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Here, we consider five broad questions –

• What is Long Covid?
• Is Long Covid the same as Chronic Fatigue Syndrome?
• How is Long Covid caused?
• Why do some people develop Long Covid, while most recover – and why does Long Covid vary so much between people?
• Is there an effective treatment for Long Covid?

This article builds on the 2024 blog post ‘Is there hope for people with Long Covid?’

What is Long Covid?

Long Covid is the name given to a variety of symptoms and signs that persist for weeks, months or even years following acute Covid or, less often, vaccination against the Covid virus, SARS-CoV-2. The condition, which affects about 10% of people who contract Covid, can be severely debilitating, and both its severity and its course are unpredictable. The symptoms vary widely between people: common problems include chronic fatigue, which is often worsened by exercise, headache, and cognitive difficulties often referred to as ‘brain fog.’

The extraordinary heterogeneity of problems in Long Covid raises the questions – which are still debated – how it should be defined, and whether it should be regarded as a single entity or as a collection of different conditions. But since the initial trigger for all manifestations of Long Covid is infection with the virus SARS-CoV-2 (or, more rarely, a vaccine that contains the spike protein of the virus) we should perhaps start with the idea that there is a common underlying mechanism that starts the disease and perhaps also prolongs it. Possible factors that trigger or contribute to Long Covid, and how the wide range of symptoms can result, are discussed below.

One working definition of Long Covid (footnote 1), by a committee of the national academies in the USA (footnote 2), demonstrates the difficulty in formulating a precise diagnosis. The authors acknowledged that this definition is – perhaps inescapably – over-inclusive, and so may lead to false-positive diagnoses.

In this article, the familiar term ‘Covid’ is used to denote the infection formally called COVID-19, and ‘Long Covid’ for the syndrome also known by other terms including Post-Acute Sequelae of Covid (PASC) or Post-Acute Covid Syndrome (PACS).

Is Long Covid the same as Chronic Fatigue Syndrome?

Chronic Fatigue Syndrome (CFS), which is sometimes misleadingly called myalgic encephalomyelitis (ME), can occur in otherwise healthy people following certain infections. Viruses associated with CFS include flu and the glandular fever virus, and ‘post-viral fatigue’ is another common name for the syndrome (footnote 3). Bacteria associated with CFS include the organism that causes Lyme Disease.

CFS shares many features with Long Covid, in particular severe tiredness often induced or worsened by physical or mental exertion, muscle pains, and sometimes neurological problems such as Postural Orthostatic Tachycardia Syndrome or POTS – dizziness or fainting caused by standing up, with a racing pulse (footnote 4). POTS results from a malfunction of the autonomic nervous system, the system that controls some important ‘automatic’ body functions such as blood pressure and heart rate. The similarities between CFS and Long Covid encourage the view that advances in understanding or treating either condition might be valuable in managing both.

Fortunately, fewer people now wrongly dismiss Long Covid or CFS as a psychological or psychosomatic condition. But it is equally important to recognize the devastating impact that Long Covid can have on mental health: it is not surprising how the symptoms such as chronic fatigue, pain and disability can lead to depression.

How is Long Covid caused?

Urgent research is continuing in centres round the world in an attempt to understand how Long Covid is caused and so how it can be treated. And despite the difficulties in defining, diagnosing and investigating the condition, some potentially important findings have been made which may lead to new types of treatment.

While the virus SARS-CoV-2 is the trigger, it seems clear that a number of factors make Long Covid more likely, or contribute to the disease:

• no previous vaccination against SARS-CoV-2
• infection with an early strain of SARS-CoV-2 (eg, the delta variant)
• persistence of the virus or its fragments in the tissues
• immune suppression or persistent abnormalities in the immune system
• autoimmunity to tissues in the nervous system
• other chronic conditions, especially affecting the heart, kidneys or lungs
• reactivated herpesviruses (eg, Epstein-Barr Virus, Varicella Zoster Virus)
• age

Although Covid vaccines can occasionally cause a protracted illness, Long Covid is significantly more frequent in unvaccinated people (footnote 5). Severe symptoms are often associated with reactivation of viruses in the herpesvirus family (footnote 6), including EBV, the virus VZV (which causes chickenpox and shingles) and Human Herpesvirus type 6 (HHV-6). These ubiquitous viruses persist indefinitely in healthy people, but they are normally suppressed by the immune system after the initial infection. But it is still uncertain whether these reactivated viruses – or possibly the immune response to them – are a cause of the symptoms or a side-effect.

Malfunction of the cells lining blood vessels, resulting directly or indirectly from infection of the cells with SARS-CoV-2, may contribute to organ damage, and since all organs need a blood supply, such damage may help to explain the range of organs that can be affected in Long Covid. Earlier in the pandemic it was suggested that widespread small blood clots were a cause of tissue damage, but this is now thought less likely.

