What is Long COVID?

A Beginner's Guide

Like many people with Long COVID, I spend a good amount of time learning about my disease. I spend an additional large chunk of time educating friends, family, the audience of my newsletter, and even my own doctors about Long COVID.

Without the help of clear, frequent, and reliable public health communications about what we’ve learned, the public remains ignorant about Long COVID. And that isn’t likely to change with Trump in the White House, Elon’s minions skulking around federal agencies like the NIH, and RFK Jr eyeing HHS; it’s likely to get much, much worse.

With that in mind, this article aims to outline the basics of Long COVID. What the term refers to scientifically and colloquially, how it can present, hypotheses as to its pathogenesis/es, and where we go from here. It presents some broad definitions, explores some subcategories, and leaves you with the open questions and debates researchers and patients are asking, exploring and living out. There are still many things we don’t know yet. But what we do know, should be shared.

Although a more severe infection increases your risk of Long COVID, most Long COVID cases- over 90%- began with a mild infection, due to the much larger number of mild infections. And recent studies have found that the risk of developing Long COVID is cumulative, meaning that three infections are more dangerous than one, five more dangerous than three, and so on.

Immunity to SARS-COV-2 is short-term, and new variants are constantly arising because of our collective decision to continue spreading the virus. Since we must all expect, in the current “new normal” of recurrent SARS infections, to continue to be exposed to COVID, we must all learn the risks of exposure our government has failed to inform us about.

---

Under the Long COVID Umbrella

Long COVID is an umbrella term that generally refers to symptoms which persist more than three months after a COVID infection. The definition of Long COVID itself has been a subject of debate and advocacy for years now; the term was first coined by patient and advocate Elisa Perego of Lombardy, who found herself struggling to recover from her acute infection in early 2020. Since then, patients have had to continually fight for recognition from the medical community, as resources initially focused heavily on the deadly acute phase of the illness.

In 2024, The National Academies of Sciences, Engineering, and Medicine published a paper titled, “A Long COVID Definition: A Chronic, Systemic Disease State with Profound Consequences”. A committee of 16 subject matter experts, in collaboration with 18 reviewers and a handful of other contributors, produced the final document, with the consensus definition below:

Long COVID (LC) is an infection-associated chronic condition (IACC) that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.

This definition is sufficiently broad to encompass the wide range of symptoms and damage seen to follow infection with the SARS-COV-2 virus. In this case, the definition refers in particular to the chronic condition Long COVID, which accords more closely with the colloquial definition of LC. In the past, researchers have also used a more basic definition of any symptoms persisting beyond a certain time point, usually 3 months. This can make talking about LC confusing, as it can refer to both the chronic condition, as well as the larger umbrella of post-COVID health complications.

It’s critical to note that Long COVID can affect any and all organ systems in the body. It can impact the heart, lungs, digestive system, pancreas, brain, kidneys, liver, and more. It can harm the immune system. For this reason, the damage SARS-COV-2 can leave behind in a body may seem random, strange, or hard to believe.

For instance, it may be confusing to hear that COVID is increasing heart attacks and strokes if you’ve only heard from public health guidance that SARS-COV-2 is a respiratory virus. In fact, COVID is highly vascular, attacking the blood vessels and increasing your risk of blood clots. And at this late date, there’s no excuse for the public to be under the impression that COVID solely affects the lungs; it is a deliberate decision to leave people in the dark.

The Long COVID umbrella helps explain a few things that confuse the public.

The first: why do studies keep finding such high rates of Long COVID after SARS-COV-2 infection? For example, this systemic review of 429 studies published between 2021-2024 found that 1/3 of people who contract SARS-COV-2 go on to develop Long COVID. The pooled global estimate was 35% - more than one in three people. How could the number be that high?

The reason large studies find very high rates of post-COVID health effects is that studies are able to look at how COVID has affected all organ systems at a population level. Whereas you, in your day-to-day life, just experience friends and family having heart attacks and strokes, or developing diabetes and autoimmune diseases, the studies show that the people who had COVID infections saw those poor health outcomes more often than those who didn’t. That’s Long COVID.

