Preprint Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in [CFS] and Long COVID, 2026, Petrov, Maes et al

[forestglip]

Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID

Spoiler: Authors

Petrov, Steliyan I; Bozhkova, Martina; Ivanovska, Mariya; Kalfova, Teodora; Dudova, Dobrina; Todorova, Yana; Dimitrova, Radostina; Murdjeva, Mariana; Taskov, Hristo; Nikolova, Maria; Maes, Michael

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T-cell subsets.

A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted ANCOVA, correlation network analysis, and principal component analysis (PCA).

Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion.

In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired CCR7-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions.

These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches.

Web | DOI | PDF | medRxiv | Preprint

 

[nataliezzz]

One of the questions I always have about these studies comparing ME/CFS and Long COVID is: is there a significant difference between length of illness between the two groups? Could the differences reflect that and changes that occur over time rather than distinct underlying pathophysiology?

 

[DHagen]

From the paper:
4.2. Inclusion Criteria
CFS patients were included in the study according to the diagnostic criteria proposed by the
Institute of Medicine (IOM) in 2015, based on the following three symptoms: 1. Significant
reduction or limitation in the ability to perform pre-illness levels of daily activities that persists for
more than 6 months, accompanied by fatigue that is often profound, of recent or definite (not
lifelong) onset, and is not substantially relieved by rest. 2. Post-exertional malaise. 3. Unrefreshing
sleep. At least one of the following is also required—cognitive impairment or orthostatic
intolerance [29]. LC group participants were categorized, based on a positive SARS-CoV-2 PCR
test and persistence of symptoms (fatigue/post-exertional malaise, dyspnea, joint pain, cognitive
impairment, sleep disturbances, cardiovascular and gastrointestinal symptoms) that cannot be
explained by other conditions for more than 4 months after recovery [30,31]. 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 absence of: LC/CFS symptoms; systemic autoimmune diseases,
administration of immunostimulatory or immunosuppressive drugs, history of chronic disease
(including diabetes, impaired renal or hepatic function), hospitalization or viral/bacterial infection
in the last 2 months preceding the study, abnormal complete blood count and/or biochemical
status, increased C-reactive protein, chronic HIV infection, alcohol addiction and other
dependencies.

Once again, it seems the LC criteria is so broad as to be essentially useless as a category.

 

[DHagen]

One of the questions I always have about these studies comparing ME/CFS and Long COVID is: is there a significant difference between length of illness between the two groups? Could the differences reflect that and changes that occur over time rather than distinct underlying pathophysiology?

From the paper:

Participants with CFS had a longer median duration since symptom onset (36 months)
compared to those with long COVID (23 months, p=0.001), with sex-specific medians of 24 and
36 months in men and women with CFS, and 25 and 20 months in men and women with long
COVID, respectively.