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.”
  • 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.

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.
  • 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 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
  • fluctuate in severity

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:

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 included data for 1.2 million individuals from 22 countries who had COVID-19 in 2020 and 2021 and presented modelled prevalence estimates as follows:
    • 6.17% of symptomatic COVID-19 patients who survived their acute episode experienced at least one of three long COVID symptom clusters (fatigue, cognitive and respiratory) at three months after symptom onset.
    • Twelve months after symptom onset, this prevalence decreased to 0.9%.
  • systematic review noted that 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%).^
  • nationwide cohort study from Israel, on pre-Omicron variants, reported:
    • Patients with mild initial infections had an increased risk for a small number of health outcomes (6 out of 70 outcomes) during up to one year follow-up compared to the controls with no infection history. At 180-360 days, the risk difference per 10,000 patients for these outcomes ranged from 8.3 to 50.2.
    • Findings remained consistent across the pre-Omicron variants.

Effect of variant

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

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

Protective factors:

  • vaccination (including primary and booster^)
  • young age
  • antivirals
    • 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.^
    • However, another study of nirmatrelvir-ritonavir and molnupiravir use in veterans did not demonstrate evidence of protection against post-acute conditions at six months follow-up
  • early outpatient COVID-19 treatment with metformin^

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

Phenotypes

  • Numerous studies have proposed different types or subphenotypes^ of long COVID, however, their conclusions differ considerably and as yet there is no consensus.
  • Long COVID may be classifiable by severity.
  • 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:

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.
  • A comprehensive approach to neurorehabilitation has been suggested, which includes cognitive rehabilitation, cognitive behavioural therapy and aspects of acceptance and commitment therapy such as mindfulness.

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 15 Mar 2023

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