Long Covid continues to affect millions globally, with persistent symptoms and a growing need for better diagnosis and treatment. Photo / Getty Images
Although the pandemic is long over, for many people their illness continues. We examine the latest data, research and possible treatments.
Four and a half years on from the start of the Covid-19 pandemic, vast numbers of people remain desperately unwell, two, three or even four years after first contracting the virus.
“The planet has acquired a huge new medical speciality of chronically unwell people,” says Professor Danny Altmann, an immunologist from Imperial College London. “Estimates range from between 65 million to 200m people who still have Covid. It’s enough to fill hospital departments in every city in the world.”
The latest report from Britain’s Office of National Statistics in March showed that an estimated 3.3% of people in England and Scotland are living with long Covid, of whom 71% have had symptoms for one year, 51% for at least two years and 31% for at least three years. The latter category alone is thought to comprise 750,000 people, although – because there is no formal diagnostic test for long Covid – these figures are all self-reported.
Cat Rowles, 40, a former child and adolescent nurse in the National Health Service (NHS), caught Covid in the spring of 2020. “Initially I just felt tired, groggy and breathless – which was strange as I used to cycle everywhere and I could previously run up a flight of stairs and think nothing of it.
“I tried to return to work but I couldn’t cope physically and ended up becoming bedbound for a few months. Since the summer of 2020, I’ve suffered from fatigue and worsening brain fog to the point where I struggled to speak in sentences. I forgot how to do the simplest of tasks such as making a cup of tea.”
Rowles tried all the common supplements to alleviate her symptoms: vitamins, probiotics, even nicotine patches for a few weeks, after one small study suggested it might improve fatigue. “The only thing which has made a difference is a super-healthy diet with no refined sugar, gluten, alcohol and minimally processed food, along with intermittent fasting and a couple of 24-hour fasts per week. This has helped maintain what I can still do. I’m still unable to work.”
She remains unwell. “On my worst days, I struggle to move even a few metres and really bad crashes can last over a week. While I’m one of the lucky ones, as my family, friends and partner have all been understanding, I’ve essentially lost my life for the past four years.”
Numerous patients have experienced gaslighting from doctors and other medical professionals, many of whom are convinced that their illness is psychological in origin.
Manoj Sivan, a consultant in rehabilitation medicine and professor at the University of Leeds, has been leading a long Covid study called Locomotion. He says that many end up being misdiagnosed with depression, anxiety or chronic pain.
“There is still a disbelief about the condition, and healthcare professionals don’t always refer these patients on to long Covid clinics,” he says. “So these patients end up being told, ‘Well, this is just a worsening of your anxiety, it’s a reaction to what’s happening in your life.’”
Wendy Crawford, 47, a finance officer, had Covid four years ago and never recovered. “I have easily spent thousands [of pounds] on consultations, tests and treatments trying to find solutions.
“In Scotland, long Covid patients are still hearing the same old story from the Government. We get told to go to our GPs, who then refer us to various clinics. The specialist long Covid clinics are not doctor-led so we merely get shown slides on how to manage symptoms from physios and occupational therapists, before being discharged after 12 weeks.”
While the majority of studies suggest that taking antivirals during an acute Covid infection provides some protection against the later development of long Covid, many people struggle to obtain these medications on the NHS. Crawford says that, despite her prolonged illness, she has been unable to get antivirals.
“My last reinfection put me in bed for over a year but, when I tried to try to get access to antivirals after I tested positive, I was told that this wasn’t possible as I wasn’t classed as vulnerable.”
David Putrino, an associate professor at New York’s Mount Sinai Health System, who researches long Covid, is hopeful that new diagnostic tools based on AI can eventually reach clinics, making it easier for doctors to separate long Covid cases from psychiatric illnesses – and also providing indications of possible therapies that might work.
Last year, he published a new model that was able to correctly classify long Covid patients from people with other conditions, using the levels of various hormones and immune cells. “For each patient that receives a diagnosis using the algorithm, the features which led to their individual diagnosis can then go on to guide treatment,” he says.
Long Covid is a disease of myriad complexities that have often led to confusion and scepticism about the condition. More than 200 different symptoms have been associated with the condition, according to a 2023 study in the journal Nature Reviews Microbiology.
These symptoms can impact the brain, heart, lungs and other internal organs, along with the vascular system, gastrointestinal tract and reproductive system.
Patients commonly describe suffering from severe fatigue and brain fog but also problems relating to the autonomic nervous system, which regulates heart rate and blood pressure, sometimes making it impossible even to stand without becoming dizzy and unwell.
Some patients can also experience rare and bizarre symptoms in disparate parts of their body, from sudden allergic reactions to blood clots. Symptoms range from persistent low-grade fevers to tinnitus.
Melanie Morby, 62, a former community nurse who used to run half-marathons, describes her symptoms as joint pain, migraines and breathlessness, after contracting Covid three times. “I have this endless fatigue. Doing anything feels like trudging through treacle.”
Putrino says the array of differing and overlapping symptoms experienced by patients has made studying the condition incredibly challenging.
“Certain people have immune dysfunction, certain people have vascular dysfunction or gut dysbiosis and some unlucky people have all of these things, all at the same time. We’ve seen that there’s a lot of different ways in which an acute Sars-CoV-2 infection can trigger chronic health problems.”
