Scientists haven’t figured out long Covid. Here are 5 of their best hypotheses.

Most people who get the coronavirus will fully recover and go right back to their lives. But the latest research suggests that at least 10 percent have long-term symptoms, even after their body has apparently cleared the virus.

The condition, known as “long Covid,” has emerged as a scary feature of the pandemic — a reminder that even as hospitalizations and deaths come down, millions of people will continue to suffer from the aftermath of infection.

And, as it turns out, “this isn’t unique to Covid,” Akiko Iwasaki, an immunologist at the Yale School of Medicine, told Vox.

Instead, Covid-19 appears to be one of many infections, from Ebola to strep throat, that can give rise to stubborn symptoms in an unlucky subset of patients. “It is more typical than not that a virus infection leads to long-lasting symptoms in some fraction of individuals,” Iwasaki said.

The difference now is that, with 137 million Covid-19 cases worldwide and counting, long-haulers are more visible: Their suffering has come on in unprecedented numbers. It’s also possible the coronavirus causes long-term symptoms even more frequently than other infections.

In this week’s episode of Unexplainable, we dive into what we know about long Covid and what other viruses can teach us about the condition, including the leading hypotheses for what might be driving symptoms in Covid long-haulers.

We also look at what we can learn from patients who have been grappling with medically unexplained symptoms — the kind that don’t correspond to problematic diagnostic test results or imaging — for years before the pandemic hit. Here’s a rundown of what scientists think could explain the mysterious symptoms, and why even the vaccine might not help.

1) The virus and “viral ghosts” didn’t actually leave the body

Cell nuclei (blue) being infected by SARS-CoV-2 (red areas), the virus that causes Covid-19.
Jane Barlow/PA Images via Getty Images

The first explanation for what might cause persistent symptoms in people who’ve been infected with Covid-19 is the simplest: The virus or its components might still be lurking in the body somewhere, long after a person starts testing negative.

We’ve learned from other long-term viral illnesses that, in some cases, pathogens do not fully clear the body. “It’s out of the blood but gets into tissue in a low level — the gut, even maybe the brain in some people who are really sick — and you have a reservoir of the virus that remains,” PolyBio Research Foundation microbiologist Amy Proal told Vox. “And that drives a lot of inflammation and symptoms.”

These viral reservoirs have been documented following infections with many other pathogens. During the 2014-2016 Ebola epidemic, studies emerged showing the Ebola virus could linger in the eye and semen. There were similar findings during the 2015-2016 Zika epidemic when health officials warned about the possibility that Zika could be sexually transmitted. (Viral reservoirs are also why the moniker “post-viral” can be problematic, Proal added.)

A related explanation for what might be happening with long-Covid patients is what Iwasaki calls “viral ghosts.” While the intact virus may have left the body, “there may be RNA and protein from the virus that’s lingering and continuing to stimulate the immune system,” Iwasaki said. “It’s almost like having a chronic viral infection — it keeps stimulating the immune system because the virus or viral components are still there, and the body doesn’t know how to shut it off.”

Recent studies in Nature and The Lancet documented coronavirus RNA and protein in a variety of body systems, including the gastrointestinal tract and brain.

In autopsies of people with chronic fatigue syndrome, researchers also found enterovirus RNA and proteins in patients’ brains, including, in one case, in the brain stem region. The brain stem controls sleep cycles, autonomic function (the largely unconscious system driving bodily functions, such as digestion, blood pressure, and heart rate), and the flu-like symptoms we develop in response to inflammation and injury.

“If that area of the brain signaling becomes dysregulated [by viruses],” Proal said, “[that] can result in sets of symptoms that meet a diagnostic criteria for [chronic fatigue syndrome], or even for long Covid.”

2) Other pathogens lurking in the body reawaken

Other pathogens already lurking in the body prior to a coronavirus infection might also exacerbate symptoms. For example, viruses in the herpes family — such as Epstein-Barr (the cause of mono) or varicella zoster (the cause of chickenpox and shingles) — stay dormant in the body forever. Under normal conditions, the immune system can keep them in check.

“So, for example, 90 percent of people in the world already have herpes viruses,” said Proal. “But in those patients, the immune system keeps them in a place where they can’t replicate, where they can’t express proteins. They’re kind of controlled.”

But then Covid-19 comes along, and all of a sudden these other viruses get a chance to gain a foothold again. With the immune system tied up fighting Covid-19, the other viruses may reawaken. And they — not the coronavirus — drive symptoms.

3) The immune system turns on the body

Another key hypothesis: Long-Covid patients have developed an autoimmune disorder. The virus interrupts normal immune function, causing it to misfire, so that molecules that normally target foreign invaders — like viruses — turn on the body.

These “rogue antibodies,” known as autoantibodies, “attack either elements of the body’s immune defences or specific proteins in organs such as the heart,” according to Nature. The assault is thought to be distinct from cytokine storm, an acute immune system disorder that appeared as a potential threat early in the pandemic.

