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Long Covid: Explaining the unexplainable?

Long Covid is affecting 2 million patients in the UK, and GPs are struggling to treat them. But the volume of patients may prompt more research into treatment for medically unexplained symptoms. Emma Wilkinson reports

While the world remained in lockdown in the early waves of the pandemic and intensive care units were still filling up, another story was unfolding, initially on social media, of a group of ‘long haulers’, who were suffering from a wide range of ongoing and often debilitating symptoms after a Covid-19 infection. Medics infected in the first wave were among those who warned the symptoms of Covid could persist.

More than two years on, the Office for National Statistics has put a figure of 2 million people in the UK – or 3.1% of the population – as experiencing self-reported long Covid symptoms.1 Around one patient in five has had symptoms for at least two years and 19% say their ability to carry out day-to-day activities has ‘been limited a lot’.

The majority of cases involve ambiguous symptoms that GPs have struggled to deal with in other scenarios – fatigue, shortness of breath, muscle ache and brain fog. Such symptoms may have previously been labelled fibromyalgia, or chronic fatigue syndrome (CFS/ME). 

GPs know these patients are suffering. Hertfordshire GP Dr Neena Jha says: ‘What we see in general practice is how people have had to change their lives. I have patients who have lost their jobs and had to move back in with their families – and these are people who are young and were healthy and well before.’

Yet often there is little GPs can offer these patients. As with many secondary care services, referral to long Covid clinics brings its own problems. And even when referral is possible, those clinics are faced with a lack of evidence on what management will be most effective. Patients end up returning to the GP having had many investigations, and frustrated at the limited treatment options. 

Even before long Covid, medically unexplained symptoms made up a significant proportion of GPs’ workloads and the struggle to find any treatments that work causes great frustration to patients and GPs alike. 

However, there may be light at the end of the tunnel. The sheer numbers of people developing long Covid in a relatively short period has prompted research that is starting to unpick the underlying pathology of symptoms like fatigue and brain fog and may open the door to potential treatments.

Long Covid clinics 
Currently, long Covid is placing huge pressure on general practice and the NHS. Around 75,000 patients have now been referred to around 90 long Covid clinics across England, averaging around 5,000 patients a month. Scotland and Wales have set up their own services across health boards, although figures are not available. 

Yet more than one referral in 10 is rejected for being clinically inappropriate and in July 2022, around a third of those referred were waiting 15 weeks or more to be seen. Professor Azeem Majeed, a GP and professor of primary care and public health at Imperial College London, says: ‘The current process is very time consuming and bureaucratic for patients and professionals. The NHS also needs to be able to deal with a much larger number of patients than it currently does without the long delays and frequent rejection of GP referrals.’

Vaccination may help
Studies suggest2 that vaccination programmes have helped to reduce the burden of long Covid.
Dr David Strain, senior clinical lecturer at the University of Exeter Medical School, says initially one in 10 patients reported ongoing symptoms at 12 weeks but that figure is now around 3%. ‘But 3% of a large number is still a large number and in the next wave, I’m not worried about hospitals being overrun, I’m worried about the impact on referrals for long Covid services.’

Alongside the issues with referrals, the expertise available at long Covid clinics can vary widely as they have all been set up in different ways. They can be physiotherapy based, or centred around psychological services. Some of the first long Covid services were organised by respiratory clinicians who expected to see lots of breathlessness. Dr Strain says there is a significant subgroup of long Covid patients who are experiencing respiratory and cardiac symptoms.

Professor Majeed says patients can often be very disappointed to discover the limited options available to them, after waiting a long time to be seen in a specialist clinic and undergoing a large number of assessments and investigations. It’s thought that around 65%-75% of those who have symptoms at four weeks will have recovered in a year. The ONS datasuggest around 400,000 patients are still suffering symptoms from that first wave. What isn’t clear is what comes next for that group. ‘Many patients find their symptoms will improve over time and need to be encouraged by their GPs and primary care teams that some recovery is possible,’ Professor Majeed adds.

