In short: ‘Long-Covid’ is not unique among viral diseases

The pandemic leaves perhaps millions of patients struggling with long-term Covid, a debilitating illness characterized by fatigue, post-activity malaise and brain fog.

Immunologists aren’t sure why SARS-CoV-2 causes long-term ill health. But it’s similar to “post-viral fatigue syndrome,” which has been known for decades. “Brain fog and general malaise are classic symptoms. It’s very real and we’d like to know more about it,” said Prof. Luke O’Neill, immunologist at Trinity College Dublinabout this syndrome.

Scientists have different ideas about how the coronavirus could cause long-term Covid symptoms. “There are some strong views and premonitions,” says Prof Danny Altmann, immunologist at Imperial College London, but he remains open minded. And Pros O’Neill and Altmann both say there could be more than one cause.

The data is piling up. A study in the Lancet this summer looked at 3,762 people with confirmed or suspected Covid-19 from 56 countries, before June 2020, who had been sick for more than 28 days. More than 200 symptoms were recorded, with ten organs affected, and most people took more than 35 weeks to recover. A study by the British Medical Journal estimated that a third of people with Covid-19 developed Covid for a long time, indicating two million cases in England alone.

ACE2 is the gateway protein that the virus attaches itself to, and many organs express this protein, Altmann notes: “So perhaps it should come as no surprise to us that when you do an MRI analysis of kidneys or lungs or hearts , you see what looks like scars from the virus.”

Reservoirs of viruses have also been found in some people’s guts, and some long-term Covid infections may be associated with such an ongoing infection. Or SARS-CoV-2 might do what some herpes viruses do, and be “incredibly disruptive to normal immune function,” Altmann adds, which is the case with the Epstein-Barr virus (EBV).

Alternatively, the mechanism could be more like the chikungunya virus, a mosquito-borne virus that causes joint pain in many people for months or years after infection. These longer symptoms are due to the immune system targeting the body’s own tissues, says Altmann, who has studied this disease in Brazil. Immune-friendly fire was also common in the 2009 swine flu because some of that flu strain resembled a protein in the brain. In certain susceptible individuals, this led to targeting of the protein and resulted in narcolepsy.

Those who were seriously ill from long-term Covid and required hospitalization are often believed to be the ones who develop long-term Covid. The evidence doesn’t pile up that way, Altmann says: “Tall Covid patients are completely split between those who had asymptomatic infections, those with mild infections, and those who had severe infections or were hospitalized.”

Viruses known to cause similar symptoms after infection include the original SARS virus, Ebola and influenza

It can be tricky to get a formal diagnosis. If a patient with long-term Covid goes to a primary care physician, they may be “dismissive as self-reported,” he says, “but I don’t see how it could be anything other than self-reported.” Because we have no official tests. His lab is looking for signs of long-term Covid from patients’ blood samples, hoping to create a diagnostic test. The risk of long-term Covid appears to be slightly higher in women, women with a high BMI and asthma, but only slightly.

Not unique
Prof Akiko Iwasaki is an immunologist at Yale University. She sees lung Covid as not unique and sees clear parallels with chronic fatigue syndrome. “It’s very difficult to diagnose chronic fatigue syndrome and it’s very difficult to treat it because we don’t understand the underlying disease mechanism,” she explains. “It’s one of those diseases that has been rejected and, in some cases, patients have been mistreated.”

Even the term “chronic fatigue syndrome” is sometimes criticized for failing to reflect the range of symptoms and severity of the illness. Viruses known to cause similar symptoms after infection include the original SARS virus, Ebola, and the flu.

Among autoimmune diseases where infection is suspected as a cause or trigger are rheumatoid arthritis, lupus, and MS. “People with rheumatoid will have symptoms a lot like long-Covid,” notes O’Neill. “They often get fatigued and often get brain fog.” Certain pro-inflammatory cues promote these symptoms, he notes, and some arthritis medications successfully target them and can clear up the fatigue and brain fog.

There are currently no proven treatments for long-term Covid. But scientists hope that by understanding the mechanism behind the condition, they can learn how best to treat it.

A silver lining in the pandemic cloud is rapid approval of newer vaccines

Many post-viral infection syndromes are extremely rare and may only occur in genetically susceptible individuals. This makes it difficult for them to study. Long-Covid is different. “The more people have it, the easier it is to study,” adds O’Neill. The UK has long set up Covid clinics and funds research into the condition, such as at Altmann’s London lab.

“Covid has affected so many millions of people that the sheer number of patients now suffering from long-term Covid is now simply impossible to ignore or ignore,” says Iwasaki. “We need to figure out what’s going on, and if that helps people with chronic fatigue syndrome, so much the better.”

One challenge is that people with similar symptoms may have different subtypes of long-term Covid, with different disease mechanisms.

A silver lining in the pandemic cloud is the rapid approval of newer vaccines. Before the Covid-19 mRNA vaccine entered the first arms of volunteers, Moderna had developed a vaccine against EBV. This is usually transmitted in saliva and infects cells that line our organs and blood vessels, as well as our antibody-producing B cells. The virus can cause mononucleosis in teens and adults and has been linked to chronic fatigue syndrome.

As with other herpes viruses, infection is for life, as this DNA virus hides in our cells. EBV infection also increases the risk of certain cancers and is a suspect in MS. Vaccines are also being developed for cytomegalovirus, a herpes virus associated with lupus, type II diabetes and rheumatoid arthritis.

“If there’s a viral origin for lupus or MS or rheumatoid arthritis, then we’d have a way to stop it,” says O’Neill. “Vaccinate against [the virus].” Preventing viral infections could then reduce the incidence of autoimmune diseases and prove their link to viruses.

Viral Suspect for MS
According to some scientists, the Epstein-Barr virus is a suspected trigger for MS, especially when the first infection is during the teens or later years. However, it is virtually impossible to establish cause and effect, as more than 95 percent of adults eventually become infected with this herpes virus, usually through saliva.

Many people become infected in childhood and have no symptoms or a short-term illness. But if contracted by teens or adults, it can cause glandular fever, which can last for weeks or months. There are no drugs to get rid of EBV.

“A very strong argument for the role of EBV is that essentially all children with MS are infected with EBV, while the percentage of EBV infected healthy children of the same age is significantly lower,” said Dr. Gunnar Houen to the Staten Serum Institute in Denmark, which says the evidence linking the virus to MS is growing. It’s best to get EBV early in life and avoid smoking and obesity later in life, which can weaken a person’s control over this herpes virus, he suggests.

Other immunologists say the jury is out on whether this virus causes MS or plays a role. A vaccine shot could eventually protect people against EBV, glandular fever and associated cancers — and possibly MS as well. Such a vaccine seems more likely due to the advances sparked by the Covid-19 pandemic.

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