, or day 10 after onset of symptoms, that the person is no longer contagious.
The fact that some of the lingering, active virus can reinfect new host cells after the main illness has passed is occasionally seen in all upper respiratory viral illnesses, not just COVID. It is uncommon, perhaps occurring about 1% of the time. An analogy might be a house fire that is “put out” by the fire department, but then flares up again a few hours or days later because of some smoldering embers that were missed. These reactivations of the infection are usually brief and the person may not even experience much in the way of symptoms since their immune system is already fully activated and will quickly move to quell the reactivation.
Rebound COVID is a term that I think should be reserved for specific situations where a person received an antiviral treatment, such as Paxlovid or molnupiravir, got better and then got sick again. The important distinction here is that the symptoms came back after the drug was stopped. This can happen with other viral illnesses treated with an antiviral drug. For example, people can get rebound influenza after completing a course of Tamiflu.
The reason this happens is that all these drugs are working by turning off viral replication inside host cells. This gives the immune system time to get ahead of the infection. Hopefully, during that time, the immune system will detect and destroy any transformed host cells so that the infection does not come back. However, some infected cells might go undetected, probably because they had only just become infected. Virus production will start up again in these cells once the drug is stopped.
So, what does a case of COVID rebound look like? Here is a typical example. Joe has an exposure to COVID when his grandson comes to visit. The grandson turns out to be infected when the child later develops symptoms and tests positive a few days after visiting grandpa. Joe starts feeling ill 4 days after the visit (the incubation period). Since he has learned that the grandson is positive, he suspects he is now infected and does a home test that is positive. He calls his doctor, who orders a medical PCR test, that is also positive. The doctor informs Joe that he must isolate for 10 days from onset of symptoms. The doctor then calls in a prescription for Paxlovid and Joe starts the treatment later that day. This is day 5 of the infection and day 1 from the onset of symptoms. Joe notices that he feels better the very next day and he completes the full five days of the treatment. During this time, he feels well. About 3 days after completing the treatment, he starts feeling tired again and the next day has a low grade fever and his cough returns. This is now about day 12 of the infection and day 9 from onset of the original symptoms. Joe calls his doctor who tells him that he most likely has rebound COVID, that repeat testing is not necessary since he is expected to still be positive regardless, and that he needs to continue his isolation now for an additional 10 days. For the next five days or so, Joe feels like he has a bad cold, mostly he just feels tired. Then gradually, these symptoms resolve and in a few weeks he feels back to his old self.
The Paxlovid worked. It helped prevent Joe from becoming seriously ill, which is what it is intended to do. It did this by suppressing the viral replication long enough for Joe’s immune system to become fully engaged in battle against the virus. Once the medication was stopped, the virus replication started again and the immune system went on the counterattack. Joe felt the symptoms caused by the immune reaction (fever, cough, fatigue, achiness), but he never got seriously sick. Note that this scenario is the same regardless of the person’s vaccination status.
According to the CDC, return of COVID symptoms following completion of Paxlovid appears to occur between about 3% and 5% of the time, or about 1 in 20 treatments. The symptoms are generally relatively mild and do not last as long. Less than 1% of those who had rebound require hospitalization. The important take away, though, is that a person is still potentially contagious for another 10 days after the symptoms recur.