Post-viral syndrome is a wide range of complex conditions involving physical, cognitive, emotional and neurological difficulties that vary in severity over time.

These conditions frequently lead to a sense of tiredness and weakness, pain, difficulty concentrating and headaches that linger after the viral infection has cleared. Symptoms may continue for weeks, months or longer.

While post-viral syndrome may appear similar to other health issues, it is important to exclude other conditions to have a clear understanding of the problem. Post-viral syndrome is triggered by a reaction to a virus which does not resolve in the normal way but continues in the form of sustained inflammation.

Various microbial and viral infections are possible trigger factors for post-viral syndrome, including Epstein-Barr virus, cytomegalovirus, human herpesvirus, enteroviruses, Lyme disease and more.

For patients, a sense of fatigue persists regardless of rest or additional sleep. Painkillers are often prescribed for aches and pains. Patients are advised to conserve energy, practice stress management techniques and eat a healthy diet. The jury is currently out regarding the benefits of exercise, with many individuals reporting a worsening of symptoms.

Many viral infections can trigger post-viral syndrome, with individuals who have weakened immune systems appearing to be at heightened risk. It remains unclear why the effects of a virus can linger in the body. Some theories suggest that the virus 'overloads' the immune system, preventing healthy immune system resolution for weeks, months or years. Continued inflammation, mediated by proinflammatory cytokines, could be at play.

The conditions myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) both cause symptoms similar to those of post-viral syndrome, and there is uncertainty over possible links to initiating viruses. Research exploring this area is underway at many centres around the world.

ME and CFS are sometimes considered interchangeable names for the same debilitating illness characterised by profound fatigue and impairment that lasts for at least six months. Usually the patient also experiences cognitive issues, muscle pain, gastrointestinal problems and a flu-like feeling.

The World Health Organization classifies ‘Postviral fatigue syndrome’ - incorporating both ME/CFS and chronic fatigue syndrome - as a disorder of the nervous system. There are no standardized biological markers or tests so diagnosis is based on exclusion of other underlying physiological causes. The efficacy of therapies to manage symptoms varies between patients.

In a 2021 article in the Journal of Clinical Medicine, researchers from Latvia explain that due to its unclear origins, treatment of post-viral ME/CFS is complicated, but one of the initial problems is the insufficient diagnostic process.

They report that, "ME/CFS creates a significant shadow burden on society, even considering only the direct medical costs of undiagnosed patients - the number of whom in Latvia is probably at least five times higher than the number of diagnosed patients. A similar situation can be observed in other countries."

"Preventive measures are becoming significantly more important," they write, adding, "an integrated diagnostic approach and appropriate treatment could reduce this burden in the future."

Dr Charles Shepherd, medical adviser to the UK's ME Association and former sufferer, agrees that the underlying cause of ME/CFS is "subject to much uncertainty and medical debate".

In a 2015 summary document, he writes, "This is one of the reasons why doctors have differing views on how the condition should be managed. At one end of the spectrum of medical opinion are those - myself included - who believe that ME/CFS is caused by a physical disease process that results in a number of symptoms affecting different parts of the body.

"This has now been shown to involve the brain and central nervous system, muscle, immune and endocrine systems. Mental health symptoms, where they occur, are a consequence and not a cause of ME/CFS."

He points out that research into causation of ME/CFS "has to carry a serious note of caution - because the research has been carried out on a very diverse group of patients who have differing clinical presentations and almost certainly have different disease pathways".

But despite all the problems relating to definition and patient selection for research, he believes there is considerable agreement over a three-stage process in ME/CFS, involving factors that predispose, precipitate and perpetuate the various symptoms.

The predisposing factor may be a genetic predisposition, which then precipitates ME/CFS when a trigger event takes place, such as an infection.

"Most people with this illness pre-date the onset of their symptoms to an infection - normally viral but sometimes bacterial - from which they ‘fail to recover’ and continue to have ‘flu-like symptoms’, along with the very characteristic muscle and brain symptoms that are associated with ME/CFS," explains Dr Shepherd.

In terms of perpetuating factors, the situation becomes far more uncertain. It may be that ME/CFS is perpetuated by a combination of changes to the way in which the brain, muscle, immune and endocrine systems respond to the triggering viral infection, or other immune system stressor.

Brain and central nervous system abnormalities in post-viral syndrome have been investigated using a variety of techniques. There appears to be consistent evidence of abnormalities in the autonomic nervous system which may help explain symptoms such as sudden low blood pressure on standing and an increase in the pulse on standing, as well as the cold hands and feet experienced by some people with ME/CFS, and irritable bowel and bladder problems.

Abnormalities in blood flow to parts of the brain may also explain the cognitive symptoms such as problems with short-term memory and concentration, as well as poor temperature control and pain.

But what mechanisms lie behind this extended immune response to infection? One commonality among the viruses linked to ME/CFS is the ability to bypass and evade immune cells, and thereby alter immune cell functions.

