COVID - summary of COVID-19 rapid guideline: managing the long-term effects of COVID-19 (long COVID)

This is a summary of the NICE guideline relating to:

• new and emerging condition, which has been described using a variety of terms including ’long COVID’,
• this condition can have a significant effect on people’s quality of life
• there is no clinical definition or clear treatment pathway, and there is a minimal, though evolving, evidence base

The clinical case definitions, the term ’long COVID’ is commonly used to describe signs and symptoms that continue or develop after acute COVID-19.

• Three definitions were developed (1):
  
  
  • acute COVID-19 (0 to 4 weeks),
    
    
  • ongoing symptomatic COVID-19 (4 to 12 weeks) and
    
    
  • post-COVID-19 syndrome (12 weeks or longer)

* the Office for National Statistics estimate that one in five people have symptoms that persist after 5 weeks, and one in ten have symptoms for 12 weeks or longer after acute COVID-19 infection (2)

NICE guidelines on managing the long term effects of covid-19 and the CDC define long covid patients or covid long haulers as individuals with ongoing symptoms of covid-19 that persist beyond four weeks from initial infection (3).

The panel of UK doctors who contributed to the article by Gorn et al (2) have provided a list of conditions, never experienced before their episodes of acute
COVID-19

Panel: Conditions experienced by members of the UK doctors #longcovid group

• Myocarditis or pericarditis
• Microvascular angina
• Cardiac arrhythmias, including atrial flutter and atrial fibrillation
• Dysautonomia, including postural orthostatic tachycardia syndrome
• Mast cell activation syndrome
• Interstitial lung disease
• Thromboembolic disease (pulmonary emboli or cerebral venous thrombosis)
• Myelopathy, neuropathy, and neurocognitive disorders
• Renal impairment
• New-onset diabetes and thyroiditis
• Hepatitis and abnormal liver enzymes
• New-onset allergies and anaphylaxis
• Dysphonia

Crook et al have described the long term sequalae of covid-19

• (1) in the alveoli of the lungs:
  • chronic inflammation
    • results in the sustained production of pro-inflammatory cytokines and reactive oxygen species (ROS) which are released into the surrounding tissue and bloodstream
  • endothelial damage
    • triggers the activation of fibroblasts, which deposit collagen and fibronectin resulting in fibrotic changes
  • endothelial injury, complement activation, platelet activation, and platelet-leukocyte interactions, release of pro-inflammatory cytokines, disruption of normal coagulant pathways, and hypoxia
    • may result in the development of a prolonged hyperinflammatory and hypercoagulable state, increasing the risk of thrombosis
• (2) in the heart:
  • chronic inflammation of cardiomyocytes
    • can result in myositis and cause cardiomyocytes death
  • dysfunction of the afferent autonomic nervous system
    • can cause complications such as postural orthostatic tachycardia syndrome
  • prolonged inflammation and cellular damage prompts fibroblasts to secrete extracellular matrix molecules and collagen, resulting in fibrosis
  • fibrotic changes are accompanied by an increase in cardiac fibromyoblasts
    • damage to desmosomal proteins results in reduced cell-to-cell adhesion
• (3) in the central nervous system:
  • long term immune response
    • activates glial cells which chronically damage neurons
  • hyperinflammatory and hypercoagulable states
    • lead to an increased risk of thrombotic events
  • blood-brain barrier damage and dysregulation
    • results in pathological permeability, allowing blood derived substances and leukocytes to infiltrate the brain parenchyma
  • chronic inflammation in the brainstem may cause autonomic dysfunction
  • effects of long covid in the brain can lead to cognitive impairment
• (4) possible mechanisms causing post-covid-19 fatigue
  • a range of central, peripheral, and psychological factors may cause chronic fatigue in long covid
    • chronic inflammation in the brain, as well as at the neuromuscular junctions, may result in long term fatigue
    • skeletal muscle
      • sarcolemma damage and fibre atrophy and damage may play a role in fatigue
    • psychological and social factors may play a role in chronic fatigue in long covid

The PHOSP-COVID Collaborative Group undertook a study investigating recovery 1 year after hospital discharge for COVID-19 (4)

• study (n=2320) reported 29% full recovery at 1 year with female sex, obesity and ventilation associated with being less likely to feel fully recovered at 1 year
  • several inflammatory mediators were increased in individuals with the most severe physical, mental health, and cognitive impairments compared with individuals with milder ongoing impairments

Metformin and risk of long COVID

• study evidence showed that there was a 42% relative decrease and 4.3% absolute decrease in the Long Covid incidence occurred in participants who received early outpatient COVID-19 treatment with metformin compared to exact-matching placebo (5)

Reference:

1. NICE. COVID-19 rapid guideline: managing the long-term effects of COVID-19. NICE guideline NG188. Published December 2020, last updated January 2024
2. Gorn R et al. Long COVID guidelines need to reflect lived experience. Lancet 2021 Feb 6;397(10273):455-457. doi: 10.1016/S0140-6736(20)32705-7. Epub 2020 Dec 23.
3. Crook H, Raza S, Nowell J, Young M, Edison P. Long covid - mechanisms, risk factors, and management BMJ 2021; 374 :n1648 doi:10.1136/bmj.n1648
4. PHOSP-COVID Collaborative Group. Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study. Lancet Respiratory April 2022.
5. Bramante CT et al Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up. medRxiv [Preprint]. 2022 Dec 23:2022.12.21.22283753. doi: 10.1101/2022.12.21.22283753. PMID: 36597543; PMCID: PMC9810227