Dealing with unexplained illness 
But there is another reason the long Covid clinics haven’t helped much – because for patients with unexplained medical symptoms, especially fatigue and brain fog, there is often little even specialist clinics can offer. In this aspect, there are parallels with other conditions, says Dr Strain: ‘There is
a group of long Covid patients who are absolutely typical of CFS/ME.’ Indeed, in June 2020, some of his CFS/ME patients said their symptoms had been reactivated by long Covid. 

Understanding of the pathophysiology of long Covid is growing, but – like CFS/ME and fibromyalgia – it is hard to unpick cause and effect. Some research is focusing on microvascular dysfunction, while other work has shown markers of inflammation months after infection. Dr Strain adds: ‘Personally, I’ve bought into the fact that this is residual virus hanging around in the gut or the nervous system. It fits with the trajectory.’

Professor Carolyn Chew-Graham, professor of general practice research at Keele University, also sees parallels with CFS/ME. ‘There is so much resonance between how people with long Covid talk about their condition and how people with chronic fatigue or fibromyalgia talk about theirs.’ 

Mental health
And there are similarities in patients’ expectations of treatment, she adds. While people with long Covid may have co-existing anxiety or depression, the problem is not primarily one of mental health: ‘I think patients feel if a psychological approach has been offered or a rehabilitation approach, that doesn’t meet their needs and is dismissing their concerns.’

GPs, therefore, are in a difficult position when patients want treatment: ‘We still don’t know what the aetiology of long Covid is, although we do know that it’s possibly vascular. But that isn’t something we can investigate and manage in general practice,’ says Professor Chew-Graham.

Some patients with sufficient resources have been travelling to Germany, having tests and coming back on anticoagulants, she adds. ‘For the GP this is difficult because this is all very new and nobody knows if it is the right way or wrong way. Also, you don’t want to dismiss your patient who’s just trying anything they can.’

Professor Chew-Graham adds while we may not yet understand exactly what is going on in long Covid, there are things that can be done to help patients once other potential causes have been ruled out (see box, below). ‘The management tends to be supportive, maybe psychological input and physio for dysfunctional breathing or a trial of different medications if you have postural orthostatic tachycardia (POTS) or gastrointestinal disturbances, but often we’re treating the symptoms,’ she says.

But long Covid might have one potentially positive impact. ‘It may be that because of long Covid, there may be more work to try to find the reason for CFS/ME, an underlying pathology.’

Tips for supporting patients with long Covid

  • Remember the key recommendation from NICE guidance1 – listen and believe the patient, be
  • Remember patients may experience a variety of symptoms, which may fluctuate and change
  • Do not automatically attribute symptoms to anxiety
  • Take a full history – long Covid is a multisystem disease
  • Consider impact of symptoms on work, family life
  • Physical examination is key – think about postural orthostatic tachycardia syndrome (POTS); also consider whether this could be pulmonary embolism 
  • Assess cognitive function
  • Identify and address comorbid anxiety or depression – if present
  • Important to investigate as per NICE guidance
  • Signpost to Your Covid Recovery 
  • Consider referral to post-Covid clinic if function is impaired and patient meets criteria for your local clinic
  • Consider how to support return to work, signpost to support for people with caring responsibilities
  • Take a shared decision-making approach with your patient
  • Code once a diagnosis is made of either:
    – Ongoing symptomatic Covid-19
    – Post-Covid-19 syndrome

Professor Carolyn Chew-Graham, Professor of General Practice Research at Keele University

1 NICE. Covid-19 rapid guideline: managing the longterm effects of COVID-19. London: NICE, 2022. Link

Where do we go from here? 
Under NHS England’s long Covid action plan, integrated care systems (ICSs) will decide how to support general practice in managing this growing problem. There is the possibility of setting up ‘one-stop shops’ so patients do not have to go back to the GP for multiple tests. 

