Critical Intelligence Unit

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

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'.

Definition

  • The Australian National Clinical Evidence Taskforce defines long COVID as “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. It usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body. Post COVID-19 condition may be considered before 12 weeks while the possibility of an alternative underlying disease is also being assessed.”1
  • The World Health Organization has also published specific information on the definition and nature of long COVID in children and adolescents.2

Challenges

  • The definition of long COVID varies considerably across studies. Researchers have called for consensus in definitions.3
  • 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.4
  • 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.5

Regular checks are conducted for new content and any updates are highlighted.

TopicEvidence

Symptoms

Symptoms may:6

  • range from mild to severe
  • be singular or multiple
  • be continuous or episodic
  • symptoms can fluctuate or even increase in severity throughout the course of long-COVID.

More than 200 persistent symptoms of COVID-19 have been reported in the literature.7 Only commonly reported and emerging symptoms have been included here.

  • Respiratory symptoms5, 8
    • shortness of breath or difficulty breathing
    • persistent cough
    • chest pain or discomfort
  • Generalised symptoms5, 8-12
    • fatigue
    • weakness, effort intolerance, post exertional malaise
    • rash and hair loss
    • general pain
  • Cardiovascular symptoms13-15
    • chest tightness and pain
    • cardiac symptoms, including chest pain, primary arrhythmia, palpitations, dyspnoea on exertion
    • poorer cardiovascular fitness
    • Autonomic dysfunction including postural orthostatic tachycardia syndrome
  • Neurological symptoms8, 10, 16-18
    • cognitive impairment  including memory loss, concentration difficulties and brain fog
    • loss of smell or taste
    • headache
  • Gastrointestinal symptoms19, 20
    • irritable bowel syndrome
    • diarrhoea, constipation, abdominal pain, nausea/vomiting and heartburn
    • inflammatory conditions such as ulcerative colitis , acute pancreatitis, and multisystem inflammatory syndrome in children
  • Musculoskeletal symptoms21, 22
    • musculoskeletal pain
    • muscle weakness
  • Psychological / psychiatric symptoms23
    • anxiety
    • depression
    • insomnia
    • psychotic disorders
  • Other
    • kidney outcomes24

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:

  • pulmonary fibrosis secondary to acute lung injury25
  • myocarditis which may lead to persistent cardiac dysfunction26
  • pulmonary thromboemboli27
  • diabetes28, 29
  • cardiovascular disease13
  • dyslipidaemia30

Symptom patterns were similar but distinguishable between school-age children and adolescents.31

Four symptom clusters in school-aged children include:31

  • High rates of many symptoms
  • Predominately headache, body/muscle/joint pain, and daytime tiredness/sleepiness or low energy
  • Predominately trouble sleeping and trouble with memory/focusing
  • Predominately stomach pain and nausea/vomiting

Three symptom clusters in adolescents include:31

  • High rates of many symptoms
  • Predominately daytime tiredness/sleepiness or low energy and body/muscle/joint pain
  • Predominately change/loss in smell or taste

Prevalence

Prevalence estimates from Australian studies:

  • A long COVID clinic in Melbourne found that 5.7% of COVID-19 positive patients invited to answer a survey reported ongoing symptoms at eight weeks post-infection which required medical and allied health specialist assessment and management, namely memory or concentration problems, dyspnoea, and extreme fatigue.32
  • 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).33
  • A modelling study projected that approximately 0.7% to 3.4% of Australians would have symptoms of long COVID by December 2024.34

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

  • A global systematic analysis included data for 1.2 million individuals from 22 countries who had COVID-19 in 2020 and 2021 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%.5
  • A 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%).35
  • Large cohort studies with test-negative control groups report:
    • England – at ≥12 weeks and ≥52 weeks post symptomatic infection, 7·5% and 5·2% of patients self-reported ongoing symptoms respectively. Compared to Wild-type, those infected during Omicron dominant period were 88% less likely to report symptoms beyond 12 weeks.36
    • Israel - Patients with mild initial infections have an increased risk for a small number of health outcomes (6 out of 70 outcomes) at 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 six outcomes ranged from 8.3 to 50.2.37
    • Scotland - At six and 12 months, one or more symptom was reported by 71.5% and 70.7% respectively of those previously infected, compared with 53.5% and 56.5% of those never infected. Altered taste, smell and confusion improved over time compared to the never infected group.38
    • United States – Excess incidence of symptoms concordant with long COVID among the SARS-CoV-2 test-positive cohort was 4% in children and ranged from 4-7% in adults compared to test-negative or historical pre-COVID controls. 39^

Effect of variant

  • Earlier 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. 40, 41
  • A recent large cohort study from Scotland found higher rates of long COVID prevalence in subsequent variants: 6.7% for Delta and 7.9% for Omicron compared with 3.9% for the Alpha variant.42

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).43
  • Prevalence of long COVID in children and adolescents is around 3.7%, specifically 1.7% in non-hospitalised children but up to 5.2% in hospitalised children, at three months post infection. At six-month follow-up, the symptom prevalence in adolescents with an infection history is comparable to the symptom prevalence in adolescents without a history of infection.44, 45
  • In a longitudinal serological study from Canada, the incidence of post-COVID-19 conditions in children persisting for a minimum of eight weeks was 0.4%.46

