Long COVID pathophysiology

A number of research studies have investigated long COVID or Post-Acute Sequelae of COVID-19 (PASC), the long term health problems that occur in a significant minority of people who remained ill for an extended time after developing COVID-19.

Diagnosis
A blood test to identify Long COVID patients by (IFN-gamma + IL-2)/CCL4 > 0.4) could identify Long COVID patients with 100% sensitivity and 88% specificity in a cohort of 144 individuals among them 64 individuals with Long COVID.

Infection and immunity
A range of antibodies have been found in patients with persistent post-acute COVID symptoms. Elevated G-protein coupled receptor autoantibodies have been found. One study founded elevated antinuclear antibody (ANA) titles in 43.6% of long COVID patients twelve months after symptom onset.

Long COVID may be associated herpesvirus reactivation such as Epstein-Barr Virus, which has been shown to cause elevations of certain G-protein coupled receptor autoantibody types.

Non-classical monocytes (CD14low, CD16+) have been found in the blood of Long COVID patients up to 15 months after infection. It has been determined that these particular non-classical monocytes express the fractalkine receptor and the CCR5 receptor. Since TNF-alpha and IFN-gamma, which is elevated in Long COVID patients, cause endothelial cells to produce fractalkine (CX3CL1) ligands , said monocytes bind to endothelial cells and cause inflammation. The presence of fractalkine (CX3CL1) and TNF-alpha inhibits apoptosis and thereby allows these non-classical monocytes to survive for a long time.

Pulmonary
In a single cardiopulmonary exercise test, Post-COVID-19 patients exhibited markedly reduced peak exercise aerobic capacity (VO2) compared to controls and impaired oxygen extraction, even in those without cardiopulmonary disease.

Prevention
The best way to prevent Long COVID is by preventing an infection with SARS-CoV-2. Antibodies can protect against an infection in case of exposure to the virus. However, in breakthrough cases, the probability to develop Long COVID is independent of the presence of antibodies.

Post-Treatment Lyme disease syndrome
Post-treatment Lyme disease syndrome (PTLDS) is hypothesized to be caused by the presence of residual bacterial debris (possibly bacterial cell envelope fragments) stimulating the immune system. The relapsing character and the symptoms of this syndrome are very similar to the symptom presentation of Long COVID. The discovery of antigen-presenting non-classical monocytes in Long COVID supports the theory that both syndromes are similarly caused by residual debris of pathogens after the infection is cleared.

Notable studies

 * 2021, 18F-FDG brain PET hypometabolism in patients with long COVID (Full text)
 * 2021, Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients (Full text)
 * 2021, Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID (Full text)
 * 2021, Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19 (Full text) - Pre-print
 * 2021, Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin (Full text) - Pre-print
 * 2021, Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection (Full text) - Pre-print
 * 2021, Clinical characterization of dysautonomia in long COVID-19 patients (Full text)
 * 2021, Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing (Full text)
 * 2021, Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome (Full text)
 * 2021, Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms (Full text)
 * 2020, Long COVID-19: Challenges in the diagnosis and proposed diagnostic criteria (Full text)
 * 2020, Multi-organ impairment in low-risk individuals with long COVID (Full text) - Pre-print
 * 2020, Living with covid-19. A dynamic review of the evidence around ongoing covid-19 symptoms (often called long covid) (Full text)

News and articles

 * Aug 2021, When it comes to breakthrough cases, are we ignoring long Covid once again? - Hannah Davis, The Guardian

Learn more

 * Long COVID Resource Hub (database of Long COVID research)