WHAT IS LONG COVID?

As the COVID-19 pandemic wears on, more and more attention is being given to long COVID: a set of symptoms people experience after their initial infection. Since it is so new, we are still learning about it, and putting it into context with other sets of symptoms that accompany other infections. Because long COVID is not our first run-in with post-infection syndromes. Which means it can be helpful to look at them as a whole. The more we understand post-infection syndromes, the more we can help people with both long COVID and everybody else.

So let us take a deep dive into what we know. Starting at the beginning, with how we are defining long COVID so far. Even the name is kind of up for debate right now. Those with long COVID started out dubbing themselves “long haulers”, with the research community still settling on a formal term that’s accurate but doesn’t overlap with other acronyms and stuff like that. But whatever you call it, everyone seems to agree that the condition is a host of symptoms that persist or develop after an initial COVID-19 infection has resolved. We will stick with “long COVID” for today.

~ Similar to the name “long COVID,” different health agencies also have slightly different definitions. Health agencies in the US and UK both describe long COVID as symptoms persisting four or more weeks after initial infection. The World Health Organization says that long COVID health problems arise three months after initial infection, and last at least two months, but it’s not too surprising for definitions to vary. The list of symptoms is sprawling, and isn’t fully defined yet either. From person to person, the experience of long COVID can vary massively. And it’s not just a case of COVID19 symptoms that hang around longer than expected.

People with long COVID can experience more generalized symptoms - like fatigue and headaches, respiratory issues, cardiac issues, neurological, gastrointestinal, dermatological, and cognitive symptoms, as well as more severe symptoms like organ damage. And the list keeps expanding as we learn more. All of these symptoms, even the ones that may seem mild, have potential to significantly affect the day to day lives of those with long COVID. For example, fatigue can cause people to have to rethink the entire way they live in order to accommodate new, lower levels of stamina. Searching for less demanding careers, having to sleep more often, even giving up hobbies they love.

Estimates vary, but around 60% of people with long COVID may have to contend with this symptom alone. For those experiencing cognitive symptoms, like brain fog, even completing everyday tasks can be super difficult and overwhelming. This was shown in the results from a 2021 preprint study, not yet published or peer reviewed, from Oxford University on the lived experience of brain fog in long COVID. Participants reported struggling with everything from coping with sensory overload at the grocery store, to navigating the healthcare system to get help in the first place.

And that’s all without mentioning those who require specialized therapy and rehabilitation following COVID. Because of this broad impact on day-to-day functioning, long COVID is now recognized as a disability in several countries. The thing is, long COVID doesn’t just occur in those who experienced the most severe COVID infections. One study in particular by academics at the University of Augsburg found that one year after a mild COVID infection, around one in four were experiencing long-term symptoms.

And even though it’s been more than two years since the start of the pandemic at this point, we still don’t know exactly how long long COVID lasts. The same study found that over half of those who experienced long COVID symptoms saw them resolve over the course of a year. Of course, this is still a new condition, and we are still learning how it works. So we can’t necessarily predict whether those numbers will hold. But it seems likely that there will be a whole lot of people with a new and often disabling condition. Long COVID is a frightening prospect when we’re facing an already frightening disease. But it isn’t the first post-infection syndrome we know of.

And looking at the others can give us some context for understanding long COVID. Viruses like Epstein-Barr Virus or EBV, the virus that causes mono, can integrate their genomes permanently into infected cells. From there they can make more virus, or just… hang out. And while EBV and other viruses can do this and have few or even no long-term effects, in a minority of people, EBV seems to trigger much more severe illness down the road. Infection is associated with a number of long term conditions, including cancers and multiple sclerosis, or MS for short. In fact, a 2022 paper suggests that EBV is likely the main cause of MS. And, while being infected with other viruses had no effect on the likelihood of developing multiple sclerosis, those that contracted EBV had a 32-fold increase in their risk of developing the disease.

This link opens up new potential avenues to treat and even prevent MS by targeting EBV. And of course, not everyone with EBV develops MS. However, other infections cause long term problems at a much higher rate. Ebola virus disease, for example, is a very severe infection. Symptoms include fever, muscle pain, fatigue, diarrhea, vomiting, rash, and in some cases, unexplained internal or external bleeding. It is often fatal, especially without specialized treatment and support.

Past outbreaks have seen between 25 and 90% of patients dying from the disease. But survival is often far from a return to their normal life for patients. In 2018, a study by researchers in Ghana and Liberia sought to pin down the prevalence of what is known as Post-Ebola Syndrome, or PES. That is, persistent physical and psychological symptoms affecting those who had survived Ebola. Among their sample of 268 Ebola survivors from Montserrado County in Liberia, they found that 90% reported the onset of symptoms consistent with PES between one and 12 weeks after being discharged from an Ebola treatment unit.

Just understanding that other post-infection syndromes exist isn’t enough, though. We need to know more about how an initial infection can have lasting results. So what causes long COVID? We don’t know yet, but there are some ideas. One possibility is related to the activation of immune cells called mast cells. These cells may be involved in the often-fatal acute respiratory distress syndrome often seen in COVID-19, and if they continue to activate once the initial infection is gone, they could also be central to the kind of widely varying, multisystemic symptoms typical of long COVID.

Which brings us to Mast Cell Activation Syndrome. Also known as MCAS, it’s a chronic multisystem disorder causing inflammation and allergy-like symptoms. Mast cells are immune cells that hang out throughout the body, and act as a kind of guard patrol. If they detect a potential threat, they release inflammatory substances to fend it off. In someone with MCAS, the mast cells are easily triggered to release their contents, kicking off inflammatory or allergy-like attacks in response to things that don’t really need it.

The symptoms of MCAS are about as nebulous and unpredictable as long COVID’s: headaches and fatigue, cognitive symptoms, irregular heartbeat, digestive issues, neurological symptoms… It can even cause allergic-like reactions to pretty innocuous things, like sudden changes in temperature. A study published in November 2021 found that MCAS symptoms were very prevalent in long COVID patients. In fact, before their COVID infection, the health of long COVID participants and healthy controls were pretty much the same. Post-COVID, those same long COVID participants had symptom profiles that were virtually identical to those with MCAS. If it turns out that mast cells are chronically active in long COVID, it’s possible that therapies aiming to bring them back under control could reduce or even eliminate long COVID symptoms.

One candidate that seems to affect symptoms of long COVID, specifically, is over-the-counter antihistamines. A case report from February 2022 detailed how two people with long COVID had taken diphenhydramine, a sleep aid and antihistamine, and noted that their symptoms rapidly resolved while it was in their system. One patient saw about 95% of her long COVID symptoms resolve when taking the medication daily. The other took diphenhydramine for some time and was subsequently prescribed a similar drug, hydroxyzine, to similar results.

This is also in line with findings from a clinical trial, published in October 2021, that had long COVID participants take antihistamines. Results showed that 72% of participants receiving this treatment showed significant improvement in their symptoms. That said, many of these studies have made conflicting findings about which antihistamines work and which don’t, so more research is needed. And this revelation about mast cells and antihistamines may help us understand a few other conditions that have historically proved a bit of a mystery, like chronic fatigue syndrome, or myalgic encephalomyelitis. CFS/ME for short. CFS/ME can be diagnosed based on symptoms like pain, chronic tiredness affecting day to day functioning, and exercise actively making things worse. Symptoms are surprisingly comparable to those that have been reported for long COVID, from fatigue to neurological problems.

The exact causes of CFS/ME are not clear, but one of the main hypotheses is that it comes from an abnormal immune response to common pathogens, such as our old friend EBV. There's also fibromyalgia, which is similar to CFS/ME, but doesn't have the same negative results when diagnosed patients exercise. Both of these conditions are often used as "wastebasket diagnoses" for symptoms doctors can't entirely pinpoint, or don't have diagnostics for. But the similarity of its symptoms, plus an association between pathogens and later diagnoses, seems to suggest that there may well be a post-infection aspect to the condition too.

For example, a study from October 2021 found that after an outbreak of Giardia lamblia infections in Belgium in 2004, 8.6% of people infected went on to have a diagnosis of fibromyalgia ten years later. In those who weren’t infected, only 3.1% developed fibro. Giardia is a single-celled parasite akin to malaria, not a virus. But infection could spark some kind of similar stress or reaction in the body. Some academics have noted the similarities between fibromyalgia, CFS and long COVID. And a few have even proposed that they might all be the same post-infection condition.

Or at least the same flavor. What does this tell us? While it helps to draw parallels between these diagnoses, and we have some research to sift through that might help with long COVID, there’s still a lot we just don’t understand about post-infection syndromes. In part, that’s because the symptoms are so varied. But it’s also unfortunately in part due to stigma and misclassification of these symptoms as psychological, especially in fibro, among women and patients assigned female at birth. More women are being diagnosed with long COVID, which could mean they face similar stigma.

But if the parallels to CFS/ME and fibro hold, it could be that long COVID might finally help bring an end to the stigma around these diagnoses, and get needed support to these patients who are often overlooked. It might mean that understanding the causes of long COVID could in turn give us treatments for potentially identical issues that, so far at least, have been classified as fibro or CFS/ME. With long COVID being so widespread, prevalent and impossible to shrug off, it’s even possible that this might be the moment that attracts the right research funding and scientific interest to get to the bottom of what causes post-infection issues, and how we might finally treat them. Until then, vaccines and any necessary booster shots, and following public health recommendations, remain the most effective tools to help slow the spread of the virus. And for now, we’re going to have to wrangle with the practicalities of treatment and support for those with long COVID.

The sheer number of patients mean that existing disability services are likely to be overwhelmed and we will need more capacity to be able to assist everyone who needs it. Some doctors note that there was initially a big push to use exercise therapy to treat those with long COVID, but it’s since become evident that many experience adverse effects from exertion, just like in CFS/ME. We still have a lot to learn. One thing is clear: many with long COVID, like those with post-infection symptoms in years gone by, have found themselves having to adjust to new capabilities. But this influx of people likely represents an influx of research. And maybe that will benefit the disability community at large. Because that means we can work on improving treatments and accessibility for everyone. Whether they have long COVID or not.