The long and short of it – ‘Long-Covid’ is not unique in viral illnesses

Immunologists don’t know for sure why SARS-CoV-2 causes extended ill health

The pandemic is leaving in its wake perhaps millions of patients struggling with long-Covid, a debilitating illness marked by fatigue, malaise after activity and brain fog.

Immunologists don't know for sure why SARS-CoV-2 causes extended ill health. But it resembles "post-viral fatigue syndrome," which has been known for decades. "Brain fog and general malaise are classic symptoms. It is very real, and we'd love to know more about it," says Prof Luke O'Neill, immunologist at Trinity College Dublin, about this syndrome.

Scientists have various ideas about how the coronavirus might cause long-Covid symptoms. "There are some strongly held views and hunches," says Prof Danny Altmann, immunologist at Imperial College London, but he remains open minded. And Profs O'Neill and Altmann both say there could be more than one cause.

Data has piled in. A study in the Lancet this summer looked at 3,762 people with confirmed or suspected Covid-19 from 56 countries, before June 2020, ill for more than 28 days. Over 200 symptoms were recorded, with ten organs affected, and most people took more than 35 weeks to recover. A British Medical Journal study estimated that a third of people with Covid-19 went on to develop long-Covid, suggesting two million cases in England alone.


ACE2 is the gateway protein that the virus docks onto, and lots of organs express this protein, notes Altmann: “So maybe it shouldn’t be a surprise to us that when you do an MRI analysis of kidneys or lungs or hearts, you see what looks like scarring from the virus.”

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

Alternatively, the mechanism could be more like for Chikungunya virus, a mosquito-borne virus that in many people inflicts joint pains 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 illness in Brazil. Immune friendly fire also happened with the 2009 swine flu, because part 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 severely ill from Covid, requiring hospitalisation, are often assumed to be those who go on to develop long-Covid. The evidence doesn’t stack up that way, says Altmann: “Long-Covid sufferers are completely distributed across those who had asymptomatic infections, those who had mild infections, and those who had severe infections or were hospitalised.”

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

It can be tricky to get a formal diagnosis. If a patient goes to a GP with long-Covid, they may be “referred to, dismissively, as self-reported,” he says, “but I don’t see how it could be anything other than self-reported.” Since we don’t have official tests. His lab is seeking tell-tale signs of long-Covid from patient blood samples, in the hope of creating a diagnostic test. The risk of long-Covid seems slightly higher in women, those with a high BMI and those with asthma, but only slightly.

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

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

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

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

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

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

“Covid has affected so many millions of people that the sheer volume of patients now suffering from long-Covid is just impossible to ignore or dismiss now,” Iwasaki says. “We need to find out what is going on, and if that helps folks with chronic fatigue syndrome, that is all the better.”

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

A silver lining in the pandemic cloud is speedy approval of newer vaccines. Before its Covid-19 mRNA vaccine went into the first arms of volunteers, Moderna had been developing a vaccine against EBV. This is usually transmitted in saliva and infects cells lining our organs and blood vessels, as well as our antibody-producing B cells. The virus can cause glandular fever in teens and adults, and it been linked to chronic fatigue syndrome.

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

“If there is a viral origin to lupus or MS or rheumatoid arthritis, then we would have a way to stop it,” says O’Neill. “Vaccinate against [the virus].” Preventing viral infections might then reduce the incidences of autoimmune conditions, and to prove their link to viruses.

Viral suspect for MS
Epstein-Barr virus is a suspected trigger for MS, especially when first infection is during teenage or later years, according to some scientists. However, it is virtually impossible to prove cause and effect, since more 95 per cent of adults eventually get infected with this herpes virus, usually through saliva.

Many people are infected in childhood and get no symptoms or a brief illness. But if contracted by teenagers or adults, it can cause glandular fever, which can last for weeks or months. There are no medicines to get rid of EBV.

"A very strong argument for the role of EBV is that essentially all children with MS are infected by EBV, whereas the percentage of EBV-infected healthy children of the same age is significantly lower," according to Dr Gunnar Houen at the Staten Serum Institut in Denmark, who says the evidence linking the virus to MS is strengthening. It is best to get EBV early in life, and to avoid smoking and obesity later in life, which can weaken a person's control over this herpes virus, he suggests.

Other immunologists say that the jury remains out on whether this virus triggers or plays a role in MS. A vaccine jab might eventually protect people against EBV, glandular fever and associated cancers – and potentially also MS. Such a vaccine looks more likely due to progress spurred on the Covid-19 pandemic.