The establishment of a persistent infection is influenced by immunosuppression which may cause and maintain chronic inflammation. This chronic immune system activation is linked to changes in regulation of the immune-system chemicals cytokines, which can set the stage for post viral symptoms.

Cytokines are produced in response to any type of infection and result in a range of symptoms that include loss of appetite, wanting to sleep more than normal, and aches and pains in muscles and joints.

Hence a build up of inflammatory cytokines in the central nervous system may lead to post-viral syndrome, with one possible pathway being the movement of cytokines across the blood brain barrier. Support for this idea comes from research in which patients given interferon alpha (a type of cytokine) as a treatment for hepatitis C develop an ME/CFS-like illness as a side-effect.

Some evidence suggests that chronic pain may be caused by inflammatory signals that are spread by glial cells throughout the nervous system, activated by cytokines.

In addition, ME/CFS is associated with changes in the activity of mitochondria in cells, the energy-producing organelles. This appears to allow enhanced viral replication together with reduced mitochondrial DNA replication and increased oxidative damage.

Recently the autoimmune elements of post-viral syndrome have become a subject of intense research. Viruses contribute to autoimmune diseases in a variety of ways. An abnormal immune profile after acute infection may allow for continuous reactivation and incomplete clearance of pathogens, resulting in tissue damage and an overactive yet ineffective immune response leading to inflammation and autoimmune changes.

So both the viral activity itself and the immune response against the viral infection may contribute to produce symptoms of the condition, although immune cell activity has been found to vary across studies of ME/CFS and even within studies.

In 2018, Dr Bhupesh Prusty of the University of Wurzburg, Germany, and colleagues report, "At least in a subset of patients, the mitochondrial dysfunction and elements of autoimmunity that characterise ME/CFS may be linked to viral pathogenesis.

"Lack of extensive analysis of molecular mechanisms linking viral pathogens to ME/CFS restricts our understanding of this disease. Future studies need to focus on this aspect of ME/CFS research."

They state that currently available data on the role of chronic viral infection with ME/CFS is still controversial, but shows "potential viral involvement for at least a subgroup of ME/CFS patients".

They urge clinicians to "assess the presence and markers of viral activity at the initial stage of the disease to evaluate possible etiological factors", and call for "longitudinal and standardised studies determining ME/CFS course and therapy effectiveness with follow-up measurements".

This research will allow prognosis of the disease and help develop a specific definition for diagnosis and treatment plans.

All researchers in this field agree that the only way that firm conclusions about causation can be reached is through well-designed studies using carefully selected patients.

Nevertheless, as Dr Charles Shepherd of the ME Association points out, "Important clues are emerging and new types of drug treatment are being assessed on the basis of these abnormalities. So there is now real hope that effective forms of treatment will eventually emerge."

References and Resources

1. Medical News Today: What to know about post-viral syndrome, https://www.medicalnewstoday.com/articles/326619
2. Healthline: Understanding Post-Viral Fatigue, https://www.healthline.com/health/post-viral-fatigue
3. Patient.info: What you need to know about post-viral fatigue, https://patient.info/news-and-features/what-you-need-to-know-about-post-viral-fatigue
4. Hickie, I. et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ, 16 September 2006 doi: 10.1136/bmj.38933.585764.AE, https://www.bmj.com/content/333/7568/575.long
5. Stormorken, E. et al. Factors impacting the illness trajectory of post-infectious fatigue syndrome: a qualitative study of adults’ experiences. BMC Public Health, 13 December 2017 doi: 10.1186/s12889-017-4968-2, https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-017-4968-2
6. Araja, D. et al. Shadow Burden of Undiagnosed Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) on Society: Retrospective and Prospective. Journal of Clinical Medicine, 6 July 2021 doi: 10.3390/jcm10143017, https://www.mdpi.com/2077-0383/10/14/3017/htm
7. Dr Charles Shepherd, Medical Advisor to the ME Association. What do we know about the causes of ME/CFS?, https://meassociation.org.uk/wp-content/uploads/MEA-What-do-we-know-about-the-causes-of-MECFS-Shepherd-2015.pdf
8. VanElzakker, M. B. et al. Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods. Frontiers in Neurology, 10 January 2019 doi: 10.3389/fneur.2018.01033, https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full
9. Rasa, S. et al. Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Journal of Translational Medicine, 1 October 2018 doi 10.1186/s12967-018-1644-y, https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1644-y

About the Author:

Jane Collingwood is a medical journalist with 17 years experience reporting on all areas of medical research for online and print publications. Jane has also worked on a range of medical studies funded by the UK National Health Service within the University of Bristol in the South West of England. Jane has an academic background in psychology and has authored books on stress management and respiratory infections. Currently she is combining journalism with a national coordinating role on the UK's largest surgical research trial.