There are many indications of persistent abnormalities in the immune system, including abnormal numbers of lymphocytes and high concentrations of some inflammatory proteins that are produced by cells in the immune system. But again, cause and effect can be hard to distinguish.

A recent discovery of particular potential importance is that some of the most common and serious symptoms of Long Covid appear to be caused by antibodies that react with normal tissues in the nervous system (footnote 7), known as ‘autoantibodies’. These self-reactive antibodies have been known for some time to appear in acute Covid, and they often persist in high concentrations in Long Covid. As in the case of reactivated viruses, the question arose whether the autoantibodies are a cause or a side-effect of the disease, but the investigators found that injection of the autoantibodies into mice could reproduce some of the neurological signs that are seen in Long Covid, strongly indicating that they are an important part of the cause.

But the question remains: how does one virus cause these multifarious problems? It is important to emphasize that this is not yet fully understood. However, if, using Occam’s Razor, we suppose that there is a common factor at the start of the chains of events that result in the persistent immune abnormalities, inflammation, herpesvirus reactivation and tissue damage, then a likely candidate is the virus itself.

There is evidence that SARS-CoV-2 can persist in different tissues (footnote 8), perhaps indefinitely in some people, either as the whole virus or, more likely, as the RNA genome or individual proteins of the virus. The RNA or the proteins – or both – could cause a chronic inflammation and immune system activation, which in turn could cause the tissue damage and also the virus reactivation and autoantibody production which themselves may add to the damage and worsen the condition.

Why do some people develop Long Covid, while most recover – and why does Long Covid vary so much between people?

Covid vaccination roughly halves the risk of developing Long Covid (footnote 9). The strain of the virus also affects the likelihood of developing Long Covid (footnote 10) – the omicron and later strains caused Long Covid about 30% less often than the delta and earlier strains – but the strain does not seem to influence the type of symptoms. There are several well understood reasons why one virus such as SARS-CoV-2 can cause such different infections in different people. First, Covid is often more severe and more likely to persist if the person has certain other conditions: immune suppression, in a transplant recipient or a person treated for cancer or someone with untreated HIV-1 infection, is especially likely to worsen the outlook. And those with cardiovascular disease, kidney or lung disease are also predisposed to worse outcomes in Covid and Long Covid.

But the most important difference between otherwise healthy people that determines the outcome of infection with a particular pathogen is in their genes. The efficiency with which our immune system deals with viruses (and other infections, toxins and allergens) varies widely between people. The main reason for this variation is that the immune response to a particular substance depends strongly on certain genes: in fact, the genes that vary most between individuals. The main genes concerned – the HLA system – are the same ones that determine who can accept an organ transplant from a given donor. These same genes directly determine how our immune system responds to a particular virus. I have a different set of variant HLA genes from you, so for example you might recover quickly from flu but suffer from shingles, while I do not get shingles but spend a week in bed with flu.

Lastly, there are significant differences in susceptibility to Covid and Long Covid due to age and sex: acute Covid is less often severe in the young and in women, but Long Covid is commoner in women than in men.

Each person has a unique combination of genes and other conditions which, together with their age, sex and the strain of the virus, result in the diverse outcomes of infection with SARS-CoV-2 – the duration and severity of the disease and the widely varying symptoms.

Is there an effective treatment for Long Covid?

Long Covid, like Chronic Fatigue Syndrome, poses serious challenges in trying to find an effective treatment. But as the understanding of Long Covid improves, some leads to possible new forms of therapy are emerging.

The National Institute for Clinical Excellence (NICE) has concluded that the regimes of graded exercise that were previously tested don’t give a significant benefit in most people with Long Covid, and so these regimes are no longer recommended.

Many studies of dietary supplements have been carried out (footnotes 11-13) and, while not all studies show a significant benefit in Long Covid, some clinical trials have shown that supplementation with certain vitamins (vitamin D), amino acids (L-arginine or taurine) or a combination or ‘probiotic’ bacteria may be able to reduce some symptoms. The benefits are often small but measurable, but could be important in someone with a specific deficiency, for example of a vitamin.

Because the immune system plays a part in causing or contributing to Long Covid, therapies directed against specific parts of the system are being considered. One that shows some promise, albeit at an early stage of testing, is intranasal administration of an antibody that attacks T lymphocytes (footnote 14). And the recent discovery of the part played by autoantibodies against nervous system tissues (6) raises the question whether depleting the antibody-producing B lymphocytes or the antibodies themselves might help, although such treatments would carry risks of their own.

The unpredictability of the course of Long Covid can have its upside too: while many people with the condition make a slow recovery, some return to normal quickly, even over the space of one day, after months of illness.