Five years after the World Health Organisation declared Covid-19 a pandemic on 11 March 2020, scientists still don’t fully understand why some people develop disabling chronic conditions after the initial viral infection.
And while America may be coming through its first post-pandemic winter without a major surge in cases, each infection carries a risk of developing long Covid – with some scientists now calling for new types of clinical trials to be designed for the most debilitated long Covid sufferers.
The condition is known to cause more than 200 different symptoms in nearly a dozen organ systems, including those of the heart, lungs, kidneys, brain, eyes and skin, but there’s no approved test for it or recommended treatment. Research shows it is more common in middle-aged people, particularly women and those with weakened immune systems, but anyone who catches the virus can get it.
The US Centres for Disease Control and Prevention has estimated that one in 20 adults in the US, or about 14m people, have long Covid.
Other data show that up to 5.8m children may be affected by the condition as well, reports NBC News, but experts say these numbers are probably under-estimated because there’s no official surveillance system in place.
A $1bn research initiative called RECOVER – launched by the National Institutes of Health to find the causes of long Covid as well as potential treatments – has fallen short on its promises, scientists and patient advocates say.
Meanwhile, experts fear the Trump administration’s extreme cuts in federal spending may undermine long Covid research efforts, which could further delay the discovery of therapies. Last month, President Donald Trump terminated the Health and Human Services Secretary’s Advisory Committee on long Covid.
Dr W Michael Brode, medical director of UT Health Austin’s Post-Covid-19 Programme in Texas, said: “We’re building the boat while we’re at sea, trying to figure it out (with patients) … but we absolutely need to build on the progress we’ve already made.
“We have not delivered the answers commensurate with the public health crisis we’re facing,” he said.
What causes long Covid
SARS-CoV-2, which causes Covid, isn’t the only virus that causes lingering symptoms. Another condition, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which shares many similarities with long Covid, is thought to be triggered by infections with the Epstein-Barr, influenza and varicella-zoster viruses, among others.
Covid is unique because it seems more likely to cause chronic illness than other pathogens, Brode said. Why it may lead to long-lasting symptoms is as yet undetermined.
Experts have so far landed on several theories.
One idea is that remnants of the virus hide in different tissues after an infection subsides, he said. These viral particles continue to multiply or stimulate the immune system in ways that trigger long Covid symptoms.
Another potential cause involves the reactivation of other viruses, such as EBV and HIV, that have been sitting in a dormant state in people’s bodies.
It’s also possible that Covid tricks the immune system into producing antibodies that attack a person’s own healthy organs and tissues, said Dr Igor Koralnik, co-director of Northwestern Medicine’s Comprehensive Covid-19 Centre.
Some evidence shows that Covid affects the inner lining of the blood vessels, which can lead to the formation of tiny clots and help explain symptoms like irregular heartbeats and heart failure experienced by some long Covid patients, Koralnik said.
It’s unclear whether one or a combination of these factors causes long Covid, but evidence suggests that they’re all associated with increased inflammation in the body, he added, which is why your risk of long Covid increases with each Covid infection.
“It’s like a river going over a dam,” Koralnik said. “The more episodes of Covid, the more the river level goes up to the point it overflows and there’s a flooding of long Covid symptoms.”
Diagnoses can be complicated. Although we have tools to confirm symptoms of long Covid, such as MRI scans for heart abnormalities, there’s no test that can diagnose the condition or distinguish it from similar illnesses, the CDC said.
As a result, people have to step away from work, school or other responsibilities to endure dozens of laboratory tests and scans that are not only expensive, but also stressful and time-consuming. It’s an extensive process of elimination that prevents people from getting the help they need, Brode said.
Clues in the eyes, gut and immune system
The challenge now is finding one or more biomarkers – genes, proteins or other substances associated with a specific condition – that can help diagnose long Covid.
A RECOVER study published last year found that routine lab tests, including 25 standard blood and urine exams, found few differences in biomarkers between people with and without prior Covid infection. The researchers concluded that these tests may not be useful in diagnosing long Covid.
Koralnik and his team recently discovered that people with long Covid have decreased blood flow in the small blood vessels in their retina. This reduced flow is thought to decrease blood circulation in and around the brain, he said, which might “poison” tiny organelles called mitochondria that convert oxygen into energy.
This theory can explain why many people with long Covid experience cognitive issues, fatigue and exercise intolerance. Overall, the findings, published recently in the Journal of Imaging, suggest the retina could be a long Covid biomarker.
Other research suggests promising biomarkers might exist in the gut and immune system, but Brode noted that these early findings are based on small groups of people and should be considered with a grain of salt.
As helpful as a diagnostic test would be for people with lingering symptoms, some experts say the lack of one shouldn’t slow scientists down in their search for long Covid treatments.
Julia Moore Vogel, senior programme director with Scripps Research and contributor to the Patient-Led Research Collaborative for long Covid, said other conditions like migraine don’t have reliable biomarkers or tests to confirm diagnoses, yet several drugs are approved to treat it.
Disappointing progress in treatments
The Food and Drug Administration (FDA) hasn’t approved any treatments specifically for long Covid, and experts aren’t sure we’ll get any soon.
Most clinical trials are testing whether drugs used to treat other conditions prove helpful for long Covid.
Researchers at the University of British Columbia, for example, are looking into low-dose naltrexone – a medication approved for opioid and alcohol use disorder. The drug is thought to have anti-inflammatory and pain-relieving properties, and is used off-label in people with fibromyalgia and ME/CFS, so it carries potential as a long Covid treatment.
Other drugs like baricitinib, approved to treat rheumatoid arthritis and acute Covid, and temelimab, an experimental drug often given to people with multiple sclerosis, are also being investigated as potential long Covid treatments.
In lieu of specific treatments, people with long Covid must balance their rest and activity in a strategy called pacing, Brode said, and receive physical and cognitive behavioural therapy for further support. More often than not, many people end up relying on several drugs, including the antiviral Paxlovid, to treat symptoms.
Realistically, however, “we may not actually have a single, silver bullet treatment”, said Alison Cohen, an epidemiologist with the University of California-San Francisco, who has had long Covid for three years.
Long Covid manifests in such a wide variety of ways that it’s going to take a “multi-pronged approach” to find effective treatments, she said.
What’s ahead for recovery?
As long as SARS-CoV-2 continues to spread, everyone is at risk of long Covid, Cohen said – and right now, evidence shows recovery from the condition is rare. A study published last month found only about 6% of people with long Covid recover after two years, she said.
Covid vaccination was associated with better long-term recovery, especially among people who got the booster shots.
Those who do improve experience many “ups and downs”, Koralnik said. “You have to expect a lot of bumps ahead.”
In the meantime, clinical trials must be designed to accommodate and include the patients they’re intended for, Vogel said. Many people are house- or bed-bound and can’t travel for multiple in-person visits and risk triggering a flare-up of symptoms. “There’s just too much that you can’t know until you have them at the table,” she said.
There’s no telling when the long Covid community will finally get the answers and relief they need, but Vogel is keeping her head high.
“I know we can do it. I’m confident that with enough trials that are well-designed, we can at least improve quality of life – if not cure the disease entirely. But I also can’t think any other way; I just can’t accept that this is it for my life.”
See more from MedicalBrief archives:
Common lab tests unable to diagnose long Covid – US study
‘The problem with the National Academies’ long Covid report’: US expert
US National Academies’ report underscores severity of long Covid
Multiple forms of long Covid hamper diagnosis