Living Evidence - post acute sequelae of COVID-19 (long COVID)
Living evidence tables provide high level summaries of key studies and evidence on a particular topic, and links to sources. They are reviewed regularly and updated as new evidence and information is published.
Most people with COVID-19 will recover completely within a few weeks. However, some may keep experiencing symptoms for weeks or months after their diagnosis. This is called 'long COVID', ‘post acute sequelae of SARS-CoV-2’ or 'post COVID-19 condition'.
- The World Health Organization defines long COVID as “[a] condition that occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.”
- The National Institute for Health and Care Excellence (NICE) in the United Kingdom categorises long COVID into the following definitions:
- ongoing symptomatic COVID-19: signs and symptoms of COVID-19 from 4–12 weeks.
- post-COVID-19 syndrome: signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis.
- The World Health Organization has also published specific information on the definition and nature of long COVID in children and adolescents.
- The definition of long COVID varies considerably across studies. Researchers have called for consensus in definitions.
- More recent studies have confounds associated with variants, vaccines and reinfection history. When studies pool data across subgroups, it is difficult to tease apart the role of different variables on long COVID.
- Methods of data collection vary. The prevalence of long COVID in self-report longitudinal studies versus evidence of long COVID documented in electronic health records can be substantially different.^
- Uncertainty intervals around result estimates are wide in long COVID studies, reflecting as yet limited and heterogeneous data.
- Long COVID is heterogenous, meaning not everyone will experience the same symptoms.
- A clear distinction between long COVID and post-intensive care unit syndrome is often not made in studies.
- Research definitions of long COVID have been developed through a Delphi process for adults and for children.
- The United States National Institutes of Health launched RECOVER, a research initiative that seeks to understand, prevent, and treat long COVID.
- In the United Kingdom, the REACT Long COVID (REACT-LC) study aims to better understand the genetic, biological, social and environmental factors that affect people's likelihood of developing long COVID.
- Various models of care and clinical guidelines have been developed, however, the evidence-base for these is low quality and is continually evolving. There is emerging evidence on developing a framework for a coordinated national health policy action and response and research priorities for long COVID, including the use of big data and meaningful involvement of patient advocates.
Regular checks are conducted for new content and any updates are highlighted. All highlights are removed each Monday.
More than 100 persistent symptoms of COVID-19 have been reported in the literature. Only commonly reported and emerging symptoms have been included in here. .
There are a number of chronic sequelae of severe acute COVID-19 disease that might lead to persistent impairment and may result in chronic disease:
Symptoms in children and adolescents can include:
Estimating prevalence is complicated by several confounds, for example:
Recent prevalence estimates from larger and more rigorous studies (adults or all ages):
Effect of variant
A global systematic analysis identified that:
A health record analyses from Israel suggests that, in patients with mild infections (pre-Omicron), most long COVID symptoms resolve within a year.
Protective and risk factors
Risk factors for long COVID are likely multifactorial and interrelated and include:
A large study of veterans noted that long COVID care was documented more commonly in older persons, those with higher comorbidity burden, those with more severe acute COVID-19 presentation and those who were unvaccinated at the time of infection.
Reinfection in the United States has been associated with an increased risk of death, hospitalisation, and sequelae in multiple organ systems, compared to no reinfection, especially in patients older than 55.
|Mechanisms / Aetiology|
Little is known about the underlying cause of long COVID, as per most post-acute infection syndromes.
Other respiratory illnesses, such as influenza, have also been associated with persistent symptoms of a similar nature.
Two overarching mechanisms have been proposed to explain the underlying pathophysiology of long COVID: organ damage from the initial acute infection phase, and long-term inflammatory mechanisms. Specific hypotheses include:
Somatic and mental affective symptoms of long COVID were found to be associated with the immune-inflammatory response during acute COVID-19 and partially mediated by neuro-oxidative damage and lowered ANTIOX. A systematic review found that increased interleukin-6 levels are associated with long COVID.^
In a small study including healthy controls, patients with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood.
When compared to matched controls, people with long COVID were more likely to have lower cortisol levels, elevated humoral responses directed against SARS-CoV-2 and increased antibody responses against non-SARS-CoV-2 pathogens such as Epstein-Barr virus.^
|Differential diagnosis and assessment|
In a clinical setting, there is no definitive test for long COVID, and diagnosis is based on ruling out other similar conditions. There can be considerable clinical uncertainty during the diagnostic period.
Differential diagnosis is critical, since the clusters of symptoms associated with long COVID can overlap with other post-acute infection syndromes, such as post intensive care syndrome.
A meta-analysis demonstrated that the most common investigation findings in people with long COVID include abnormalities on lung CT and abnormal pulmonary function tests.
Guidance on assessment for long COVID has been published by the
Guidelines advocate for a holistic, person-centred approach to diagnosis. A core outcome set has been suggested for use in clinical practice and research which includes outcomes for: fatigue; pain; post-exertion symptoms; work or occupational and study changes; survival; and functioning, symptoms, and conditions for each of cardiovascular, respiratory, nervous system, cognitive, mental health, and physical outcomes.
Patient reported outcome measures
Management of long COVID is evolving and is based on the management of symptoms.
The evidence-base for managing long COVID is low quality, with very few randomised control trials published, although a number are currently underway.^
Existing models of care can vary quite widely, even within jurisdictions. Co-designed models are becoming more common.
Guidance or recommendations on management for long COVID have been published by the:
General management and support principles include:
Guidelines for primary care have highlighted that:
Patient Education and Self-management
* Preliminary data, not fully established, in some cases small numbers or short follow up; interpret with caution
^ Commentary, grey literature, pre peer review or news
The "last updated" date refers to the date when the evidence was last reviewed.
Living evidence tables include some links to low quality sources and an assessment of the original source has not been undertaken. Sources are monitored regularly but due to rapidly emerging information, tables may not always reflect the most current evidence. The tables are not peer reviewed, and inclusion does not imply official recommendation nor endorsement of NSW Health.
Last updated on 15 Mar 2023