COVID versus influenza

  • Compared to hospital admission for seasonal influenza, admission for COVID-19 (between 1 March 2020 and 30 June 2022) has been associated with higher long-term risks of death and adverse health outcomes in nearly every organ system (except for the pulmonary system) and significant cumulative excess disability-adjusted-life-years.47

Duration

There is a higher chance of recovery during the first year following acute infection.48

Long COVID symptoms tended to last longer for those infected with wild-type variant which were dominant in 2020.36

A global systematic analysis identified that:5

  • 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:

  • vaccination49-51
    • particularly any vaccination history prior to infection52
    • particularly booster vaccination after Omicron infection53
  • young age54
  • antivirals55-58 although some evidence is conflicting59
  • treatment with monoclonal antibodies,60 although some evidence is conflicting61
  • sleep quality pre-infection62
  • early treatment with ensitrelvir,63 especially among patients with high COVID-19 symptom scores at baseline or BMI of ≥25 kg/m2

Risk factors for long COVID are likely multifactorial and interrelated and include: older age, being female, higher weight or underweight, co-morbidities (including anxiety, depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, obesity and ischaemic heart disease), pre-existing cardiovascular diseases such as hypertension and heart failure, previous hospitalisation with COVID-19, frailty and being from an ethnic minority.64-70

Reinfection 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 55.71 In a large cohort study, persistent symptoms were more common after reinfection than following a first infection.72 However, the risk of new-onset long Covid after a second SARS-CoV-2 infection is lower than that after a first infection for those ≥16 years.73 In children and young people, reinfection was not associated with an increased risk of long COVID.74

Mechanisms / Aetiology

Little is known about the underlying cause of long COVID, as per most post-acute infection syndromes.75

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.76-79

There is evidence of attendant autonomic nervous system (ANS) dysregulation and mitochondrial pathology in long COVID cases which may contribute to exercise intolerance.80

Differential diagnosis and assessment

In clinical settings, there are no definitive test for long COVID, and diagnosis is based on differential diagnosis.81, 82

Guidance on assessment for long COVID has been published by the

  • Australian National COVID-19 Clinical Evidence Taskforce1
  • National Institute for Health and Care Excellence (NICE)81

Guidelines advocate for a holistic, person-centred approach to diagnosis.83

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 small numbers, with very few randomised control trials published yet.84 Most existing RCTs are small in size and had small event numbers. Follow-up periods are often too short to provide solid evidence.85

Guidance or recommendations on management for long COVID have been published by the:

  • Australian National COVID-19 Clinical Evidence Taskforce1
  • National Institute for Health and Care Excellence (NICE)81

The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications.86

  • Self-management strategies are promoted87
  • Multidisciplinary care is promoted88
  • Symptom management is provided in primary care or referral to specialised care as required.89
  • Physical activity and particularly inspiratory muscle training and pulmonary rehabilitation have been associated with positive outcomes, however, a graded and individualised approach to exercise may be required, especially if post-exertional malaise is present.1, 90-94
  • Emerging evidence demonstrate that hyperbaric oxygen therapy is effective in improving a range of  long COVID symptoms and quality of life, and have acceptable safety profiles.9596
  • Real-time telerehabilitation and online supervised group physical and mental health rehabilitation programme for adults has demonstrated promising results.97, 98

Pharmaceutical treatments

  • As yet most pharmaceutical treatments are experimental.
    • In a single-centre, double-blind, randomised controlled phase 2a pilot study, patients with long COVID were treated with 4 weeks of AXA1125, an orally administered endogenous metabolic modulator. Treated patients reported significant improvement in fatigue-based symptoms compared to controls.99
    • In a randomised controlled trial, a 15-day-course of Nirmatrelvir-Ritonavir in a population of patients with post-acute sequelae of SARS-CoV-2 infection was generally safe, but did not demonstrate a significant benefit for improving select symptoms in a mostly vaccinated cohort with protracted symptom duration.100

References

  1. National Clinical Evidence Taskforce COVID-19 (NCET). Australian guidelines for the clinical care of people with COVID-19: Care after COVID-19. Australia: NCET; 2023 [cited 29 Jun 2023]. Available from: https://app.magicapp.org/#/guideline/L4Q5An/section/jDJJJQ
  2. World Health Organization (WHO). A clinical case definition for post COVID-19 condition in children and adolescents by expert consensus, 16 February 2023. Geneva: WHO; 2023 [cited 29 Jun 2023]. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post-COVID-19-condition-CA-Clinical-case-definition-2023-1
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  4. Knuppel A, Boyd A, Macleod J, et al. The long COVID evidence gap: comparing self-reporting and clinical coding of long COVID using longitudinal study data linked to healthcare records. medRxiv. 2023:2023.02.10.23285717. DOI: 10.1101/2023.02.10.23285717
  5. Global Burden of Disease Long COVID Collaborators. Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA. 2022;328(16):1604-15. DOI: 10.1001/jama.2022.18931
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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 6 Nov 2024

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