While you experience health changes after COVID as your cholesterol and blood pressure mysteriously going up at your next doctor’s appointment, the study may see that it’s Long COVID. While you experience your partner’s underlying health conditions worsening as “aging”, the study can see that, statistically, many people who think they are “aging” are experiencing Long COVID. While you see your kid’s range of recurrent infections, psychiatric and cognitive issues as disconnected problems, a study might see that kids with this constellation of issues are suffering from Long COVID.

How? Because the same things didn’t happen at the same rates to the uninfected group as in the matched controls, and the differences were statistically significant.

So, while you say you “don’t know anyone with Long COVID”, it’s not always possible for you to separate out what is Long COVID versus what is aging, and what is from other risk factors like smoking, drinking, genetics, poor eating habits, or bad luck. It’s only possible to know that by looking at large populations of people, and each time we do that, we get the same result: COVID makes all of these health conditions worse, accelerates aging, damages organ systems, and causes the onset of new health conditions.

---

An Infection Acquired Chronic Illness

Okay, so Long COVID manifests in many ways, and sometimes those effects may be more subtle and easily confused with aging or other lifestyle factors. But what about all those people demanding a “cure” for Long COVID? What are they referring to? Surely, they aren’t demanding a cure for diabetes, high cholesterol, migraines, and heart attacks?

This is where the “chronic condition” part of the definition comes in. PWLC, or People with Long COVID, are people who live with a syndromic form of post-COVID disease. This form of post-viral illness may cause significant difficulty participating in day-to-day life and is often characterized by dozens of symptoms including severe fatigue, brain fog, headache, heart palpitations, tremors, memory loss, rashes, hair loss, muscle weakness, nausea and more. The symptoms each person experiences vary widely from person to person, as does severity. Patients may be homebound, they may be bedbound, or they may be able to participate in some proportion of everyday activities as normal.

Looking more closely at PWLC, we see yet more subtypes. Some patients have more neurological and cognitive symptoms, some more gastrointestinal symptoms, some more cardiac damage or immunological damage. Most have a combination of symptoms that can span the entire body, from top to toe. Studies have often grouped patients together by “phenotypes”, e.g., more neurological symptoms, more immunological symptoms, more gastrointestinal symptoms, but there’s no consensus about how to define cohorts of patients, especially since the underlying mechanisms are still opaque.

About half of patients with Long COVID that presents as a syndrome meet the diagnostic criteria for ME, or Myalgic Encephalomyelitis. ME, formerly called Chronic Fatigue Syndrome, is a neuro-immune disorder that can also be triggered by other illnesses, and is characterized by PEM, or post-exertional malaise. This cardinal symptom sees patients experience a worsening of symptoms following any exertion; a recent study demonstrated that mitochondrial damage may be responsible for the phenomenon.

ME and other Infection Acquired Illnesses have long been neglected by medical science. Although first believed to be a form of polio in the 1930s, the disease went on to be psychologized in the 60s and 70s and labeled “mass hysteria” because the patients were majority-women. UK writer George Monbiot has written extensively about what he calls “the greatest medical scandal of the 21st century,” the entire field’s refusal to engage with the science on ME, which has consistently shown biological abnormalities, leaving patients without treatment options for decades. In recent work conducted by NIH-funded RECOVER study, a shocking 4.5% of those infected with COVID went on to develop ME, or ME/CFS.

ME isn’t the only previously neglected chronic illness that COVID can trigger. It can trigger POTS, or postural orthostatic tachycardia syndrome, a form of dysautonomia that causes blood to pool in the lower half of the body, leading to faintness and high heart rate on standing. Since 2020, POTS cases have more than tripled in the US.

We’re not sure why some people experience Long COVID one way, and others experience it another way. It may be that the pathogenesis of the disease, or the disease process, is different in different people, or it may simply be that the complex systems that govern our bodies can break down in myriad ways in the face of a single disease process.