Just as the precise collective of symptoms can vary enormously between patients, so can the underlying cause. Scientists now believe that some patients may have remnants of the Sars-CoV-2 genetic material still lurking in parts of their bodies such as the brain and spinal cord, many years after the original infection.
Yet in other patients, the virus may have long disappeared but its initial presence was sufficient to send the immune system into overdrive, precipitating an autoimmune response in which the body is still attacking itself.
Sivan has witnessed numerous studies showing that long Covid patients have higher levels of auto-antibodies. These are different to normal antibodies as, instead of fighting off foreign invaders, they attack the body’s cells, tissues and proteins.
“The acute Covid infection might trigger an immune overreaction which hasn’t been dialled back down,” says Putrino. “So the body is mounting a prolonged and non-stop immune response to what it thinks is still there.”
Researchers suspect that, in many cases, long Covid is essentially an autoimmune disease mediated by auto-antibodies. Putrino and his collaborator Professor Akiko Iwasaki at Yale University have conducted an unpublished study demonstrating how auto-antibodies are likely to be behind various symptoms.
In a recent lecture, Iwasaki described how they took blood samples from long Covid patients and healthy controls and extracted immunoglobulin G (IgG) – a protein which can exist as both an antibody and an auto-antibody – which they injected into lab mice. Within six days, the animals that received IgG from long Covid patients developed balance and muscle strength issues and signs of chronic pain, while mice that received IgG from healthy people remained symptomless.
“This tells us that there is a percentage of people with long Covid who definitely have some sort of auto-immunity and it’s transmissible,” says Putrino. “It suggests that, in at least some patients, targeted immunotherapies could be an option to switch off these auto-antibodies.”
We are still learning why some people have been more vulnerable to developing long Covid. Sivan says vaccines have had a strong protective effect.
“There’s a clear pattern of people who contracted long Covid during the first wave, before the vaccines were introduced, having a poorer prognosis. But once you do get long Covid, the vaccines only have a minimal protective effect. They reduce the impact of further infections but they can’t repair the damage which has already happened.”
According to Sivan, people of a lower socioeconomic status or with pre-existing illnesses relating to the immune system also seem to have been markedly more vulnerable to long Covid.
“We’ve also found that middle-aged people, working stressful jobs, have just gone back to work without making a full recovery and then they’ve struggled,” he says. “It means the immune system has not been allowed to recover, and so it’s been repeatedly challenged and it keeps crashing.”
The limited treatment options for long Covid patients are merely ways of managing or masking their symptoms.
For severe fatigue, Sivan says the advice focuses on pacing, and the concept of staying within your energy limits to avoid relapses. Patients presenting with symptoms of mast cell activation syndrome – a condition that also occurs after an allergic reaction – such as rashes, swelling, low blood pressure and breathing difficulties, can be given antihistamines to manage their flare-ups.
Sivan’s study has focused on managing symptoms of autonomic nervous system dysfunction, such as dizziness, drops in blood pressure and surges in heart rate when standing up.
“You give them medications to control heart rate, increase blood pressure and other strategies such as increasing fluid and salt intake, and we’re getting very nice results,” he says. “People start to feel better and this improves their ability to work because it alleviates some of the brain fog.”
New treatments specifically aimed at addressing fatigue may soon become available. These consist of drugs or supplements that attempt to heal some of the damage inflicted on the mitochondria – the energy-generating structures within our cells – either by the virus or a subsequent autoimmune response.
Last year, a clinical trial conducted by researchers at the University of Oxford found that an amino acid cocktail developed by Axcella Therapeutics showed signs of alleviating fatigue in long Covid patients.
Because of its complexities, Putrino says finding a single cure for long Covid is unrealistic. Instead, there needs to be more focus on identifying patient subgroups who are likely to respond best to various therapies.
While studies have indicated that the antihistamine famotidine can improve brain fog in some patients, and others have found a combination of L-arginine and vitamin C improved exercise tolerance, experts still have little idea why certain patients respond to such interventions and others do not.
Putrino points to another study that found taking a combination of co-enzyme Q10 and alpha lipoic acid for two months led to complete resolution of fatigue in half of the points. “The best we can do is tell people there’s a 50-50 chance that it will work,” he says. “That’s not really a financial risk that a lot of these patients are able to take, given that supplements are expensive and not available on the NHS.”
While trials around the world are examining the efficacy of more intensive medications such as immunotherapies and broad-spectrum antivirals, Putrino says we need better ways of screening patients to identify who is likely to benefit and who might even be at risk from these treatments.
Back in 2020, the UK was ahead of many nations in recognising the problem of long Covid, establishing dedicated clinics and putting money into research through the National Institute for Health and Care Research (NIHR), says Altmann, the Imperial College immunologist. Since then, this momentum has not only stalled but gone into reverse.
While the NIHR initially funded 19 multi-year studies into long Covid, these were all due to finish in June. Even the long-term existence of specialist centres is far from guaranteed, with current funding streams for the UK’s 100 long Covid clinics in question beyond March 2025.
“We have all the right hunches about things which might work for these people, from antivirals to immune modulators to anticoagulants, you name it,” says Altmann. “But somehow, we can’t seem to get the momentum to do that – but people are so desperate and we’re so close to being able to offer them solutions.”
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