Long COVID: Cleveland Clinic Researchers Discover That Immunometabolic Rewiring Is Responsible For Chronic Headaches In long COVID Individuals
: COVID-19 is a respiratory illness caused by the novel coronavirus SARS-CoV-2, which has affected millions of people worldwide. Although most people with COVID-19 recover within a few weeks, there is increasing evidence that some individuals experience long-term symptoms, even after they have cleared the virus from their bodies. This condition is known as post-acute sequelae of SARS-CoV-2 infection (PASC) or "long COVID."
Among the various symptoms reported by long COVID patients, chronic headache is one of the most common neurological symptoms, affecting up to 40% of COVID-19 patients.
The etiology of Long COVID
headache is not yet fully understood. To better understand the underlying mechanisms, a team of researchers from Cleveland Clinic, Ohio-USA conducted a longitudinal multi-omics analysis of blood leukocyte transcriptomics, plasma proteomics, and metabolomics in long COVID patients with chronic headache.
The study included both long COVID patients with chronic headache (+LC) and COVID-19 patients without chronic headache (-LC), as well as healthy controls.
The researchers analyzed blood samples from all groups at various time points, including during acute infection and convalescence. They also collected information on the patients' clinical symptoms and disease severity.
The results of the study showed that long COVID patients with chronic headache experienced a state of hyper-inflammation prior to the onset of chronic headache and maintained persistent inflammatory activation throughout the progression of chronic headache.
The researchers observed elevated levels of cytokines and chemokines, as well as increased activity of immune cells such as macrophages.
Metabolomic analysis revealed that long COVID patients with chronic headache had augmented arginine and lipid metabolisms, which skewed towards a nitric oxide-based pro-inflammation.
This suggested that the dysregulation of these metabolites could contribute to sustained inflammation and chronic headache.
The researchers also found that the metabolism of neurotransmitters including serotonin, dopamine, glutamate, and GABA were markedly dysregulated during the progression of long COVID headache.
Specifically, serotonin was significantly elevated across all timepoints even before headache onset, whereas dopamine metabolites, glutamate, and GABA metabolites were significantly reduced during the same periods.
The researchers also noted that the l
ong COVID patients with chronic headache exhibited higher levels of dehydration compared to the no-LC group.
CBC tests showed that the Long COVID patients had modest increases of RBC, hemoglobin, and hematocrit levels at early convalescence and detectable increases of platelet and WBC counts at late convalescence compared to non-Long COVID patients.
The researchers also observed higher CRP levels in COVID-19 patients compared to healthy controls at the time of positive COVID-19 diagnosis.
However, the CRP levels of both (-)LC patients and (+)LC patients fell to the moderately elevated ranges (1-10mg/dL), suggesting that CRP level may not be a right inflammation predictor of long COVID headaches in the early and late convalescence phase of COVID-19.
The study also identified elevated levels of lipids, including sphingomyelins, plasmalogen, phospholipids, sphingolipids, and cholesterol, which were present exclusively in the plasma of long COVID patients throughout the progression of chronic headache. This suggested the involvement of dysregulated lipid metabolism in meta-inflammation-like conditions in long COVID patients with chronic headache.
Furthermore, the researchers found evidence of neuroinflammation in long COVID patients with chronic headache, which was supported by the upregulation of IFN, chemokine, and complement pathways in a single-nucleus transcriptomic study of brain tissues of deceased severe COVID-19 patients.
The researchers observed elevated levels of IFN-associated factors, chemokines, and other inflammatory cytokines such as IFNγ, IL-6, IL-7/20/31 in the long COVID patients with chronic headache.
It should be noted that the study also found that despite seemingly mild COVID-19 illness during the acute stage of infection, many of these patients progressed into long COVID headache during the convalescence phase of infection. It found that the onset of long COVID headache might be triggered by a state of hyperinflammation which was sustained throughout the progression of chronic headache even months post infection.
The study concluded that hyperinflammation was involved in triggering the onset of long COVID headache, while sustained inflammation might contribute to the development of long-term post-COVID headache. The immuno-metabolic reprogramming in long COVID headache patients might drive the accumulation of arginine and lipid metabolites
The study findings were published on a preprint server and is currently being peer reviewed.
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