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Long COVID: major findings, mechanisms and recommendations
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We need a comprehensive long COVID research agenda that builds on the existing knowledge from ME/CFS, dysautonomia and other viral-onset conditions, including but not limited to brain and brainstem inflammation, appropriate neuroimaging techniques, neuroimmunology, metabolic profiling, impaired endothelial function, mitochondrial fragmentation, antiviral and metabolic phenotypes, hypoperfusion/cerebral blood flow, nanoneedle diagnostic testing, overlaps with connective tissue disorders, autoimmunity and autoantibodies, viral/microbial persistence, intracranial hypertension, hypermobility, craniocervical obstructions, altered T and B cells, metabolomics and proteomics, elevated blood lactate level, herpesvirus reactivations, immune changes in the early versus late postviral years, and changes to the gut microbiota. The mechanisms of and overlaps between long COVID and connective tissue involvement, mast cells and inflammatory conditions such as endometriosis are particularly understudied and should be focused on. Because of the high prevalence of ME/CFS, POTS and other postinfectious illnesses in patients with long COVID, long COVID research should include people who developed ME/CFS and other postinfectious illnesses from a trigger other than SARS-CoV-2 in comparator groups to improve understanding of the onset and pathophysiology of these illnesses113. Additionally, there is a known immune exhaustion process that occurs between the second and third year of illness in ME/CFS, with test results for cytokines being different between patients who have been sick for shorter durations (less than 2 years) than for those who have been sick for longer durations43. Because of this, studies should implement subanalyses based on the length of time participants have been ill. Because ME/CFS and dysautonomia research is not widely known across the biomedical field, long COVID research should be led by experts from these areas to build on existing research and create new diagnostic and imaging tools.
In addition to providing education on long COVID to the biomedical community, we need a public communications campaign that informs the public about the risks and outcomes of long COVID.
Policies and funding
Finally, we need policies and funding that will sustain long COVID research and enable people with long COVID to receive adequate care and support. For instance, in the USA, the creation of a national institute for complex chronic conditions within the NIH would go a long way in providing a durable funding mechanism and a robust research agenda. Further, we need to create and fund centres of excellence, which would provide inclusive, historically informed and culturally competent care, as well as conduct research and provide medical education to primary care providers. Additionally, research and clinical care do not exist in silos. It is critical to push forward policies that address both the social determinants of health and the social support that is needed for disabled people.
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