Comparable Immune Alterations and Inflammatory Signatures in ME/CFS and Long COVID, 2025, Petrov et al

[John Mac]

Abstract​

Background: Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), is a debilitating condition characterized by persistent fatigue and multisystemic symptoms, such as cognitive impairment, musculoskeletal pain, and post-exertional malaise. Recently, parallels have been drawn between ME/CFS and Long COVID, a post-viral syndrome following infection with SARS-CoV-2, which shares many clinical features with CFS. Both conditions involve chronic immune activation, raising questions about their immunopathological overlap.

Objectives: This study aimed to compare immune biomarkers between patients with ME/CFS or Long COVID and healthy controls to explore shared immune dysfunction.

Methods: We analyzed lymphocyte subsets, cytokine profiles, psychological status and their correlations in 190 participants, 65 with CFS, 54 with Long COVID, and 70 healthy controls.

Results: When compared to healthy subjects, results in both conditions were marked by lower levels of lymphocytes (CFS—2.472 × 109/L, p = 0.006, LC—2.051 × 109/L, p = 0.009), CD8+ T cells (CFS—0.394 × 109/L, p = 0.001, LC—0.404 × 109/L, p = 0.001), and NK cells (CFS—0.205 × 109/L, p = 0.001, LC—0.180 × 109/L, p = 0.001), and higher levels of proinflammatory cytokines such as IL-6 (CFS—3.35 pg/mL, p = 0.050 LC—4.04 pg/mL, p = 0.001), TNF (CFS—2.64 pg/mL, p = 0.023, LC—2.50 pg/mL, p = 0.025), IL-4 (CFS—3.72 pg/mL, p = 0.041, LC—3.45 pg/mL, p = 0.048), and IL-10 (CFS—2.29 pg/mL, p = 0.039, LC—2.25 pg/mL, p = 0.018).

Conclusions: Notably, there were no significant differences between CFS and Long COVID patients in the tested biomarkers. These results demonstrate that ME/CFS and Long COVID display comparable immune and inflammatory profiles, with no significant biomarker differences observed between the two groups.

https://www.mdpi.com/2227-9059/13/12/3001

 

[Utsikt]

Figure 1. Results from age-adjusted ANCOVA test, showing distribution of lymphocytes, NK and CD8+ T cells in the three studied groups as individual points (circles). Exact p values are provided. Results are presented as median values and interquartile ranges (coloured lines).


Figure 2. Results from age-adjusted ANCOVA test, showing serum levels of IFN-γ, TNF, IL-4, IL-2, IL-10, and IL-6 in the three studied groups as individual points (circles). Exact p values are provided where statistical significance was established. Results are presented as median values and interquartile ranges (coloured lines).


Figure 3. Results from age-adjusted ANCOVA test, showing z-score ratios of Th1 ctokine profile, Th1/Th2 + Treg ratio, proinflamatory/antiinflammatory profile, and IRC/CIRS ratio in the three studied groups as individual points (circles). Exact p values are provided where statistical significance was established. Results are presented as median values and interquartile ranges (coloured lines).

 

[Utsikt]

Using ANCOVA to adjust for age differences, we found no significant distinctions between the two syndromes in almost any of the examined lymphocyte subsets or cytokine biomarkers. These results suggest overlapping immunological chnages and support the possibility of common underlying mechanisms in both conditions. The prominent low lymphocyte numbers documented in this study might be a result of chronic immune activation caused by viral infections, leading to immune exhaustion, a phenomenon depicted before [49,50,51,52,53].

They are keen on viral persistence theories.

On the other hand, the presence of an underlying infection, combined with low NK and CD8+ T cells with possible impaired function in viral defense, may be one of the reasons why patients report frequent common viral infections, causing the flu-like, GI symptoms typical for ME/CFS [54].

It doesn’t look like they understand ME/CFS. The flu-like feeling is rarely constant, it’s usually only experienced when in PEM.

They spend an unreasonable amount of time talking about depression, like here:

The increased CD4+/CD8+ ratio observed in both groups, compared to HC, could potentially serve as a marker for disease severity and could be used for monitoring therapy effectiveness. This statement can be supported by the observed negative correlation between CD4/CD8 ratio and the qSUM z-score. An early meta-analysis shows a link between depression, commonly observed in CFS/ME patients [62,63,64,65], and an increased CD4+/CD8+ ratio [66].

They also seem confused about what inflammation is:

The presence of chronic low-grade inflammation may be a potential cause of the symptoms characteristic of ME/CFS, including musculoskeletal pain and persistent fatigue [78]. The presence of low-grade inflammation in ME/CFS is determined by the predominance of the Th1 cytokine profile, which was also seen in the patients in our study and has been documented by other researchers [79]

I have no idea if this data is relevant, but I don’t think their interpretations are of much use..

 

[Holinger]

It doesn’t look like they understand ME/CFS. The flu-like feeling is rarely constant, it’s usually only experienced when in PEM.

That is not my experience. It is worse when in PEM but otherwise the flu like feeling is always there for me since 1999. Only dead sleep is a break. Obviously.

 

[ScoutB]

Sounds like the healthy controls weren't sedentary

Healthy subjects were enrolled based on the absence of an active SARS-CoV-2 infection, confirmed by positive PCR/anti-SARS-CoV-2 IgG, and an absence of Long COVID-19/CFS symptoms.

could that impact these results?

In any case, it's interesting that LC and ME/CFS were so similar. We often see LC more of an intermediate halfway between HC and ME/CFS in these kinds of tests. I wonder if these LC patients were more ME-like than others have been. Haven't looked into it very far though.

Participants in the LC group were categorized as such, based on a positive SARS-CoV-2 PCR test and persistence of symptoms (fatigue/post-exertional malaise, dyspnoea, joint pain, cognitive impairment, sleep disturbances, cardiovascular and gastrointestinal symptoms) more than 4 months after recovery that cannot be explained by other conditions.

 

[Jonathan Edwards]

I would say that the data posted by @Utsikt show nothing of explanatory interest. The populations almost entirely overlap. There is a tail of outliers in the controls which produces the statistical difference in at least some measures. Maybe because they are active, yes. I think this is all noise.

 

[ME/CFS Science Blog]

The statistical tests used age as a covariate, but suspect that the data points shown do not take this into account. The HC group had a mean age of 31, and the LC group of 51.

They also don't give much info about how the patients were selected. Suspect the study was done on patients in Bulgaria?

There's also a weird lack of variability in the IL-2 measurements in the HC group.