Two months after contracting Covid-19 in August 2021, Heather Marti, a university programme administrator from West Virginia, began to experience a terrifying array of symptoms that have changed her life.
The 52-year-old describes agonising muscle pain, gastrointestinal problems, weeks-long migraine-like headaches, brain fog and “extreme mental fatigue similar to what has been described after a traumatic brain injury” among a litany of other problems.
Grasping for an image to explain the devastation, she said: “All of the wires in my body are crossed — if you turn the water faucet on, the door would open. There isn’t a system in my body that has not been impacted.”
Marti is far from alone in her search for answers. Four years after the emergence of the Covid-19 pandemic, the quest to uncover the causes of long Covid, and develop treatments for the condition, continues.
The World Health Organization this month estimated that around 6 per cent of those who contract the disease end up with long Covid, defined as the continuation or development of symptoms three months after initial infection with Sars-Cov-2, with these symptoms lasting for at least two months. The global health body estimated that at least 17mn people joined the ranks of the “long-haulers” in Europe alone in the first two years of the pandemic.
“We are not expecting a simple cure, a silver bullet, because we know from other complex illnesses that that’s rarely achieved,” said Melissa Heightman, who opened one of the first specialist long Covid clinics at University College London Hospitals in the UK, pointing to the multiple factors behind the condition.
For experts striving to unravel its causes, one of the biggest shocks has been that many who have suffered from long Covid were never badly sick with the virus in the first place.
Walter Koroshetz co-chairs a nationwide research programme at the US National Institutes of Health, designed to uncover the “biologic mechanisms” behind long Covid and potentially develop a cure.
He said hospitals had set up clinics to support those who had ended up in intensive care, believing only the severest Covid cases would need continued attention. But “people started to come who . . . were never in the intensive care unit” — the first sign of the risk of prolonged after-effects even in cases of mild or moderate infections.
Although the high number of sufferers may have been unexpected, the notion of a puzzling constellation of symptoms coming hard on the heels of a viral infection was all too familiar to infectious diseases experts.
Koroshetz said the NIH’s Recover Initiative, in which Marti is one of almost 30,000 participants, also hoped to provide answers to those living with myalgic encephalomyelitis, another post-viral condition commonly known as chronic fatigue syndrome.
Researchers believe long Covid sufferers, at least those who experienced severe infections, may never have managed to fully rid their bodies of the virus, allowing it to continue to replicate, or pieces to be retained, even after they had tested negative. This may lead to “persistent activation of the immune system and cause all these chronic symptoms”, Koroshetz said.
An NIH study, based on autopsies, found evidence that some who had lost their lives up to 280 days after becoming infected with severe disease had died with active traces of the Covid virus.
A longer course of antiviral drugs could help to wipe out any remaining pockets of the virus. Some patients in the Recover trial are now receiving Paxlovid for up to 28 days — far beyond the customary five-day course prescribed for higher-risk patients when they contract Covid-19.
A second approach is based on the theory that long Covid is primarily an autoimmune disorder. This suggests sufferers’ immune systems “rev up” to the point where they move from protect to attack mode, weakening healthy cells. Recover investigators will be testing an autoimmune treatment called intravenous gamma globulin (IVIG), which Koroshetz said “resets the immune system and is kind of an immune suppressant”.
Janet Diaz, a critical-care leader for the WHO, noted that alongside these approaches, metabolic drugs like Metformin, used in diabetes, and dietary supplements were being tested in long Covid sufferers to see if they alleviated symptoms.
Research published last month in the journal Science, and led by Professor Onur Boyman of Zurich university, reported that changes in blood protein had been found in people suffering from long Covid, offering another avenue for research.
Heightman and her UCLH colleagues have focused on helping patients to cope with symptoms such as disordered breathing, and techniques to manage fatigue and the psychological impact of the condition.
The extreme tiredness that characterises long Covid seems to be one of the most important indicators of how quickly a patient will recover, experts have found. “When they have severe fatigue, recovery can be extremely slow,” Heightman said.
While classic long Covid is associated with a particular constellation of symptoms, the mysteries of which scientists are still trying to fathom, some researchers are focused on an apparent link between infection and a rise in all too familiar conditions such as heart disease, stroke and diabetes.
Ziyad al-Aly, R&D chief at Veterans Affairs St Louis Health Care System and clinical epidemiologist at Washington University in St Louis, discovered that patients in the VA’s extensive database who had recovered from Covid were significantly more likely than those who had not contracted the disease to suffer heart attacks and strokes, or to develop diabetes.
A similar picture was evident in data from countries including Germany and the UK. “The global evidence woven together suggests that Sars-Cov-2 infection leads to an increased risk of chronic disease,” he added.
However, Aly and colleagues are examining whether people infected with Omicron, the dominant variant since the end of 2021, are less likely to face a heightened health risk than those contracting earlier versions of the virus — whether because of mutations, the protection offered by widespread vaccination, or an unknown factor. They plan to publish their conclusions later this year.
Heightman said the original “wild type” of the virus “seems to be the worst”, while vaccination not only seemed to reduce the chances of developing long Covid in those with breakthrough infections but “we have increasing signals that it can reduce the severity of [the condition] as well”.
While researchers hope this points to an eventual easing of the long Covid burden, Aly fears that Covid’s enduring impact on health is such that the incidence of some diseases such as strokes has now permanently risen.
There are few signs that governments have fully grasped the costly implications for healthcare systems, he warns.
“We have almost accepted as a fact of life that it is going to be like that,” he said, adding that there is “not a lot of concern as to the level of spending [required] on healthcare resources. People are at a stage where they want to really move on.”
