I have written a lot about Long Covid, ME/CFS and chronic inflammation. In a previous post, I have also clearly written how, in my opinion, ME/CFS should have a different name. Now, a new study further demonstrate how the subset of patients with Long Covid fullfilling the criteria of ME/CFS have chronic inflammation.
The authors specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R).
The cohort 1 (discovery cohort) comprised of 44 LC with ME/CFS, individuals who had been infected with SARS-CoV-2 but recovered R, (n = 24) without any symptoms, healthy controls (HCs, whose samples were collected before the COVID-19 pandemic without exposure to SARS-CoV-2, n = 33, median age 49 ± 15.6), and acute COVID-19 (recruited from those with mild/moderate or severe disease in 2020 [14], n = 30, median age 66.13 ± 11.86)
The findings are quite impressive and relevant:
1- ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes.
2- Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients.
3- LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC. The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted.
4- elevation in a variety of autoantibodies in LC.
5- the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group.
6- a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group.
What these findings mean?
First, this study further demonstrates diverse immunological alterations in the subroup of patients with Long Covid having ME/CFS criteria and a dysregulated or impaired hematopoiesis (suggested by the existence of relatively reduced lymphocytes but increased neutrophils, monocytes, and CECs even 12 months after acute SARS-CoV-2 infection). Mechanistically, microbial products and the consequences of SARS-CoV-2 infectioninduced mediators (e.g. cytokines, chemokines, and growth factors) can have a prominent impact on hematopoietic stem and progenitor cells. Lingering dysregulated hematopoiesis in LC suggests a potentially impaired antiviral response and/or increased innate immune response (e.g. cytokines, chemokines, and Gal-9). Subsequently, an impaired antiviral response may increase antigen persistence and promote chronic inflammation, which contributes to the upregulation of co-inhibitory receptors. Therefore, prolonged antigenic stimulation may also enhance T-cell differentiation into effector and terminal effectors. This was supported by a significant reduction in naïve T cells but an increase in terminal effector T cells in LC patients, as reported elsewhere. Alternatively (or, in addition), chronic T cell activation may result in T cell exhaustion, as reported in other LC cohorts.
Secondly, the authors observed a significant elevation in the plasma Gal-9 in LC patients. This elevation has been noted in the acute stage of SARS-CoV-2 infection [14]. Gal-9, as a potent immunomodulatory protein, can interact with different receptors on different immune cells, such as TIM-3, CD44, TCR, CD137, PD-1, etc. This interaction may result in T cell exhaustion or apoptosis (e.g. TIM-3), immune cell activation (e.g. monocytes, NK cells, and macrophages), and induction of proinflammatory mediators [14,50,53]. In agreement with these observations, a recent study has highlighted T cell dysregulation, systemic inflammation, and a lack of coordination between SARS-CoV-2 specific B and T cells in patients with LC.
Third, the authors found that circulating neutrophils in LC patients exhibit an activated phenotype, suggesting an altered metabolic profile and potentially impaired capacity to respond to signals from other immune cells. LC patients had high levels of the neurotrophic factor ARTN, which was also linked with pain and neurocognitive symptoms, potentially playing a role as biomarkers of into the pathogenesis. However, whether the elevated levels of ARTN in LC function pathologically or act as a compensatory mechanism to repair neural damage needs further investigation.
In conclusion, I more and more believe that we need to target chronic inflammation, rather than viral persistence. I am not saying that viral persistence does not play a role, but like I said in the previous post on EBV, it is probably that persistence of viral particles in some individuals that are not able to clear the virus, triggers other inflammatory events. The persisting viral particles are not actively replicating and most probably will not be targeted by antiviral, unless - probably - you have an amazing antiviral drug (which we don’t have yet in general, not only for covid), and therefore targeting chronic inflammation with targeted drugs, as I discussed in a previous post, may be in theory a better option. To know that, we will need several trials investigating several different options.
What would be your proposal to try regarding the inflammation?
Thank you for this article. When will be the online meeting of September about long covid? Thanks a lot!