That’s one of the things clinical studies are trying to understand. If we can understand the disease process, then we can understand where to target treatments. Right now, there are several hypothesized disease mechanisms.

---

Hypothesized Disease Mechanisms

For Science, Drs. Ziyad Al-Aly and Eric Topol, two respected experts in the Long COVID world, wrote an excellent piece titled, “Solving the puzzle of Long Covid,” where they explored the hypothesized mechanisms of the disease. The two scientists list five possible “pathogenic pathways” of Long COVID: viral persistence, autoimmunity or immune dysregulation, mitochondrial dysfunction, endothelial and/or neuronal inflammation and microbiome dysbiosis.

Let’s step these out, starting from the top: viral persistence is what it sounds like. Viruses like HIV, HPV, and HSV can all persist in the body, and there’s no reason to assume SARS-COV-2 couldn’t too. If the virus is replicating in hard-to-reach tissues, it could potentially be leaving the immune system “activated”, and over time wearing it down. Our body knows there’s a foreign invader …. somewhere. But it can’t locate the invader and clear it. So, the immune system stays switched “on,” using up its resources. This could lead to the immune system aging and becoming damaged as T cells become exhausted. In this video, Dr. David Putrino speaks about evidence of prolonged T cell activation in Long COVID patients, which can also lead to other problems like the reactivation of latent viruses. In this case, we would expect to see things like younger people getting shingles (we have) and more people getting TB, which is often dormant in healthy people (we have).

That brings us to the second mechanism on the list, immune dysregulation. We’ve all seen the data, as well as observed ourselves, that people really are sicker after COVID, but our press continues to attribute this, bafflingly, to lockdowns in 2020-21. In fact, there’s plenty of data to show immune damage in Long COVID.

Immune damage is a huge topic; too large to cover in a single paragraph. But we know that COVID is affecting CD4 and CD8 T cells, dendritic cells, and the complement system. Most recently, new evidence from PolyBio Research Foundation found that NK cells or cytotoxic natural killer cells levels are reduced in Long COVID patients vs those who successfully cleared the virus. Additionally, we know that COVID can leave people struggling with new autoimmune diseases.

Mitochondrial damage was mentioned above in the discussion of PEM and exercise intolerance; you may recall from middle school that mitochondria are the powerhouse of the cell. When they aren’t functioning properly, the body has difficulty producing energy. The hallmark fatigue and muscle weakness symptoms of Long COVID may be related to mitochondrial dysfunction which in turn leads to impaired cellular energy and oxidative stress.

Endothelial inflammation is inflammation of the lining of your blood vessels. We know it’s being damaged by SARS-COV-2, and that that damage can have severe repercussions throughout the body. In September 2022, Dr. Rae Duncan, a consultant cardiologist, spoke with Dr David Nabarro, a Special Envoy of the World Health Organization (WHO) Director-General on COVID-19 at an open online briefing. Here are her words about the damage:

The inflammatory cytokines are inflaming the endothelium, which is the inner lining of the blood vessels, that then triggers another response, and you get platelet activation, which are the molecules involved in blood clotting, and it triggers the coagulation cascade, and you end up with this cytokine and clot soup. Now, in Long COVID these clots are very small, they’re amyloid microclots.

The other thing to mention is, they’re not normal clots. In the presence of spike protein, fibrin, which is the molecule that’s involved in the clotting, becomes misfolded into an amyloid formation. And when it does that, it also traps other molecules inside it. So you end up with these fibrin-amyloid microclots.

Microclots have become another target of Long COVID research and therapeutics, with scientists like Resia Pretorius in South Africa wondering whether the clots could serve as a biomarker, or whether clearing the blood of detritus could help the body recover.

