Cytokine profiles associated with persisting symptoms of post-acute sequelae of COVID-19, 2025, Kwon et al

[forestglip]

Cytokine profiles associated with persisting symptoms of post-acute sequelae of COVID-19

Ji-Soo Kwon, Euijin Chang, Hyeon Mu Jang, Ji Yeun Kim, Woori Kim, Ju Yeon Son, Junho Cha, Choi Young Jang, Seongman Bae, Jiwon Jung, Min Jae Kim, Yong Pil Chong, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Sung-Han Kim

Background/Aims
Post-acute sequelae of COVID-19 (PASC) are highly heterogeneous; therefore, the pathophysiological mechanisms for PASC remain unclear. In this study, we aimed to examine the immunologic aspects of various PASC symptoms.

Methods
We prospectively enrolled adults aged ≥ 18 years who were diagnosed with COVID-19 between August 2022 and September 2023. Blood samples were collected from all participants, who were interviewed using a questionnaire for PASC symptoms at least once between 1 and 6 months after the COVID-19 diagnosis. For immunological evaluation, plasma concentrations of SARS-CoV-2 spike subunit 1-specific IgG and 33 cytokines were measured using enzyme-linked immunosorbent assays and multiplex-based immunoassay, respectively.

Results
In total, 156 pairs of blood samples and symptom reports from 79 participants were eligible for analysis. The most frequent symptom was fatigue, followed by post exertional malaise, chronic cough, thirst, and brain fog.

Gastrointestinal symptoms, chest pain, post exertional malaise, smell/taste change, fatigue, brain fog, abnormal movement, and palpitation were accompanied by significant increases in IL-10, VEGF, and inflammatory cytokines like MIP-1α, IL-1β, IL-6, IL-8, MIG, granzyme A, and CX3CL1 levels, while chronic cough, dizziness, dyspnea, and hair loss were not accompanied by significant differences in cytokine levels.

Conclusions
Symptoms classified into different categories based on the dysfunctional organs may share a common pathophysiology regarding elevation of certain cytokines. Although PASC symptoms are heterogeneous, our findings suggest that T-cell recruitment, thrombosis, and increased vascular permeability might contribute to various symptom clusters sharing common pathophysiological mechanisms.

Link | PDF (Korean J Intern Med) [Open Access]

 

[forestglip]

Editorial about this study:

Unraveling the immune responses in long COVID through cytokine profiling
Oh-Hyun Cho

[First paragraph with line breaks added]

As the unprecedented COVID-19 pandemic begins to subside, increasing attention has been directed toward the post-acute sequelae of SARS-CoV-2 infection (PASC) or long COVID, which affects a significant proportion of individuals recovering from the acute infection. PASC encompasses a wide range of physical, cognitive, and psychological symptoms that typically manifest within three months of the initial COVID-19 illness and persist for at least two months [1].

Extensive basic research has revealed three main mechanisms associated with PASC: persistence of the virus or its components in tissues; dysregulated immune responses, including T cell exhaustion, elevated cytokines, and autoimmunity; and endothelial inflammation with immune thrombosis [2]. However, a limited understanding of its natural history and pathogenesis continues to hinder a consensus on case definitions, making research in these areas particularly challenging.

The identification of pathogenesis-based biomarkers may significantly enhance the understanding and management of PASC. Kwon et al. provided additional insight into the immunopathogenesis of PASC [3]

PDF

 

[Hutan]

33 cytokines

Briefly, microspheres for capturing and detecting the following cytokines were incubated with the plasma samples: interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7 IL-8, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17A, IL-21, granzyme A, granzyme B, monokine induced by IFN-γ (MIG), IFN-γ in-duced protein (IP)-10, IFN-inducible T cell α chemoattrac-tant (I-TAC), tumor necrosis factor (TNF)-α, eotaxin, soluble CD40 ligand (sCD40L), C-X3-C motif chemokine ligand 1(CX3CL1), Fas ligand (FasL), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, reg-ulated on activation, normally T-cell expressed and secreted (RANTES), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and basic
fibroblast growth factor (bFGF).

I think there are issues with this study as far as telling us something about post-Covid-19 ME/CFS. There were only 79 participants, mean age 58 years, 60% male, only 15.6% of participants had been previously healthy and only around half of them experienced mild Covid-19. 27 had had a transplantation, 39 had cardiovascular disease. Many of them are on a range of heavy duty drugs.

41 of the 79 were categorised as having PASC.

The study's participants are diverse, the numbers of participants are too small, and there is a lack of clarity about when the blood samples contributing to the cytokine analyses were taken. Essentially, I think there is too much noise in this study.

I wonder if cytokine measurement methods have improved over time? I note that there was no significant difference for any of the symptoms for IFN-y, presumably because it is difficult to detect. MIG - monokine induced by IFN-y - did show up for some symptoms, so I wonder if that might be a cytokine measurable in the blood that can indicate that IFN-y is present?

 

[Hutan]

This comment from the Discussion was interesting. This team seems to be continuing to work on post-Covid-19 symptoms, with another paper forthcoming. They note that brain fog seems to be linked with PEM or fatigue, while cognitive dysfunction is more likely to be linked to neuronal damage visible on an MRI. I don't know how they are distinguishing the two, apart from perhaps by the MRI assessment.

The pre-vious studies clustered patients with similar characteristics by cytokine levels, revealing differences in prognosis despite similar clinical characteristics. This suggests that diseases with heterogeneity, it is thought to be meaningful to cluster symptoms and patients based on cytokine profiles, even among patients with similar symptoms. In the case of brain fog (symptom cluster 1), it is often considered synonymous with cognitive dysfunction (symptom cluster 2), but they are not entirely identical symptoms. Both symptoms have been thought to be associated with neuroinflammation [27-29].

Moreover, in our recent work in another indepen-dent neurological PASC cohort (not yet published) suggests that brain fog appears to be more closely associated with PEM or fatigue, whereas cognitive dysfunction may repre-sent an independent entity linked to neuronal damage and impaired recovery, accompanied by morphologic changes in magnetic resonance imaging. Alternatively, brain fog fre-quently accompanied with fatigue and high levels of blood cytokine levels in symptom cluster 1 (fatigue, PEM, and brain fog), as shown in this study, may suggest that these symp-toms might be more related with systemic inflammation.

Taken together, although the mechanism underlying the pathogenesis of brain fog and cognitive dysfunction have yet to be fully established, these symptoms, while similar in appearance, may arise from distinct mechanisms. Therefore, our clustering of various PASC symptoms based on cytokine characteristics instead of traditional organ-specific symptom classification may provide further insight into the heteroge-neity of PASC pathophysiology.

Hopefully, in their subsequent studies this Korean team can get access to larger, better characterised cohorts.

Affiliation is Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea