COVID just got a lot more complicated.
With cases rising in the U.S. and globally yet again, fueled by subvariants known to evade immunity, questions abound.
How long does immunity last?
How many times will I get COVID?
Do I have long COVID-and if not, what are the chances I'll get it eventually?
It's hard to say who's at risk for a condition that's yet to be well defined, experts tell Fortune. But just as researchers and practitioners have their theories about long COVID's root causes, they have educated guesses about who might be most at risk.
An enigmatic condition
Long COVID is, quite possibly, the great enigma of our time.
It's "a very big umbrella term," Dr. Alba Miranda Azola, co-director of the Post-Acute COVID-19 Team Program at Johns Hopkins University School of Medicine, tells Fortune.
"It's patient defined, patient created," she says of the condition federal officials say could affect up to 23 million Americans. "Thus, the patients define themselves as having long COVID, and the term is very inclusive."
As research into the nascent condition expands, it seems that almost anything and everything could be a symptom-from ear numbness, a sensation of "brain on fire," and erectile dysfunction to irregular menstrual periods, constipation, and peeling skin, according to a landmark study published last summer in British medical journal The Lancet.
Recently scientists have attempted to categorize long COVID patients into subgroups, hypothesizing that the disease isn't one thing, but many.Dr. Alexandra Brugler Yonts-an infectious disease specialist at Children's National Hospital in Washington, D.C., and the head of its new Pediatric Post-COVID Program-tells Fortune she divides long COVID into five categories, grouped by causes: long-term direct effects of the virus, inflammation, dysautonomia (a disorder of the autonomic nervous system that can cause symptoms like abnormal heart rate), ongoing viral activity, and altered immune response.
Dr. Petter Brodin-a COVID researcher, professor of pediatric immunology, and pediatrician at the Imperial College of London-tells Fortune he divides long COVID patients into three categories that may overlap: autoimmune disease triggered by COVID, metabolic disease triggered by COVID, and long-term persistence of the virus.
"In my head I have, like, a Venn diagram of overlapping clinical presentations," Azola says, illustrating just how vexing it is for even the brightest medical minds to wrap their head around the new disorder.
"I wish I knew the full answer" as to exactly what long COVID is, Brodin says.
But one thing is certain: "Long COVID is not one thing."
Six at-risk groups, maybe more
Clear as mud, right? It's easy to understand why even the experts aren't sure who might be more likely to develop long COVID.
There are, however, some well-informed theories about who's most at risk:
1) Those who've had repeat COVID infections, regardless of severity.
If you've survived COVID unscathed, the odds aren't necessarily in your favor next time around. A preprint of a study published earlier this month on ResearchSquare found that risk of long COVID, hospitalization, and death increased with each COVID reinfection, Azola says.
2) Those who had a high viral load during their COVID infection.
A recent study found that those who had higher viral loads during their acute COVID infection-regardless of severity of symptoms-were more likely to develop long COVID. Treatments like COVID antiviral Paxlovid may eventually reduce long COVID in this at-risk population by squashing their viral loads, Azola says.
3) Those who harbor dormant Epstein-Barr Virus.
Epstein-Barr Virus (EBV) is one of the most common human viruses. Many are infected during childhood and don't know it, according to the U.S. Centers for Disease Control and Prevention. The virus can cause mononucleosis and, according to some researchers, Chronic Fatigue Syndrome-which, similar to long COVID, includes symptoms like fatigue, concentration problems, and headaches. The aforementioned study found that some long COVID patients were more likely to have levels of reactivated EBV circulating.
4) Those who have autoimmune antibodies circulating.
The aforementioned study also found that those with auto-antibodies circulating were at higher risk. Only 6% of long COVID patients with auto-antibodies had been diagnosed with an autoimmune condition before COVID, researchers wrote. "They seem to have an increased number of antibodies in their blood, but we don't know why or how," Azola says.
5) Those who had neurological symptoms during their COVID infection.
Dr. Panagis Galiatsatos-an assistant professor at Johns Hopkins' Division of Pulmonary & Critical Care Medicine who treats long-COVID patients-hypothesizes that a subset of "long haulers" who experience fatigue and shortness of breath have brains that misinterpret subclinical inflammation or remaining virus. Their neurons, damaged by COVID, signal for the body to produce sensations that encourage them to seek more sleep and oxygen. In his clinical experience, long COVID patients who fit into this bucket often experienced neurological symptoms-like loss of taste or smell and bad headaches-during their acute COVID infection.
6) Those who haven't been vaccinated.
There is conflicting data about how much vaccination reduces one's risk of long COVID. "Some studies say a lot, some say 10%, but the overarching message is that vaccines decrease the risk of long COVID," Azola says.
Unfortunately, most long COVID risk factors are out of our control and, perhaps, even our ability to know if they apply to us. The things in our control, Azola says: vaccination, masking, and social distancing.
Individuals should weigh their risks not only of coming down with severe COVID, but of developing long COVID, Azola says-especially as new variants continue to evolve and cause reinfection.
Long COVID "can happen to anyone, independent of severe disease," she says. "It can be disabling. The thought of 'COVID is over,' or that we need to put our masks away, is a completely unfair assessment. We still need to be diligent."
This story was originally featured on Fortune.com