Shifting the dial on Long Covid

You're lying in your room – the same routine as the last few months. It's 2pm and the curtains are drawn, as you ask yourself whether you have the strength to roll over. Your phone is like a brick in your hand and, knowing a glance at the screen will feel garbled and send you into a hellish migraine, you weakly debate picking it up to text a friend for moral support. They'd be there in person if they could – but you can't tolerate the presence of another person. It's sensory overload. It hurts. You didn't think you could get this sick. You can't risk another bout of Covid.

The above isn't just a creative writing exercise.

It's drawn from my own experience with Long Covid over the last year and a half, and that of a close friend who has just begun their journey with the condition after a lifetime of good health. I know that for some readers, wading into biological research can feel overwhelming, dry, or even uncomfortable. But I want you to keep that vignette in your mind as you read this. Behind the biology, those suffering from Long Covid need us to engage with current research on what's happening to them, and their bodies so that we can extend our efforts to help.

What exactly is Long Covid?

Long Covid (hereafter LC) is a multi-systemic post-acute infection syndrome with a wide range of often debilitating and distressing symptoms. The World Health Organization estimates its prevalence to be between 10 and 20 per cent of those infected by Covid worldwide, and research suggests that each Covid infection substantially increases your risk of developing it. Contrary to popular belief, it can be caused by even mild or asymptomatic Covid infections, even in those who have been vaccinated, and can affect anyone, of any age. 

Most readers will likely recognise 'fatigue' as a defining feature of the condition; this is, unfortunately, the tip of the iceberg. LC has been associated with over 200 symptoms to date, though some are more common than others. Symptoms such as post-exertional malaise (PEM, a flare of symptoms which occurs after minimal, previously tolerated mental or physical activity), dysautonomia (dysfunction of the autonomic nervous system), and cognitive dysfunction (often referred to as 'brain fog') are typical challenges for someone with LC. The list continues, extending to symptoms in every organ system. 

Not everyone with LC will present with the same symptoms, and severity can vary widely, often following a relapsing and remitting pattern. Patients typically show no abnormalities in routine blood tests, even when clearly unwell; a presentation which, while a wider understanding of post-acute infectious syndromes is sparse, often leads medical professionals to conclude the symptoms are 'all in your head'.

This is a dynamic that is familiar to those with Myalgic Encephalomyelitis. ME is a condition that appears to share many physical traits with LC, to the extent that they're often spoken about in the same breath, even in research settings. (And, as a lot of ME research informs LC research, we'll touch on both below.) Much ink has been spilled about the experiences of negative stereotyping and marginalisation in this population, and the need to make improvements to avoid exposing people with LC to the same psychological distress (e.g. see psychologist Joanne Hunt and colleagues in the Journal of Health Psychology, on 'Long Covid at the crossroads').

Thankfully, as the result of patient advocacy, an unfortunate spike in post-acute infectious syndromes following the advent of Covid, and the determination of researchers across the spectrum, there is now a wealth of peer reviewed work evidencing physical changes, damaged tissues, and pathological processes. Prominent scientists in the field have found evidence for several core hypotheses as to what drives the condition.

Immunologist Akiko Iwasaki, for example, cites four main ideas: viral persistence within the body, autoimmunity (in which our immune systems attack our own cells), reactivation of dormant viruses (such as herpes family members), and changes in inflammation status.

If we as psychologists are to progress in helping those with LC, and other post-acute infectious syndromes like ME, we need to understand where psychological topics fit into this wider biomedical picture. With that in mind, let's take a look at a selection of recent findings relating to our discipline's favourite organ: the brain.

Cognitive dysfunction

Even outside of flare-ups, cognitive dysfunction can be a persistent challenge for those with LC. Even in less severe cases of the condition, people can find their functioning in day-to-day life can be significantly impacted. Shopping for food might be completely overwhelming to the senses, for example, and simple conversations may feel impossible to conduct, or cause a flare of symptoms. In the current absence of treatments, those with LC often employ pacing strategies, to manage these symptoms.

The emotional fallout of this experience is difficult to consider. Research by Mario Samper-Pardo and colleagues details the anguish, suicidal ideation, anxiety, and fear of relapse shared by people with LC. As psychologist Louise Kenward shared with the British Psychological Society, 'there is a great deal that psychology and psychological therapies can offer people with Long Covid,' but this must be grounded in patients' realities and an understanding of the lived experiences and mechanics of the condition.

Multiple studies have evidenced cognitive dysfunction in those with LC. For example, Sijia Zhao (Department of Experimental Psychology, University of Oxford) and colleagues, who published their observations early last year in The Lancet, compared 270 UK- and Germany-based LC patients with those whose Covid had not progressed into LC on a Simple Reaction Time task and a Number Vigilance Test. 