“Under that scenario, we talk about molecular mimicry,” Proal said. “Basically, the virus creates proteins that look like human proteins or tissue, and that kind of tricks the immune system.” Here, the the immune system tries to target the virus, which “if it has a similar size and shape to a human tissue or protein, it fires on the human tissue or protein as well,” she added.

4) The microbiome gets thrown out of whack

It’s also possible the coronavirus might deplete important microorganisms in the gut microbiome — the trillions of bacteria, viruses, and fungi that live in and on the body.

In one study, researchers tracked blood and stool samples from 100 patients hospitalized with SARS-CoV-2 infection, testing some up to 30 days after they cleared the virus. (They also collected samples from a control group for comparison.) And they found Covid-19 infection was linked to a “dysbiotic gut microbiome,” even after the virus cleared the respiratory tract; they also hypothesized that it might contribute to the persistent health problems some patients are experiencing.

“Under conditions of health, those communities are in a state of balance. It’s like a forest, like different organisms are doing different things, but it’s in a harmonious state,” Proal said. But Covid-19 could lead to an imbalance in the microbiome. “And a huge number of symptoms are tied to microbiome dysbiosis. Irritable bowel syndrome or even neuro-inflammatory symptoms can be driven by these ecosystems when they go out of balance, too.”

5) The body is injured

Radiologists observe CT scans of covid-19 hospital in Cremona
Radiologists observe CT scans of Covid-19 patients’ lungs.
Nicola Marfisi/AGF/Universal Images Group via Getty Images

The virus might have cleared the body but left injuries in its wake — scars in the lungs or damage to the heart, for example — and these injuries might give rise to symptoms.

According to a recent preprint involving 201 patients, 70 percent had impairments in one or more organs four months after their initial Covid-19 symptoms set in. In other unpublished research, radiologists at the University of Southern California tracked hospitalized patients’ lung recovery using CT scans. They found one-third had scars caused by tissue death more than a month later. Other patients may have brain damage that causes neurological symptoms.

There’s also growing evidence of widespread cardiac injury, even in patients who aren’t hospitalized. In a JAMA Cardiology study, researchers performed cardiac MRIs on 100 patients in Germany who had recovered from Covid-19 within the past two to three months. An astounding 78 percent still had heart abnormalities.

For coronavirus patients who had to be admitted to intensive care units, there’s a related explanation: Long before the pandemic, the intensive care community coined a term for the persistent symptoms people frequently experience following stays in an ICU for any reason, from cancer to tuberculosis. These symptoms include muscle weakness, brain fog, sleep disturbances, and depression — the aftermath of a body lying around in a hospital bed for days on end and injuries or side effects from treatments patients received, including intubation.

The term “post-intensive care syndrome” was “created to raise awareness and education, because so many of our ICU survivors were going to their primary care doctor saying they were fatigued,” said Dale Needham, who has been treating Covid-19 patients in the ICU at Johns Hopkins. “They had trouble remembering, and they were weak. Their primary care doctor would do some lab tests and say, ‘Oh, there’s nothing wrong with you.’ The patient might walk away and feel like the doctor was saying, ‘It’s all in your head. You’re making it up.’”

The Covid-inspired medical revolution

So what might help alleviate the nagging symptoms of Covid long-haulers? One idea that’s been circulating is the Covid-19 vaccine: Some long-haulers are reporting their symptoms improving after they’ve gotten immunized. But others have reported feeling worse — and still others, no different. So researchers are racing to understand the effects of vaccination on long Covid, but it isn’t looking like a silver bullet just yet.

Proal had a simpler solution that could be implemented today: “It’s time for medicine to be rooted in just believing the patient.”

Even with growing awareness about long Covid, patients with the condition — and other chronic “medically unexplained” symptoms — are still too often minimized and dismissed by health professionals.

People “want disease to kill you, or they want you to return to miraculous good health,” said Jaime Seltzer, director of scientific and medical outreach at the chronic fatigue syndrome advocacy group ME Action. “When you stay sick, compassion can fade. And that is not just friends and family. That is your clinicians as well; they want somebody fixable.”

But long-haulers of any chronic condition can exist in a space between sickness and health for years, sometimes without a diagnosis. Their unexplainable symptoms can elicit outright skepticism in health professionals who are trained to consider patient feedback the “lowest form of evidence on [the evidence hierarchy], even under research on mice,” Proal said.

The situation can be even more challenging for patients who never had a positive PCR test confirming their Covid-19 diagnosis. Of the dozens of medical appointments one Covid-19 long-hauler, Hannah Davis, had for her ongoing symptoms — which include memory loss, muscle and joint pain, and headaches a year after her initial disease — one of the best experiences involved a doctor who simply said, “I don’t know.”

“The doctor [told me], ‘We are seeing hundreds of people like you with neurological symptoms. Unfortunately, we don’t know how to treat this yet. We don’t even understand what’s going on yet. But just know you’re not alone,’” she recounted. “And that’s the kind of conversation that needs to be happening. Because we can wait, but we can’t have the doctor’s anxiety being projected onto us as patients.”

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