“One in four consultations in primary care involve fatigue — it’s the most common reason why people go to see their GP,” says Julia Newton, a consultant physician with an interest in fatigue at Newcastle upon Tyne Hospitals NHS Foundation Trust.
At least 250,000 people in the UK live with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a long-term neurological disease with a wide range of symptoms, including debilitating pain, fatigue and crashes after activity known as post-exertional malaise. And self-reported data indicate that 50% of people with chronic conditions — such as rheumatoid arthritis, cancer, Parkinson’s disease, or multiple sclerosis (MS) — struggle with tiredness[1–3]. “Despite that, there’s very little research,” points out Newton.
Lack of funding has left fatigue science decades behind the scientific understanding of other chronic symptoms, such as pain.
In part, this is owing to the heterogeneity of how fatigue is experienced. On top of presenting across multiple conditions, it can be emotional, physical, cognitive or motivational in nature, and varies from person to person — even from day-to-day for the same patient (see Box). This diversity means conducting research can be a tricky and unattractive investment.
Box: What do we know about chronic fatigue?
“There isn’t [an accepted] scientific definition of fatigue — there isn’t a physiological, biochemical understanding of what the pathophysiology of fatigue is,” states Julia Newton, a consultant physician with an interest in fatigue at Newcastle upon Tyne Hospitals NHS Foundation Trust. “It is a symptom that is described by patients, so it’s a word that can often be used to describe a whole range of different things.”
“There are quite a few things we need to understand about fatigue,” stresses Anna Kuppuswamy, principal research fellow in clinical and movement neurosciences at University College London. “We have acute fatigue and chronic fatigue, and they are completely different from each other — that’s never made clear.”
“Early fatigue is considered part of sickness behaviour; inflammation-induced reduction of performance and activity, and a feeling of tiredness which accompanies it. It’s supposed to be an effective mechanism to focus on recovery rather than just doing things.” Like pain, fatigue is a message to our body that something is wrong.
“But if you think about chronic fatigue, that’s where it starts to get very murky; it’s sort of a free for all, it could be anything.” In chronic fatigue, the switch to turn this message off is not flicked.
It is yet to be understood what this switch is, along with the mechanisms involved in the message system; a complex mixture of inflammatory mechanisms, metabolic and autonomic dysregulation, neuroendocrine pathways, and psychological disturbances, such as sleep disorders, have all been implicated as contributors to fatigue pathology.
“It’s made more complicated by the fact it’s really hard to measure fatigue — not impossible, but it is hard, it’s really subjective,” Newton explains. “In order to encourage the pharmaceutical industry to come and to develop their drugs, you need a good end point — that’s the problem at the minute. [Without it] you’re never going to get the investment you might need to get a drug to market.”
But this could be changing. With fatigue consistently ranked as the most frequent self-reported symptom associated with long COVID, the powerhouse of global COVID research — and the funding that comes with it — has the potential to dramatically remodel the landscape of fatigue science and therapy.
And it’s sorely needed. For patients currently living with fatigue, this landscape is pretty sparse.
Getting it wrong
There are currently no approved pharmacological or non-pharmacological interventions for chronic fatigue, across any of the conditions it is present in. For ME/CFS, the 2021 revision of the National Institute for Health and Care Excellence’s (NICE’s) guidance for managing the condition removed a previously recommended therapy — graded exercise therapy (GET), a programme of fixed, incremental increases in exercise — and downscaled the scope of another — cognitive behavioural therapy (CBT) — because a re-evaluation of the evidence base for these therapies failed to show meaningful benefit.
GET and CBT were used as early interventions that aimed to improve ME/CFS symptoms by tackling ‘unhelpful beliefs’ patients were thought to hold about exercise and activity patterns; a model where psychology was considered a root cause of fatigue. In acknowledgement of current understanding for a physiological basis for chronic fatigue, together with patient and expert experience, CBT recommendations are now limited to helping patients cope with symptoms — not as a possible ‘cure’ for fatigue behaviour. Accumulating data for GET suggest that forced exercise targets actually make ME/CFS symptoms worse; in one survey, this was true for 38% of patients treated with GET compared with 6% who found it helpful[6,8].
“There was a strong signal of risk of harms from GET,” Peter Barry, non-expert chair of the ME/CFS NICE guideline committee, says of the panel’s appraisal of the evidence base.