These might be informed by various ongoing trials, which should start to provide answers over the next couple of years. So far, the National Institute for Health Research has invested more than £50m in long Covid studies to investigate aspects that include biological causes, diagnosis and treatments. There are now ‘20 or 30 papers that are very clearly showing the relationship between observable pathological processes and the symptoms of long Covid’, says Professor Brendan Delaney, a GP and chair in medical informatics and decision-making at Imperial College London.

‘Long Covid is a new long-term condition that’s affecting almost as many people as diabetes was 20 years ago and people are unlikely to get better in the short term,’ he points out. Yet compared with the speed at which research answered the question of what to do with acute Covid, funding and approval for studies has been slow. A philanthropic long Covid research initiative3 has just been announced in the US and is very welcome, he adds.

What GPs can do
In the meantime, GPs are having to get familiar with a new condition, he says. ‘There is a lot that GPs can do. You can look for POTS or other forms of dysautonomia and you can give advice about salt, fluids, compression and you can start to treat dysautonomia.’ Professor Delaney adds: ‘ß-blockers are probably the first step to doing that and I think most GPs would be happy to give a ß-blocker if there isn’t a contraindication as it’s a well- understood medication given for lots of things.’ 

He adds: ‘There are other medications some GPs feel need a specialist, like ivabradine, but a number of GPs are becoming specialists in these and starting to use them. For instance, normalising the heart rate response in POTS makes people feel a lot better.’

Professor Delaney has also found patients in his practice who come along with a cluster of symptoms that are like allergies. So new allergic responses to things – cough, wheeze, itchy eyes, skin rashes, gastrointestinal disturbances, bloating or reflux – may benefit from double-dose histamine blockade as a trial treatment. This doesn’t solve the underlying problems, he says, but the patients ‘cope with daily life a bit better’. 

Dr Strain is currently planning a trial of high-dose antivirals as a potential treatment. He had one patient with long Covid who because of a rare blood cancer was not clearing his infection and still testing positive three months later. In his case, a 10-day course of antivirals was a success. ‘You can’t start making conclusions based on one patient but it is enough to trigger a clinical trial,’ he says.

Dr Strain also doesn’t want people to dismiss the use of psychological therapy. He accepts that it is controversial but believes it should be part of a package alongside medical interventions to support patients who have been through a lot. After all, he adds: ‘Many of our patients are going through a mourning response, they have lost a chunk of their lives.’

Research on long Covid

In December 2020, the first NICE guidelines on managing the long-term effects of Covid-19 were published, and they were updated in November 2021. Developed jointly with the Scottish Intercollegiate Guidelines Network (SIGN) and the RCGP, the recommendations stratified long Covid into ongoing symptomatic Covid that lasted between four and 12 weeks and post-Covid-19 syndrome lasting longer than 12 weeks not explained by an alternative diagnosis. This definition was backed by the World Health Organization in a consensus statement published in October 2021.

NICE itself has noted that many of the earliest studies of long Covid prevalence and symptoms were of low or very low quality and had the potential for bias. More recently, a UK analysis of various data sources4 and patient surveys found a prevalence of symptoms after Covid infection lasting longer than 12 weeks of between 8% and 17%. Increasing age, being female, white, with poor pre-pandemic general and mental health, overweight/obesity, and asthma were found to be linked to ongoing symptoms. 

There is a consensus view of the potential relevance of postural orthostatic tachycardia syndrome (POTS) in the NICE guidance on long Covid.

A Belgian study5 reviewing the evidence of causes noted that long Covid is a multisystem disease not linked to initial disease severity. While the evidence remains limited, immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence and coagulation activation are the main underlying pathophysiological mechanisms so far identified.

US researchers have recently reported6 some significant immunological differences among long Covid patients compared with matched controls, including in circulating immune cells, and increased antibody and humoral responses. In their study, fatigue and brain fog were among the most common symptoms but they also found POTS in 37% of patients.