In addition to inflaming the endothelial lining, COVID causes inflammation in the brain, and this is also mentioned under hypothesized mechanism number 4: neuronal inflammation. COVID can cross the Blood-Brain Barrier, or BBB. Generally, the BBB exists to keep germs out of your brain, so crossing the BBB is, as you might imagine, a negative. You might be wondering what the BBB is made of, and why COVID is able to cross it. Well, unfortunately, it’s also made of endothelial cells- COVID’s favorite snack¹. And not only can COVID cross the BBB- it can also “increase BBB permeability”, making it easier for other baddies to get through the BBB in the future.

Once in the brain, the body has fewer defenses. After all, germs aren’t supposed to be in the delicate brain at all. It’s a little like the virus got past a bunch of expensive security tech and is now in the vault. In Long COVID patients, scientists are seeing long-term disruption of the BBB (the guards at the door are disarmed) and long-term inflammation in the brain (havoc in the vault). This leads to the neuro-COVID symptoms we see, including brain fog.

Finally, we have microbiome dysbiosis. Gut dysbiosis is when the balance of microorganisms in the body which help processes like digestion becomes dysregulated. This is the mechanism commonly looked at when Long COVID patients are suffering ongoing gastrointestinal issues. To bring us full circle, a 2022 study found that patients with IBD following COVID did indeed have SARS-COV-2 antigen persistence in their small and large intestines 7 months after a mild acute infection. So viral persistence may again be the underlying cause of the dysbiosis; and we again see these mechanisms are not necessarily competing but more likely cooperating with one another.

With Long COVID, the underlying cause is like the first domino or bouncing ball in a large Rube Goldberg machine. The virus persists; the lining of a blood vessel is inflamed; the microorganisms in the gut become unbalanced; the immune system is dysregulated, and all of the systems of the body begin to careen off target.

In this way, we begin to see how Long COVID can start with one small virus, and produce such diverse, seemingly bizarre outcomes.

---

As I write about all the damage COVID can do- and has done- to our bodies, and to mine, I am strangely filled, not with fear, but with an awful respect.

I find myself, as I read about the BBB and the amyloid-fibrin clots, not horrified, but fascinated.

I find myself, as I reflect that COVID may, indeed, already be in my bones and in my brain, more motivated to write, more excited to speak, angrier with those in power, and sadder for those with none.

We deserve- all of us- to have this information. We deserved to have it years ago, to learn it together. We deserve to understand the virus we’ve been told is harmless, what it does in our bodies, the things our bodies do for us. The way our bodies have been waging these fantastic, sci-fi sounding battles in our blood vessels, defending our neurons, activating our T-cells, forming teeny, weird little clots because they aren’t sure what to do with this strange, prickly new enemy.

I think our organs and immune system deserve a break from facing down this enemy; especially since the data shows that risk of Long COVID is cumulative, and more infections equals more risk. That’s why I wear masks in public spaces and encourage others to do so, advocate for clean air and layered mitigations, and continue to work on public education as the CDC encourages us to languish in ignorance.

Our government’s instructions could not be more clear: wait your turn to experience the inevitable consequences. Wait your turn, sitting duck. Until then, have fun at the expense of those already suffering. If they speak, laugh at them. If they yell, shut them up. If they demand something, call them crazy. If they cry, it’s not your problem.

What should be very clear from this Long COVID primer is that Long COVID is an everyone problem because everyone has blood vessels, a gut microbiome, ACE-2 receptors, T cells and a blood-brain barrier. I wanted to demystify the words so finally they become real, and a part of you.

Long COVID is simply what happens when someone does not recover from COVID. It’s not imaginary, and it’s not even particularly mysterious. It is complicated, because bodies are complicated, and the virus is doing strange, fascinating things, going through forbidden doorways, entering sacred chambers.

Long COVID is blood vessel damage, brain damage, organ damage, immune system damage, and mitochondrial damage. It is real, it is devastating, and it is happening to people every day. And it can happen to you, after any infection.

1. This is an oversimplification. COVID does not eat snacks. Please don’t quote this out of context and say I think COVID eats snacks.