Aetiology

Your Organisational Guidance

ebpracticenet urges you to prioritise the following organisational guidance:

Opvolging en revalidatie van patiënten met aanhoudende klachten na COVID-19 in de eerste lijnPublished by: KU Leuven | Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2023Suivi et revalidation des patients présentant des symptômes persistants après la COVID-19 en première lignePublished by: KU Leuven | Groupe de Travail Développement de recommmandations de première ligneLast published: 2023

Long COVID is due to acute COVID-19 (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection). The causative factors behind why certain individuals go on to develop persistent symptoms while others recover completely from their acute COVID-19 illness remain unknown.[32] Risk factors for long COVID include having a more severe acute COVID-19 illness (including being hospitalised), partial vaccination or absence of vaccination against COVID-19, and female sex. Other risk factors include age older than 40 years, body mass index >30 kg/m², being a current smoker, and presence of comorbidities.​[10][33][34][35][36][37][38][39][40][41][42][43][44]

[Figure caption and citation for the preceding image starts]: Illustration of the ultrastructure of the SARS-CoV-2 coronavirusKateryna Kon/Science Photo Library; used with permission [Citation ends].com.bmj.content.model.Caption@405c4f64

Long COVID also serves as an umbrella term that encompasses other post-viral syndromes that have historically been found to occur following acute viral and bacterial infections. Some of these syndromes include myalgic encephalomyelitis/chronic fatigue syndrome, dysautonomia (particularly postural orthostatic tachycardia syndrome), mast cell activation syndrome, connective tissue disorders, and others. Further, long COVID also includes sequelae from complications from acute COVID-19 illness including post-intensive care syndrome, thrombotic complications, lung fibrosis, and others.[32] It is possible that not all long COVID symptoms and sequelae are due to the same aetiological causes.

Pathophysiology

The pathophysiology of prolonged symptoms after recovery from acute COVID-19 remains poorly understood, although there is accumulating evidence of physiological changes in individuals with long COVID, compared with COVID survivors without residual symptoms, despite often normal routine clinical testing.[38] It is possible that there are multiple and/or overlapping pathophysiological mechanisms, particularly given the heterogeneity of ongoing symptoms.

One of the most commonly proposed mechanisms is immune system dysregulation, including alterations in circulating T cells and B cells as well as changes to the innate immune system.[32][45][46][47] There have also been elevated levels of cytokines found in individuals with long COVID.[48][49] There has been inconsistent evidence of increased levels of autoantibodies in individuals with long COVID.[45][50][51][52]

Individuals with long COVID have also been found to have decreased peripheral serotonin levels. This decrease is potentially due to viral infection leading to type I interferon-driven inflammation, decreased intestinal absorption of tryptophan (a precursor to serotonin), thrombocytopenia, and increased monoamine oxidase inhibitor (MAO)-mediated serotonin turnover. This decrease in peripheral serotonin may lead to autonomic, neurocognitive, and other symptoms related to long COVID.[53]

Other causes that have been implicated in the pathophysiology of long COVID include virus-induced inflammation, cellular injury, viral reactivation (including of Epstein-Barr virus and human herpesvirus 6), endotheliopathy, hypercoagulopathy (microclots), microbiome alterations, brainstem/vagal nerve dysfunction, metabolomic causes, mitochondrial dysfunction, and select gene expression profiles.[32][54][55][56][57][58][59][60]

One potential driver of the mechanisms discussed above is persistent viral infection or reservoir. Although residual viral ribonucleic acid has been found in the tissues of patients with long COVID, the role in symptomatology associated with the syndrome is unclear.[61][62]

[Figure caption and citation for the preceding image starts]: Long term sequelae of COVID-19. (1) In the alveoli of the lungs: (A) 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. (B) Endothelial damage triggers the activation of fibroblasts, which deposit collagen and fibronectin resulting in fibrotic changes. (C) 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: (A) chronic inflammation of cardiomyocytes can result in myositis and cause cardiomyocytes death. (B) Dysfunction of the afferent autonomic nervous system can cause complications such as postural orthostatic tachycardia syndrome. (C) Prolonged inflammation and cellular damage prompts fibroblasts to secrete extracellular matrix molecules and collagen, resulting in fibrosis. (D) Fibrotic changes are accompanied by an increase in cardiac fibromyoblasts, while damage to desmosomal proteins results in reduced cell-to-cell adhesion. (3) In the central nervous system: (A) The long term immune response activates glial cells which chronically damage neurons. (B) Hyperinflammatory and hypercoagulable states lead to an increased risk of thrombotic events. (C) Blood-brain barrier damage and dysregulation results in pathological permeability, allowing blood derived substances and leukocytes to infiltrate the brain parenchyma. (D) Chronic inflammation in the brainstem may cause autonomic dysfunction. (E) The 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. In skeletal muscle, sarcolemma damage and fibre atrophy and damage may play a role in fatigue, as might a number of psychological and social factorsBMJ 2021; 374: n1648; used with permission [Citation ends].com.bmj.content.model.Caption@45270412

Classification

There have been efforts to establish subgroups of long COVID patients based on their most prominent symptoms. However, no classification scheme has reached widespread acceptance.[8][9][10][11][12]

Use of this content is subject to our disclaimer