“We found GET produced, at best, a moderate effect in a small number of people, and that effect wasn’t long-lasting compared with no intervention, and the evidence around GET was of low or very low quality. The committee felt as a whole, that given [the] low quality of [evidence of] an, at best, moderate benefit, which wasn’t long-lasting, against a strong signal of harms, it shouldn’t be recommended.”
While these changes were mostly welcomed as a step in the right direction, it has effectively put ME/CFS care back at square one, with a distinct lack of therapeutic options.
“There’s nothing, there’s no treatments in the NICE guideline,” Newman agrees, adding: “You’re almost left with a blank piece of paper.”
So what can a patient with chronic fatigue expect from care now?
The three Ps
Both the updated NICE ME/CFS and long COVID guidance focus clinical support for fatigue on the concept of self-management — assisting the patient to build up a set of skills themselves to cope with their illness. In chronic fatigue this involves thinking carefully about energy use[7,9].
“We talk about the three Ps approach — prioritising, planning, and pacing,” says Rachel Rogers, a fatigue specialist occupational therapist at the long COVID clinic based at Churchill Hospital, Oxford, and clinical lead for Oxfordshire’s ME/CFS service. Rogers describes the patient journey for someone presenting with long COVID fatigue.
“We’ll often use the analogy of a mobile phone battery and encourage people to think about how they are using their [battery of] energy,” she says. Patients are advised to prioritise where they are going to spend their energy and not waste any unnecessarily, and plan out how they might use the limited energy across the day and week.
“And then, with pacing, how they are going to break tasks down into smaller more manageable chunks and top up that energy battery with periods of rest throughout the day,” she adds.
Pacing helps eke out the patient’s energy or ‘battery life’ so it doesn’t drain completely. If that happens, “one of the patterns that people will fall into is this ‘boom and bust’”.
“They’ll have a good day, they’ll feel as if they’ve got a bit more energy, and they’ll race around trying to get everything done that they’ve not managed to do for a while, and end up crashing in a heap, spending two or three days recovering,” Rogers cautions. “So, it’s about trying to avoid too many of those dips and crashes and spread out their energy expenditure.”
Referred to as post-exertional malaise (PEM), crashes are notoriously difficult to predict and prevent, and it is even harder to do so when already struggling with fatigue.
“Not everyone even understands they are having a bout of PEM,” says Nicholas Sculthorpe, an exercise physiologist at the University of West Scotland. “And bouts of PEM can be delayed by three or four days from what actually triggered it, so you’ve got to try and track all of that for three or four days at least to get an idea of your triggers. And on top of all that, [what if] you’ve got brain fog[?]”
As part of a recent round of National Institute for Health Research (NIHR) funding for long COVID, Sculthorpe is trialling a modern solution for PEM: a Fitbit, linked to a purpose-built app that alerts wearers if they are close to exceeding energy thresholds. “We could say, you’ve been very active this morning, maybe this afternoon you could take a rest,” says Sculthorpe, outlining the concept. As a proxy measure of energy use, the team are tracking the time spent at an elevated heart rate. “We’ll send a message that will say, you’ve used 15 minutes of your 30-minute threshold already today.”
This ‘Fitbit-in-reverse’ hopes to offer an easy way for patients to understand their energy variables; to better gauge the amount of energy different activities require to help plan better in the future, or retrospectively analyse their data to pinpoint triggers of PEM. “The whole point is to give people an external brain for all of that.”
Sculthorpe’s study, which received £317,416 in funding, is a prime example of how chronic fatigue research is starting to be taken more seriously.
But research efforts are not stopping at supportive tools; another study, receiving £640,180 of NIHR funding, is the Percutaneous Auricular Nerve Stimulation for Treating Post-COVID Fatigue (PAuSing-Post-COVID Fatigue) study, which applies electrostimulation to the auricular vagus nerve, in an intervention known as neuromodulation. “It’s what is increasingly referred to as an ‘electroceutical’,” says lead investigator Mark Baker, senior clinical lecturer at Newcastle University.
