Long Covid and its long reach

It has been some six years since the emergence of SARS-CoV-2, the virus causing COVID-19, which was recognised (and feared) because of its serious acute manifestations, involving pneumonia, respiratory failure, thrombosis, multi-organ failure and an initial high death rate. The virus affected all populations but especially those in high-risk categories, such as those with underlying disease, the immunocompromised, and older persons. SARS-CoV-2 spread quickly around the world overloading healthcare systems and affecting economies worldwide. 

It is now clear that the consequences of SARS-CoV-2 virus infection can extend beyond the acute illness in some people, manifesting as Long Covid.

Definition of Long Covid

Long Covid is known more formally as post-COVID-19 condition (PCC) or post-acute sequelae of SARS-CoV-2 infection (PASC). 

There is no universally accepted definition of Long Covid; in part because there are over 200 overlapping symptoms involving multiple organ systems, with varying severity, and there is no definitive diagnostic biomarker. Having a standardised definition is critical for accurate diagnosis and treatment, and it would be helpful for public health tracking and focused research. 

The World Health Organization (WHO) defines Long Covid as symptoms occurring usually within three months of the initial infection, lasting at least two months, and not explained by another diagnosis. In addition, WHO notes that symptoms may persist from the original illness or reappear after recovery, and may fluctuate. Definitions used by the US Centers for Disease Control and Prevention and the Australian National Clinical Evidence Taskforce are similar but not identical.

Long Covid symptoms

While more than 200 symptoms have been reported, which can range from mild to severe, some of the most commonly reported include: cognitive dysfunction or "brain fog,” shortness of breath, fatigue, joint or muscle pain, dysautonomia and neuropsychiatric symptoms, post-exertional malaise, altered smell and taste, ongoing cough, postural orthostatic tachycardia syndrome (POTS), gastrointestinal symptoms, temperature dysregulation, and sensory disturbances.

Those at greatest risk

Long Covid has affected over 400 million people globally. WHO identifies older age, female sex, obesity, smoking, chronic disease, repeated infection and severe initial illness as key risk factors for Long Covid. Children and adolescents have a lower risk than adults of contracting Long Covid and have different symptom profiles, which primarily include; fatigue, headache, gastrointestinal symptoms, cognitive difficulties and sleep disturbances.

While Long Covid can affect all age groups, there is evidence that women are more affected than men. A large study involving 12,276 infected individuals found that adult women, especially middle-aged women, had a 31–44% higher risk of Long Covid. Older people are also more affected and advancing age is a recognised risk factor for Long Covid. Distinguishing Long Covid from the sequelae of acute infection and pre-existing disease can be challenging in this group as age-related biological processes such as immunosenescence and chronic low-grade inflammation (“inflammaging”), may also contribute to persistent or overlapping symptoms.

Causes of Long Covid

There is no universally accepted explanation or single cause for Long Covid and there is debate over the primary triggers. It is most likely caused by a series of interacting processes involving replicating virus reservoirs or viral persistence, autoimmunity, molecular and epigenetic memory, microvascular disease and coagulation, autonomic nervous-system dysfunction, and reduced circulating serotonin. 

WHO identifies viral persistence as one of the leading biological abnormalities associated Long Covid, as reservoirs of SARS-CoV-2 or viral fragments such as viral RNA and proteins, have been detected in tissues, including the gastrointestinal tract and other organs. These continue stimulating the immune system and may explain why some patients experience continuing inflammation after the acute phase symptoms have abated. Continuing inflammation may also trigger the reactivation of latent viruses, eg Epstein-Barr and cytomegalovirus, which may then contribute to Long Covid symptoms.

Autoantibodies have also been reported against several cellular targets in Long Covid, which keep the immune system active. These antibodies may trigger an abnormal immune response that continues after the virus has disappeared.

Long Covid can leave lasting changes in gene regulation due to epigenetic changes — alterations in DNA methylation and chromatin regulation. A 2024 systematic review concluded that epigenetic alterations are a potentially important component of Long Covid although causality remains undetermined.