  1. ONS. Prevalence of ongoing symptoms following coronavirus (Covid-19) infection in the UK: 1 September 2022. Link 
  2. Vaccination may lessen existing long Covid symptoms. Pulse, 19 May 2022. Link
  3. Long Covid research initiative. Link
  4. Thompson E J et al. Long Covid burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat Commun 2022;13:3528. Link
  5. Castanares-Zapatero D et al. Pathophysiology and mechanism of long Covid. Ann Med 2022;54(1):1473-1487. Link
  6. Klein J et al. Distinguising features of Long Covid identified through immune profiling. medRixv preprint 2022 Aug 10. Link


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Please note, only GPs are permitted to add comments to articles

Patrufini Duffy 30 September, 2022 8:42 pm

It does knock you out.
But, so does EBV and having your life ripped apart by a hurricane or drought. What is certainly unexplainable is a certain “lot”, you know – the non-city dwellers, who have come for a bit of a charard, who have banked their fair share of off sick, but still manage the weekend out, HiiT classes and Galstonbury with being a digital nomad through summer in the South of France whilst booking their upcoming ski trip. But, feel disabled. Totally tired. And anxious. Totally unexplainable cohort.

Reply moderated
Dylan Summers 1 October, 2022 9:19 am

Yes it would be great if a specific mechanism for long covid is found and this is discovered to relate to CFS/ME.

However I don’t see that we have good grounds to hope that CFS/ME has “a” cause or even a small number of causes.

After all, the individual symptoms involved in CFS/ME can each have innumerable different causes (EG fatigue can result from pathology of almost any type in almost any body system, before we even think of psychosocial factors). So how can we reasonably assume that people who meet CFS/ME diagnostic criteria have a shared underlying pathology?

What if there are actually, say, 6,347 separate causes of CFS/ME? This might go some way to explaining the lack of success so far in identifying causal processes.

David Mummery 1 October, 2022 12:19 pm

It’s the immune system that’s the culprit :a huge hyper inflammatory state with cytokines/IL-6 etc causing new CNS and brain neural signatures, and dysregulation of the autonomic nervous system and HPA axis, at least with the CFS and fibromyalgia type presentations

Dave Haddock 2 October, 2022 6:21 pm

Looking for a biological mechanism to explain a psychosocial phenomenon has little likelihood of success.

David Church 4 October, 2022 7:28 am

I hope Dave Haddockis not trying to suggest that covid/long covid is entirely psychosocial!
There is significant evidence of ongoing inflammation, clotting disorder, increased CVS disease and Diabetes, reduced immunity to other viruses/bacteria, dementia and breathlessness, in many of the patients. Certainly not all, but there is no way to exclude the small number of patients exploiting the sick leave for something they don;t actually believe in anyway – but they are few in comparison to genuinely disabled, often young, people.
And don’t forget the sudden outbreak of severe hepatitis in children.
Anyway we DO know how to manage PTSD from ITU admission : prevent it being needed by stopping transmission of infection!

David Jarvis 5 October, 2022 1:17 pm

Really interesting summation and no further forward. I still don’t understand why medically we can’t just talk abot chronic fatigue syndrome. Can we not just ditch the pseudo medically sounding bollocksy term that is ME. It is a syndrome until the pathophysiolgy is quantified and understood. Long covid does seem to push the post viral failure to recover model. Obviously this can be the same symptoms despite different viral triggers.

Matthew Kiln 19 October, 2023 12:25 pm

Covid 19 was just another virus when it comes down to it, and mild in most cases. Yet this one has gobbled up so much health service funding in most countries around the world through mystique and poor management. With most officials having to just do and say what other officials had been advised to do and say in other first world countries. At least having Long Covid clinics now, it can be perceived that for this media exacerbated condition, the political and medical establishment locally is getting it’s act together.