In a 16-week cross-over study in 96 subjects with post-COVID-19 fatigue, the electrical stimulation is applied for an hour, three times daily, by a transcutaneous electric nerve stimulation (TENS) machine, a small device already marketed for pain relief in conditions such as endometriosis or sports injuries. Building on a small study of 15 subjects with Sjögren’s syndrome, an autoimmune disease, that showed improved fatigue scores after 28 days of twice-daily vagus nerve electrostimulation, Baker says the team is “hoping to see improvements after eight weeks of continued treatment”[11,12]. Pathological mechanisms for chronic fatigue are not fully understood, but the autonomic nervous system — the vagus nerve and its crosstalk to the immune system — is thought to play a role in fatigue modulation.
Investment in drug-based therapies for chronic fatigue is also trickling through; an early front-runner to reach phase IIb testing in the UK is clinical-stage biotechnology sponsor Axcella’s candidate AXA1125[13,14]. An oral powder mix of six amino acids, AXA1125 has previously boosted mitochondrial function in clinical trials with subjects with non-alcoholic steatohepatitis (NASH), where mitochondrial metabolism in the liver is faulty[13,15]. Mitochondrial problems are similarly implicated in ME/CFS, and Betty Raman, clinical transition intermediate fellow at the British Heart Foundation Oxford Centre of Research Excellence and lead investigator of the AXA1125 trial, explains that evidence points to this in long COVID fatigue too[16,17].
“Cardiopulmonary testing has identified that there are abnormalities in the body’s ability to use oxygen efficiently [in long COVID fatigue]. Other tests have detected a reduced activity of the mitochondria in peripheral blood cells. So, it’s believed that one basis for [long COVID fatigue] could be mitochondrial dysfunction.
“The thinking is that the virus might be potentially hijacking the mitochondria and affecting their ability to process fuel and energy for the cell.”
Long COVID patients with fatigue in the UK are eligible for enrolment in this trial; but studies of other potential therapies are ongoing internationally too. US-based biotech company Resolve Therapeutics is testing its autoimmune disease candidate RSLV-132 in a phase II, 10-week study of 70 subjects with long COVID. RSLV-132, a ribonuclease that breaks down strands of pro-inflammatory RNA before they can be translated into inflammatory proteins, has already shown benefit in improving fatigue in Sjögren’s syndrome. “Based on our previous positive phase II clinical trial with RSLV-132 in autoimmune fatigue, we are hopeful that removing circulating RNA in long COVID patients will have a similar improvement in their fatigue and brain fog,” says James Posada, chief executive officer of Resolve Therapeutics.
Similarly, Ageless Rx, a US-based telehealth ecommerce start-up, is testing two candidates in a 12-week pilot study of 60 subjects with fatigue following COVID-19 infection[21,22]. The first intervention, oral low-dose naltrexone (4.5mg), picks up from several previous studies indicating low-dose naltrexone improved fibromyalgia symptoms, including fatigue[23,24]. The second intervention, topical patches of the metabolic enzyme nicotinamide adenine dinucleotide (NAD+), is another targeted at cell energy processing.
In June 2022, Terra Biological, also based in the United States, reported positive results from a small proof-of-concept trial in ME/CFS and long COVID fatigue patients with its nutritional supplement oxoalocetate. Another intervention taking aim at metabolic processes, the improvements seen warrant further investigation in ME/CFS and long COVID fatigue, the company says.
Investment in chronic fatigue is gathering momentum. But with most of this research in long COVID patients, what does this mean for those for whom fatigue has been a reality for decades?
The answer might not be too far away. In May 2022, the then UK health secretary Sajid Javid announced that as part of a package of government support for ME/CFS, he is co-chairing a roundtable focusing on research priorities that include exploring possible links between ME/CFS and long COVID, and whether drugs explored for fatigue in other conditions, such as low-dose naltrexone, could work in ME/CFS, as well as getting to the bottom of the biological mechanisms behind ME/CFS and symptoms such as PEM (see Figure)[27,28].
“I am excited and optimistic that this represents a new horizon for those with this terrible illness that will provide opportunities for new treatments and a greater understanding of the impact ME/CFS has on people’s lives,” says Newton, who is a participant at the roundtable.
Chronic fatigue research has an uphill journey ahead of it, but it seems to be finally moving in the right direction.
- This feature was amended on 19 July 2022 to clarify the difference between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is a long-term neurological disease with a wide range of symptoms, including fatigue, and chronic fatigue, which is a symptom of a number of different conditions
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