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.

Long COVID

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'.

Definition

  • 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.”

Challenges

  • 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.
  • Uncertainty intervals around result estimates are wide in long COVID studies, reflecting as yet limited and heterogeneous data.^

Research initiatives

  • 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.

TopicEvidence

Symptoms

Symptoms may:

  • range from mild to severe
  • be singular or multiple
  • be continuous or episodic

Common symptoms:

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:

Prevalence

Estimating prevalence is complicated by several confounds, for example:

  • Definitions of long COVID vary across studies.
  • Studies which rely on self-reported symptoms may differ in findings from study that use physician diagnosis.
  • Different studies have samples with different variants and different proportions of vaccination or reinfection levels.

Recent prevalence estimates from larger and more rigorous studies (adults or all ages):

  • Recent Victorian long COVID prevalence estimates for long COVID morbidity among adults with symptomatic infections range from 0.17% to 4.4%. The prevalence is lower among vaccinated adults who were infected with the Omicron variant (0.09% for non-hospitalised and 1.9% for hospitalised adults).^
  • global systematic analysis (involving ten ongoing cohort studies from ten countries) estimated that 6.17% of symptomatic SARS‐CoV‐2 infections who survived their acute episode experienced at least one of three long COVID symptom clusters three months after symptom onset. Twelve months after symptom onset, the prevalence decreased to 0.9% .
  • A large-scale population study from the Netherlands evaluated prevalence while correcting for individual symptoms present before COVID-19 and with a robust control group. In 12·7% of patients infected with pre-Omicron variant, increased somatic symptoms with moderate severity at three months could be attributed to SARS-CoV-2 infection. Most of this study’s participants were unvaccinated.
  • A systematic review including 120 studies noted that there was significant heterogeneity between studies and wide variation in long COVID prevalence estimates. Studies with the lowest risk of bias and with community-based samples estimated the absolute risk difference between cases and controls to be between 1% to 9% (mean 4.8%). ^

Effect of variant and vaccination

  • Studies suggest lower prevalence of long COVID following infection with Omicron (4.5%) than with Delta (10.8%), especially among double vaccinated individuals and irrespective of time elapsed between infection and most recent vaccination. The symptoms with long COVID were milder in Omicron infections than Delta infections.^
  • In triple vaccinated individuals, the prevalence was similar for Delta (5.0%), Omicron BA.1 (4.5%) and Omicron BA.2 (4.2%) infections.

Children

  • In children, COVID-19 infection (pre-Omicron) was associated with an increased risk of reporting at least one symptom lasting more than two months than controls (absolute risk difference: 12.8% for 0-3 years; 4.4% for 4-11 years; 4.7% for 12-14 years).
  • Prevalence of post-COVID-19 conditions in children and adolescents is around 3.7% generally, 1.7% in non-hospitalised children but up to 5.2% in hospitalised children, at three months post-infection.
  • Anxiety disorders, somatoform disorders, and allergic rhinitis are significantly associated with post-COVID-19 condition.
  • A large German data analysis found that incidence rate ratio estimates were similar for age groups 0 to 11 and 12 to 17.

Duration

A global systematic analysis identified that:

  • Median duration of long COVID in community infections was 4.0 months.
  • Median duration of long COVID in hospitalised cases was 9.0 months.
  • In individuals with long COVID, 15.1% of patients  continued to experience symptoms 12 months after acute infection.

Protective and risk factors

Protective factors:

  • vaccination  (including primary and booster^)
  • young age
  • Treatment with nirmatrelvir within five days of a positive SARS-CoV-2 test, in people who had at least one risk factor for progression to severe COVID-19 illness, has been associated with reduced risk of long COVID regardless of vaccination status and history of prior infection.^

Risk factors:

Risk factors for long COVID are likely multifactorial and interrelated.^

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.

Reinfections with SARS-CoV-2 are likely to increase the risk of death, hospitalisation and sequelae in multiple organ systems in the post-acute phase compared to the primary infections, 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.

The mechanisms for ongoing symptoms are proposed to be due to viral persistence, persistent immune activation or autoimmunity. A comprehensive review of pathophysiology and mechanism of long COVID found that apart from long-term organ damage due to acute-phase infection, immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation could be the main underlying pathophysiological mechanisms.

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.

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.

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

Phenotypes

  • Numerous studies have proposed different types or subphenotypes^ of long COVID, however, their conclusions differ considerably and as yet there is no consensus.
  • There is evidence to suggest that infection with different variants may be associated with different long COVID phenotypes.
Management

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:

  • Self-management strategies
  • Symptom management in primary care or referral to specialised care as required.
  • A medically-led, multidisciplinary approach
  • Individualised rehabilitation
  • Careful activity pacing (to avoid relapse)
  • Additional support for older people and children
  • Management plans, including education and skills training on energy conservation techniques, the provision and training in the use of assistive products to those who need further assistance with activity management and mobility, and a return-to-work action plan that supports a prolonged and flexible phased return.
  • In children, a review highlighted that current management relies on specialty-based diagnostics and supportive management, with a focus on goal-oriented physical and psychological rehabilitation.

Guidelines for primary care have highlighted that:

  • The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications.
  • Many patients can be supported effectively in primary care by a GP with a special interest.
  • The evidence for using medications to treat long COVID related fatigue is currently lacking.

Patient Education and Self-management

  • Self-management of long COVID symptoms is warranted in many cases and can be part of a holistic management plan.
  • Providing patients with education and strategies may increase to uptake of self-management but further research is required.^
  • The World Health Organization has produced information for patients on self-management after COVID-19. This includes a symptom tracking diary and specific symptom recommendations.
  • However, experts have cautioned that patients turning to treatments without high quality evidence for self-management may cause themselves additional harm.

Rehabilitation

  • A scoping review of rehabilitation approaches found that
    • The evidence for rehabilitation in COVID-19 is conceptual and expert-based
    • Care model components include multidisciplinary teams, continuity or coordination of care, people-centred care and shared decision-making between clinicians and patients.
    • Care model functions include standardised symptoms assessment, virtual care and follow-up systems.
  • Another review suggested that attentive rehabilitation programs with frequent follow-ups from facilitators addressing physical and psychological barriers to recovery often result in improved health related quality of life in patients.
  • Rehabilitation programs generally last 6-8 weeks, and may include inpatient, outpatient, in-person, web-based or home rehabilitation.
  • Tailored rehabilitation may include light aerobic exercises and breathing exercises.
  • A graded and individualised approach to exercise may be required, especially if post-exertional malaise is present.

More than 100 persistent symptoms of COVID-19 have been reported in the literature. Only commonly reported and emerging symptoms have been included in the living table.

Notes

* 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 24 Nov 2022

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