SARS-CoV-2 infection can cause small blood vessel and clotting problems reducing blood supply and impeding oxygen flow to tissues. These microvascular effects are thought to lead to a number of typical Long Covid symptoms, especially fatigue, brain fog, abnormal breathing, myalgia, headache, anxiety and muscle pain. 

POTS and other forms of dysautonomia are also associated with Long Covid. Such cardiovascular and neurological symptoms explain why modest physical activity can produce profound symptoms in some patients.

Recent studies have shown reduced circulating serotonin in people with Long Covid. It is likely that viral RNA and type-I interferon responses interfere with tryptophan absorption and serotonin metabolism, which may impair vagal signalling, leading to ‘brain fog’ and other cognitive symptoms. 

Does vaccination prevent Long Covid?

No. But early evidence showed that vaccination prior to infection markedly reduced the risk by 29-50%.

A more recent review by the European Centre for Disease Prevention and Control (covering the period when Omicron dominated), estimated that complete vaccination (3 doses) before infection reduced the risk of Long Covid by approximately 27% in adults. In another similar review and meta-analysis, a lower Long Covid risk was found in vaccinated individuals, with additional protection afforded by booster doses.

It is clear that vaccination reduces the severity and duration of acute infection by reducing viral burden, inflammation and immune dysregulation, which is likely the trigger needed for Long Covid to develop. However, it should be noted that vaccinated persons can still develop Long Covid after breakthrough infection, including mild and asymptomatic cases.

There is no association between vaccination (with any COVID-19 vaccine) and the development of Long Covid. However, there are well documented rare adverse events following COVID-19 vaccination, which include myocarditis and pericarditis, especially in young males receiving an mRNA vaccine, but these risks are higher with COVID-19 infection than mRNA vaccination. There are also cases of post-vaccination syndrome ie prolonged symptoms after vaccination, which are distinct from, and do not progress to, Long Covid. 

The evidence indicates that Long Covid is an unfortunate consequence of SARS-CoV-2 infection. Moreover, vaccination to COVID-19 before infection reduces the risk of Long Covid.

Whither antivirals?

As yet there are no approved specific treatments or medications that reliably cure Long Covid.

While Nirmatrelvir–ritonavir (Paxlovid) is highly effective in the early treatment of acute COVID-19 in selected high-risk patients, trials have shown that there is no significant improvement in symptoms for Long Covid patients compared with placebo. However, it is encouraging that studies suggest that effective treatment of acute infection may reduce the probability of developing Long Covid. 

Other drugs including colchicine, metformin, antihistamines, low-dose naltrexone, immunomodulators, anticoagulants and drugs targeting autonomic dysfunction have been studied but no sustained benefit was found with these drugs alone and any positive evidence remains incomplete.

Consequently, treatment must be phenotypically directed. Particular caution is needed with graded exercise as pacing and careful energy management are often more appropriate than strenuous exercise.

Prognosis

Recovery is not linear. Patients can experience periods of improvement followed by relapse, especially with illness or psychological/physiological stressors. WHO notes that most people improve and recover within 4-9 months, and many recover after 1-2 years, but a small minority develop persistent and disabling impairment and a few remain symptomatic for years. 

Conclusion

Acute COVID-19 is now a steady state infection in the community, so Long Covid cases will continue to arise; however, vaccination offers one of the clearest preventive strategies as it reduces the risk of contracting Long Covid. Long Covid is best understood as a heterogeneous collection of disorders produced by several overlapping mechanisms but the absence of a diagnostic test and the variability of definitions make accurate diagnosis difficult. Advances and opportunities lie ahead if the known molecular signatures can be converted into reliable diagnostic tests and targeted therapies.

Professor Gary Grohmann is a board member and member of the Scientific Advisory Committee of the Immunisation coalition. He is a former WHO advisor and Director of Immunobiology at the Therapeutic Goods Administration. He currently works as an independent consultant.

Acknowledgements: Gratitude to Dr. John McEwen and Professor Robert Booy for reviewing the manuscript.