“We are really working day and night” to figure out long Covid, one researcher said.

By Yasmin Tayag

Even as the number of new Covid-19 cases in the US is dropping, hundreds of thousands of Americans are still testing positive every day. More than 28 million new cases have been reported since Omicron emerged in the US just two months ago, and the variant now drives 99.9 percent of cases, as of January 22, according to the Centers for Disease Control and Prevention.

Thanks to vaccines, boosters, and increasingly available treatments, most people who get infected today won’t end up in the hospital or die. A big question, however, looms over the survivors: What about long Covid?

Long Covid is a condition that arises after acute infection and often includes shortness of breath, fatigue, and “brain fog” but can also involve a wide range of debilitating problems in the heart, brain, lungs, gut, and other organs. According to the World Health Organization’s working definition, long Covid usually occurs three months after symptomatic Covid-19 begins and lasts for at least two months. Sometimes, the symptoms just never go away after the initial infection. Occasionally, they appear months after recovery or after an asymptomatic case. This means that if you’ve recovered from Covid-19, you’re not necessarily in the clear.

How to spot the signs of long Covid — and what to do next
No one knows exactly how many people have or had long Covid. Estimates so far are “wildly disparate” in part because researchers define the condition differently and because the people seeking care may only be a small portion of those affected, said Nahid Bhadelia, an associate professor at Boston University School of Medicine. Studies on the conservative end have found that 10 to 20 percent of Covid-19 survivors get long Covid, while others report 50 percent.

Scientists have proposed numerous hypotheses to explain long Covid’s myriad symptoms since research began in earnest after the first wave of cases in 2020. Early suspects included a weakened immune system, widespread inflammation, and even low sex hormone levels.

There are no firm answers yet, but there’s now greater consensus among researchers about the two leading theories and the ways they may be connected. Scientists also have a better understanding of the people who are susceptible to long Covid.

While many used to think that the condition only affected people with severe illness, patients now range from teens to older adults, some of whom had only mild or even asymptomatic illness, said Kathleen Bell, a professor in the department of physical medicine and rehabilitation at UT Southwestern Medical Center, on a recent press call. Early research is pointing to factors that may raise a person’s risk of long Covid, such as low levels of certain antibodies, reactivated viruses in the bloodstream, and existing conditions such as diabetes or asthma.

Amid pressure from patients and concerns that the vast numbers of omicron infections might drive a new wave of long Covid, researchers around the world are racing to understand what causes the condition and how it might be diagnosed and treated. “We are really working day and night,” Resia Pretorius, a professor of physiological sciences at Stellenbosch University in South Africa whose research is explaining the role of blood clots in long Covid, told me.

It’s too early to predict an omicron wave of long Covid, but scientists are cautious
Scientists I spoke to agreed that it’s too early to know whether omicron will lead to a new wave of long Covid because less than three months have passed since the variant emerged. But David Putrino, director of rehabilitation innovation at Mount Sinai Health System in New York City, is erring on the side of caution. “Right now, we have no reason to think any differently about long Covid.”

Whether different variants change the likelihood of developing long Covid is a fundamental question among researchers, Michael Peluso, an infectious diseases doctor who co-leads a long Covid research effort at the University of California San Francisco, told me. Severe initial Covid-19 infection, he noted, tends to correlate with who is at risk, so “it’s encouraging that early data suggest that omicron might be less severe, but obviously not enough time has passed.”

Still, long Covid can develop after mild or even asymptomatic Covid-19, too. “If you say omicron’s mild, it doesn’t say anything about long Covid,” Amy Proal, a microbiologist at the PolyBio Research Foundation, told me. “We don’t even know how mild omicron is.” The WHO has pushed back against calling omicron “mild,” but it seems to result in less severe illness, especially among the vaccinated. This may be because it’s better at evading the immune system, which isn’t a good thing because it raises the possibility that the virus is remaining in the body, Proal added.

Even if long Covid turns out to be less common among people who have been infected with omicron, the sheer number of cases right now means that millions may still develop the condition. “Even if it’s rare,” said Peluso, “it will affect a lot of people.”

“We’re worried,” said Proal. “It’s not being communicated to the public as one of the things to take into consideration in how to live these days. Not as much as it should be.”

Vaccination appears to offer some protection against long Covid, but it’s not clear how much. It certainly helps by preventing serious illness in the first place, and it may help clear the virus before it can lodge in the body for the long term. It also spurs the immune system to specifically target the virus, rather than raise defenses throughout the whole body, which could cause collateral damage elsewhere.

An encouraging recent preprint from Israel shows that fully vaccinated people who had breakthrough Covid-19 between March 2020 and November 2021 report fewer long Covid symptoms than unvaccinated people who were infected, suggesting “that some ability to fight off the virus is helpful for long Covid as it is for acute Covid,” Leora Horwitz, director for the Center for Healthcare Innovation and Delivery Science at NYU Langone Health, told me.

The immune system likely plays a leading role in long Covid
The sheer range of symptoms reported by people with long Covid — more than 200 across 10 groups of organ systems, according to one patient-led survey — makes uncovering their biological origins a gargantuan task. There are likely several subtypes of long Covid, each with its own cluster of symptoms and cause. “We’re not talking about a monolithic, single entity,” said Horwitz.