They observed that those with LC responded to the Simple Reaction Time task around three standard deviations slower than controls; over 53 per cent of LC participants were slower than two standard deviations, suggesting that slowing to this extent is common. These findings were highly correlated with measures of sustained attention on the Number Vigilance Test and were not accounted for by comorbidities such as depression, fatigue, anxiety, PTSD, or sleep disturbance.

As the team states, these findings 'robustly demonstrate[s] pronounced cognitive slowing' in those with the condition. Work by James Baranuik and colleagues came to a similar conclusion, finding that those with LC and ME performed significantly worse than healthy controls on a simple Stroop test. Further efforts by Victor Serrano Del Pueblo and team, detailed in Brain, observed that 48 per cent of their LC sample had episodic memory deficits, as well as areas of cortical thinning and white matter atypicalities compared to recovered controls.

More investigation will be needed to fully appreciate the extent of these cognitive challenges. Commonly employed lab- or screen-based research designs exclude those with severe cases and typically don't allow for the capture of data during PEM states or symptom flares. To understand the full picture of LC and similar conditions, we need to try harder to find and recruit those with severe symptoms. In particular, I'd like to point to parallel work in ME led by clinical neuropsychologist Gudrun Lange, which was designed to better address these issues, and may serve as a useful template.

So, what's to blame?

With University College London analyses placing the economic cost of LC to the UK at £20 billion per year, zeroing in on the cause and finding an effective treatment is not only a just decision, but very economically valuable. As such, there is a host of work underway to better understand what leads to this cognitive dysfunction, and symptoms more broadly.

One topic of great focus is neuroinflammation. Recent efforts by Jae Kyu Ryu and colleagues have highlighted the role of microglia – cells throughout the brain which (amongst other duties) guard against pathogens within neural tissue – and their reaction to fibrin, a protein involved in the formation of blood clots (and, in the case of LC, microclots). In a typical, healthy brain, microglia tend to be in a resting state. When they sense an immune challenge, they enter an active state, spilling proinflammatory cytokines to try to protect neural tissue from the insult.

However, when a significant immune challenge arises, such as infection of the central nervous system, continuous exposure to an immune insult, or repeated exposures to insults in rapid succession, sometimes the microglia don't return to their resting state. Instead, they stay active and ready to fight all the time. This constant flow of pro-inflammatory cytokines can actually be damaging to tissue and result in fatigue, pain, and other symptoms consistent with LC. (Watch psychologist Jarred Younger's webinar on this in the context of ME.)

Several researchers have also observed a lack of oxygenation in the brains of some people with LC. One such study by Damilola D Adingupu and team found that 26 per cent of those post-symptomatic Covid infections and 12 per cent who were asymptomatic showed reduced cerebrovascular oxygenation. The altered brain perfusion and oxygen levels in those with LC have also been linked to fatigue and cognitive symptoms.

But there are many more brain-related ideas at play. Over in Australia, Leighton Bernden and team recently uncovered evidence of altered functional connectivity in those with LC during concentration and attention tasks. Namely, connectivity between the brainstem and the midbrain, and linking the brainstem with the default mode network, was higher in those with LC than in healthy controls. (Interestingly, connections between these areas were weaker in those with ME.) These connections are involved in regulating arousal, sleep-wake cycles, and autonomic function; dysfunction here may go some way to explaining the symptomology of the condition.

The role of the brainstem is also highlighted by those investigating the role of cranio-cervical instability and similar spinal conditions, which can also manifest in those with inflammatory conditions such as rheumatoid arthritis, systemic lupus, Ehlers-Danlos syndrome, and more. Here, lax connective tissue near the base of the skull can create pressure around the brain stem and cranial nerves. 

This pressure can deform these areas, impairing their ability to function typically, and limiting the flow of blood and cerebrospinal fluid to the brain. As a result, patients may experience symptoms such as muscle weakness, impaired coordination, visual disturbances, fatigue, and cognitive impairment. Research by Björn Bragée and their team has revealed the relevance of such spinal conditions in ME; however, this is a lesser-studied pathology, and further research is needed to understand whether it is also a relevant component of LC.

Of course, research efforts extend well beyond the nervous system. Interested readers can seek a grounding in current explorations in post-acute infectious research through the 'further reading' on the previous page.

Keeping up is hard… and necessary

A huge number of papers on LC have been published since 2020. Keeping up with developments can be very difficult, and in turn, lead to the perpetuation of myths and stigma. This likely contributes to generally poor provisions for patients, and gaps in care and research. Thankfully, as Michael Peluso and Steven Deeks point out in their recent review paper in Cell, this does seem to be changing for the better.

If you take anything away from this whistlestop tour, I hope that it's this: LC and other post-acute infectious syndromes are not the total mystery they're often sold as. With a wider understanding of research efforts and continued research partnerships with those who live with these conditions, our generation can be the one that shifts the dial on outcomes for this clinical group.

Further reading

Long Covid: A clinical update, from Professor Trisha Greenhalgh and colleagues

NICE guidelines for LC

NIH ME/CFS Research Roadmap webinar series

Researching Covid to Enhance Recovery