Several months into the pandemic, a new aspect of COVID-19 started gaining attention from scientists, journalists, and health-care professionals. Instead of feeling better two weeks after contracting the virus, some people were reporting prolonged, life-disrupting symptoms such as “brain fog” and fatigue. Patients needed to fight for skeptical doctors to take them seriously. They started support groups for themselves and pushed the medical establishment to study the illness. News of “long COVID” spread widely, adding to existing fears about the coronavirus. Worse, no one could explain the cause. Two years later, headlines still treat it as an enigma, describing researchers hunting for “clues” to “unravel long COVID’s mysteries.”
Despite the initial disbelief and remaining questions, the phenomenon behind long COVID isn’t entirely new. We’ve always lived with post-infection illnesses and underappreciated their consequences. A recent article in Nature Medicine lists 15 infectious agents—many of which are well-known viruses, bacteria, and parasites—that can cause these “post-acute infection syndromes.” Long COVID is unprecedented in terms of its scale—it has affected many millions of people in the U.S. alone—but we should try to understand and study it in the context of other long illnesses, not as something that emerged out of nowhere with no comparison or antecedents.
One of us—Hank Balfour—has spent decades studying the Epstein-Barr virus (EBV), which can have strikingly similar long-term patterns. EBV, named for two of the researchers who discovered it, is millions of years older than SARS-CoV-2, but its prolonged effects are only just beginning to be well understood. They’re elusive in part because the virus is so common. It infects at least 90 percent of adults, which makes establishing a clear control group and proving that EBV was the cause of a long illness very difficult.
Yet, new research is revealing more and more about the connection between EBV and chronic diseases. New studies suggest that multiple sclerosis is the result of an EBV infection, and we know for sure that EBV is the principal cause of infectious mononucleosis (mono). Most patients recover from mono in a few weeks, but some continue to have mono-like symptoms for years—or get over the initial illness only to suffer recurring bouts of sickness later on. This condition could be called “long mono/EBV” or “chronic mono.” Two prominent symptoms it shares with long COVID are brain fog and fatigue. And just as doctors didn’t believe long-COVID patients at first, chronic mono isn’t a widely accepted diagnosis among health-care professionals. That’s a shame. The similarities between long COVID and long mono/EBV, and the purported interactions between the two viruses during acute COVID or after COVID vaccination, demand further investigation.
Persistent postinfection symptoms are also found in influenza. Long influenza—which most people have never thought about, even though influenza is quite common—and its similarities to long COVID can teach us how both diseases cause brain fog. In the aftermath of the 1918 H1N1 influenza pandemic, scientists noticed that the infection can come with complications, including neurological disorders, that last longer than the acute respiratory illness. There is growing evidence that influenza viruses, much like SARS-CoV-2 and reactivated EBV, can trigger neuroinflammation by infecting white blood cells that then breach the blood-brain barrier and release proinflammatory small proteins called cytokines. Studies suggest that microglia, the brain’s resident immune cells, can also secrete these pro-inflammatory agents following viral assault and thus may be factors in the brain fog experienced as a delayed effect of both influenza and COVID. Animal studies and human-brain postmortems bolster this theory. Investigators recently found that both SARS-CoV-2 and H1N1 activate neuroinflammation through microglia, and they noted the similarity of what they observed to the “chemo fog” that patients experience following cancer chemotherapy.
Mosquito-borne viral infections can also lead to long-term illnesses and conditions, including neuroinflammation, and we’ve been dealing with the consequences for years. Zika and West Nile are “neurotropic” viruses that home in on brain cells, most notably astrocytes and microglia. Zika-activated microglia appear to be responsible for synapse and memory dysfunction and resulting cognitive deficits in mice and primates. The virus’s effect on fetal neurodevelopment can be devastating. During the Zika outbreak in Brazil in 2015, there was a spike in infants born with reduced head size to mothers who were infected with Zika during pregnancy. This suggests a link between the virus and the neurological condition microcephaly. West Nile virus, which can cause viral brain inflammation, joins Zika and EBV in being associated with activated microglia and Guillain-Barré syndrome. In this disorder, the body’s immune system attacks its peripheral nervous system, resulting in symptoms ranging from mild weakness to temporary paralysis.
Examining commonalities among those affected by these types of illnesses can help us understand who is most vulnerable and take more aggressive measures to protect them from long COVID. Sex difference appears to be a major factor. After reviewing long-term effects of viral pathogens including SARS-CoV-1 and 2, EBV, West Nile, and H1N1 influenza, the authors of the previously mentioned Nature Medicine article came to the conclusion that women are more likely to experience post-acute infection syndrome, though they acknowledged the possibility of some sampling bias in the studies they were reviewing.
Symptoms, too, seem to vary between men and women. Brain fog and fatigue are among the symptoms found more frequently in women who experience long COVID than in men who do. Indeed, a large prospective study and a literature review of long COVID show that women are more likely than their male counterparts to experience both physical and psychological symptoms, including autoimmune rheumatic conditions, fatigue, and depression.
Bugs that cause post-acute-infection illnesses cost society dearly, both economically and, more importantly, in personal suffering. Vaccines may blunt their harm, but that’s an empirical solution without a mechanistic explanation. The real scientific advance will be to pinpoint the molecular pathology that they share. Have these viruses found a common weakness in our immune armor? Do differences in individual immune responses to these pathogens influence whether delayed symptoms appear months or perhaps years after the acute infection—or not at all? If studies of long COVID can provide some answers, we will have made something good out of this terrible time.