Scientists have proposed many explanations for long Covid, but several I spoke to agreed that there are now two leading theories: that symptoms are driven by the immune system or by the persistence of the virus in the body. Importantly, these aren’t mutually exclusive, and it’s likely that both factors are at play and interconnected, together with a number of other mechanisms.

The immune theory suggests that Covid-19 turns the immune system against the body. This could explain symptoms like racing heart, dizziness, weakness, and microclots in the blood, said Putrino, whose research focuses on the former. A large proportion of his long Covid patients seem to have dysautonomia, a condition that interferes with processes like balance, heart rate, blood pressure, temperature, and digestion. With Yale University immunologist Akiko Iwasaki, Putrino is studying the blood of long-haulers for evidence of an abnormal immune response that might be throwing the autonomic nervous system off track.

Flurries of microclots — tiny blood clots — observed in the blood of people with acute and long Covid may be fueling the immune system’s reaction. Clots in healthy people usually break down easily, but those in people with long Covid resist digestion and continue to drift throughout the circulation. Pretorius’s team has discovered inflammatory molecules concealed inside these microclots that she thinks may spur the production of autoantibodies. Having clots in circulation can cause the whole vascular system to become inflamed, ultimately choking off the supply of oxygen to cells and leading to a range of issues throughout the body. “Many of the symptoms that are related to long Covid can actually be traced back to a general oxygen deprivation state,” she said.

One of the primary functions of the immune system is to keep pathogens in line — including those that live inside our bodies, like dormant viruses and normally benign gut bacteria. When it isn’t working properly, these pathogens can act up and cause illness. “Patients might clear [SARS-CoV-2] itself from tissue, but immune dysregulation might allow other viruses and pathogens to reactivate and then drive chronic systems,” said Proal. Epstein-Barr virus, for example, seems to be reactivated in people with Covid-19, and scientists are studying whether the herpes viruses and the common parasite Toxoplasma do the same.

It’s possible, too, that the reactivation of these pathogens contributes to autoimmunity. Research recently published in Science posited that prior infection with the Epstein-Barr virus drives multiple sclerosis, a chronic disease, by spurring production of autoantibodies. Proal suggested that a similar mechanism could be at play in long Covid. “What it really means is that overall, autoantibodies can be generated as part of the immune system response to infection,” she said.

Lingering virus may also be to blame
Proal is also investigating theories linked to viral persistence, the other overarching long Covid theory. The virus can remain in the body and brain long after acute infection, and its genetic material can persist up to 230 days after symptoms arise, as a recent National Institutes of Health preprint found. Lingering virus is often found not in the blood but in the tissues, an important consideration for researchers studying and developing diagnostic tools for long Covid, Proal and others emphasized.

It’s not fully understood what these so-called “viral reservoirs” do in the body. Proal’s previous work on myalgic encephalomyelitis (ME, also known as chronic fatigue syndrome), an illness that has substantial similarity with long Covid, suggests that persistent virus — Epstein-Barr virus, in the case of ME/CFS — can wreak havoc on the body long after acute infection.

In long Covid, viral reservoirs could continue to injure tissues directly. They may leak viral proteins into the bloodstream, where they can spur the formation of the aforementioned microclots and activate the immune system, leading to inflammation and further damage. Or they may do nothing at all.

One theory is that inflammation in tissues caused by persistent virus can trigger inflammation in the brain via the far-reaching vagus nerve, which runs the length of the spine and connects to the brainstem. A recent preprint from a team co-led by Yale’s Iwasaki showed that mice with mild Covid-19 had activated brain microglia cells and higher levels of some inflammatory molecules. One of those molecules has been observed at high levels in the brains of long-haulers experiencing cognitive issues like brain fog. “You can start to see a scope of connected symptoms that can really make someone ill,” said Proal.

Like the symptoms of long Covid, the research is all over the place. “It’s a mess — anyone who says they get it is lying,” said Putrino. But patterns in the data are steadily emerging, which many of the researchers I spoke to attributed to collaboration among long Covid research teams and patient advocacy groups. Organizations like the Long Covid Alliance and Survivor Corps have been instrumental in helping recruit participants and lobby for much-needed funding since research on the condition began, they said.

Recent research identifying the people who are most at risk is especially promising. A small study recently published in Cell named four factors that may put people at higher risk for long Covid: higher levels of SARS-CoV-2 RNA in the blood in the early stages of infection, Type 2 diabetes, reactivated Epstein-Barr virus (which infects over 90 percent of the global population), and the presence of certain autoantibodies — which target the body’s own cells as if they were intruders. Other risk factors could include low levels of antibodies called IgM and IgG3 and preexisting asthma, as a recent study in Nature Communications suggested. Bell cautioned, however, that such factors are for “research purposes only” and shouldn’t be viewed as metrics for diagnosis.

Fortunately, many researchers studying the basic science of long Covid already have treatment — and diagnosis — in mind. Putrino said that 70 to 80 percent of his patients respond well to intensive autonomic rehabilitation therapy, which involves coaching to improve breathing followed by physical exercises. With RECOVER, an NIH-funded nationwide study on long Covid, Horwitz is developing a list of medications and vaccines to test and put through clinical trials.

“I am quite optimistic that there will be things that will be helpful,” she said. Pretorius is developing a diagnostic tool for long Covid, and she’s trying to get funding for a clinical trial involving clot-busting drugs. “We’re not going to rest,” she said.

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