What is the underlying pathophysiology of Long Covid?

Conference:

SAPC ASM 2023 - Brighton

Talk Code:

2E.5

Presenter:

Prof Brendan Delaney

Twitter:

@bcdelaney1

Co-authors:

Nawar Bakerly, Julie Darbyshire, Emily Bullock, Joseph Kwon, Nikki Smith.

Author institutions:

Imperial College London, Salford Royal NHS Trust, University of Oxford, patient co-investigator.

Problem

As the COVID pandemic hit in March 2020 it quickly became apparent that very many patients were following a prolonged and relapsing course, regardless of the initial illness severity. Long Covid is a patient-adopted term for Post-COVID Condition, defined by the WHO in 2021. Symptoms are primarily fatigue, breathlessness, chest pain, cognitive dysfunction, especially executive skills and short-term memory and post-exertional symptom exacerbation, although every organ system can be affected to some extent. To identify potential investigations and therapies, we set out to conduct a systematic review of studies linking symptoms with pathophysiology.

Approach

Two searches were conducted; a meta-review of published systematic reviews to July 2022 and a review of original papers July 21- October 2022, to capture new studies not included in the existing reviews. Searches were conducted on: CINAHL, Embase, Medline, Medrvix, PubMed and Emcare. Results of these searches were imported onto Covidence, and then screened using the criteria: confirmed diagnosis of Covid 19, hospital and community samples, a control group, and analyses that investigated the relationship between symptoms and pathophysiology.

Findings

For the meta-review 70 studies were assessed for eligibility (blinded dual review) and 26 systematic reviews included. In the second search, 441 references were identified and 47 studies with a total of 10676 participants included. Findings suggest that significant numbers of people with Long Covid demonstrate identifiable causes. The large number of symptoms are because common symptoms such as fatigue, breathlessness and cognitive problems may have a variety of upstream causes. Identified potential causes include:1. Persisting inflammatory pathways with depletion of CD4 and NK cells and persisting populations of SARS-Cov-2 specific CD8, evidence of raised IL6 and TNF Alpha, potentially linked to viral persistence in the gut and monocytes.2. Evidence for clotting abnormalities including VWF/Ag ratio being raised, amyloid micro-clots, activated platelets and endothelial damage, leading to impaired oxygen uptake in tissues, including skeletal muscle and the brain.3. Evidence of CNS inflammation with CSF oligoclonal bands and damage to astrocytes.4. Direct organ damage to the lung, myocardium, pancreas, and kidney, possibly mediated via endothelial dysfunction.Some suggestion of damage to cellular junctions affecting the gut and blood-brain barrier.5. Viral reactivation, including EBV.

Consequences

In the UK surveys have estimated more than 800,000 people unwell for more than a year and unable to work or undertake social activities. This poses considerable challenges to those affected and their families, to healthcare planning and provision, to the workforce and to the economy. Currently the NHS is not testing Long Covid patients for the pathology identified in this review and no treatments have been proposed or studied for the abnormal processes found. Translational research and changes to clinical management are urgently required.

Submitted by:

Brendan C. Delaney

Funding acknowledgement:

This work was produced by the authors under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care for the NIHR LOCOMOTION project.