Long COVID – a dystopian game of pinball

Prof Trish Greenhalgh explains the findings of her recent comprehensive Lancet review of Long Covid

If you’ve ever had COVID-19 and got back to normal within a week or two, you’re lucky. Some people take months to recover (they have ‘Post-COVID-19 syndrome’, defined as symptoms lasting beyond 3 months) and an unfortunate few remain unwell for years (they have ‘Persistent Long COVID’, defined as symptoms remaining beyond 2 years).

These people experience (among other symptoms) profound fatigue, cognitive blunting (‘brain fog’), breathlessness, aching in the chest, body pains, palpitations, flare-ups after exercise, disturbance of gut function (e.g. trouble swallowing), altered voice, dizziness, loss of smell, allergies, and mental health conditions (such as anxiety or depression). They are often unable to do their job, either at all or at their pre-COVID level. Olympic athletes affected by Long COVID include sailor Matt Wearn, rowers Oonagh Cousins and Marie-Sophie Zeidler, and tennis player Tanysha Dissanayake.

Since many people bounce back quickly after COVID-19, and since Long COVID lacks a biomarker (a blood test or other objective way of detecting the condition and monitoring its progress), there is a temptation to assume that those who remain unwell have simply taken to their beds and given up. All they need, goes this (flawed) argument, is a bit more willpower and some targets to work towards. Boris Johnson captured this attitude when, as Prime Minister of UK, he wrote “BOLLOCKS” across the draft of a policy report on Long COVID in October 2020. 

If Mr Johnson had shown any interest in the actual science, he might have noticed evidence that Long COVID is a real condition whose complex biological basis is beginning to be understood.  The sequence of events that makes COVID-19 into a protracted (and quite possibly, lifelong) illness in some but not all people is a bit like a dystopian game of pinball. An unlucky ball hits a series of key buffers, buzzers and bells, triggering a cascade of further events. Broadly speaking, and acknowledging that there are still many unanswered questions, that sequence unfolds as follows:

First, a combination of three things (‘primary pathological mechanisms’) start the COVID-19 ball on its trajectory. SARS-CoV-2—or, perhaps, some of its components—find a way to hang around in the body long-term (perhaps they hide somewhere). The immune system, in trying to put up a fight, over-reacts and then gets tired (‘immune exhaustion’). And, given the excess of various immune trigger chemicals circulating in the blood, the lining of tiny blood vessels (capillaries) gets inflamed, increasing the tendency for the blood to clot in those vessels.

Second, these changes flip off additional cascades of biochemical messengers (‘supplementary pathological mechanisms’), which, in health, contribute to keeping the body in balance. Different pathways fire in different people, causing (for example) release of the neurotransmitter serotonin in the brain, neurones sending signals when they shouldn’t, antibodies attacking one’s own cells, mitochondria (the energy powerhouses of cells) losing their oomph, proteins that come out wonky because they’re not folded right, deposition of some of those proteins in the muscles and other tissues, and awakening of other dormant viruses (notably Epstein-Barr, which causes glandular fever). In addition, the balance between ‘friendly’ and ‘unfriendly’ bacteria in the gut can change, with the latter getting the upper hand.    

Third, these microscopic changes in genes, molecules, proteins, cells and micro-organisms produce various kinds of organ damage. The heart muscle, or its protective cover, may become inflamed (myocarditis and pericarditis respectively). The delicate filtering system of the kidney can clog up, leading to partial or complete kidney failure. Clots can occur in the blood vessels supplying the lungs (pulmonary embolus). The nerves controlling involuntary functions such as heart rate and blood pressure can malfunction (dysautonomia). The body becomes more susceptible to infections, and sometimes one infection becomes overwhelming (sepsis).  And so on.

Finally, these organ-level changes lead to the well-known symptoms of Long COVID described in the second paragraph above. Different people will experience different combinations of symptoms just as the various lights, buzzers and bells on a pinball machine react differently depending on the precise trajectory and force of the initial ball. But the process is always a whole-body phenomenon which begins with specific virological and immunological triggers and then cascades to affect multiple organs.

You didn’t get that when you had COVID-19? Lucky you. The ball of your initial infection missed a few vital targets. But that doesn’t mean you’re immune from Long COVID for life. Your next infection could light up the whole machine.

Currently, treatment of Long COVID follows what we call ‘rehabilitation therapy’, oriented to controlling patients’ specific symptoms (e.g. breathing exercises for breathlessness) and teaching them techniques (‘pacing’) to manage within their own energy limits and avoid sinking into depression while (hopefully) their body slowly recovers.

Rehabilitation therapy can work well for some Long COVID patients but those with persistent Long COVID have, by definition, failed to respond to such measures. Despite (and sometimes because of) determined efforts to get back to their previous level of performance, they remain physically exhausted, mentally shattered and in some cases barely able to perform the basic functions of feeding, washing and clothing themselves.

What we need, in addition to a focus on rehabilitation therapy, is a pinball wizard for Long COVID—ways of bringing the lights, buzzers and bells of this multi-system disease under control by attending to the underlying biological mechanisms of disease. If there is viral persistence, for example, anti-viral drugs given in a key time window should help. If inflammation is a mechanism, anti-inflammatory drugs could dampen it down. If there are micro-clots, anticoagulants may have a role (though their benefits need to be balanced against side effects). If the immune system is over-reacting in particular ways, immunosuppressants should be selected to target key immune pathways. If unfriendly bacteria are overwhelming the gut, perhaps we should recommend a balanced square diet or give a top-up of some friendly bacteria in a ‘poo transplant’. Vaccines against COVID-19 and Epstein-Barr might send those viruses back to sleep.   

All these suggested treatments for Long COVID are currently being tested; none is yet proven. Watch this space for the results of ongoing trials.

Meanwhile, three things can help prevent you from joining the miserable 1.9 million people in UK who are currently suffering from Long COVID:

1.      Get vaccinated against COVID-19, and make sure your boosters are up to date.

2.      Try not to catch COVID-19. Avoid crowded indoor spaces (wear a well-fitting mask if you can’t avoid them), especially when local rates of COVID-19 are high.

3.      If you catch COVID-19, rest up until you feel better and take anti-virals if you’re eligible.

If you’re interested in reading about Long COVID in more depth, here’s our latest state of the science article. The pinball sequence is summarised in Figure 1, reproduced below.