Peripheral blood cytokines during early and post-acute stages of SARS-CoV-2 infection are associated with disease severity and long-term symptoms

Abstract:

Background: U.S. Veterans experience a high burden of COVID-19; characterizing immune responses associated with COVID-19 outcomes could help improve treatment. Changes in peripheral blood cytokines over time may predict both acute outcomes and long COVID symptoms.

Methods: Cytokine concentrations were quantified from peripheral blood collected 0-7 days (early) and 14-42 days (post-acute) after enrollment from SARS-CoV-2 positive participants in the EPIC3 study, a prospective, longitudinal cohort following U.S. Veterans. Responses were correlated with Veterans Affairs Severity Index for COVID-19 criteria and chronic symptoms with the modified Medical Research Council Dyspnea scale, Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive function, and PROMIS Fatigue scores 3 months after enrollment (60-135 days). Trends in cytokine concentration with COVID-19 severity were assessed. Odds of COVID-19 severity and long-term symptoms were estimated with logistic regression adjusted for sex, age, and morbidity. Longitudinal changes in cytokine concentration were examined for participants sampled during both time periods, by severity and long-term symptom group.

Results: Early HGF, IL-18, IL-1RA, IP-10, and VEGF-A and post-acute MIP-1α and VEGF-A concentrations trended positively with increasing COVID-19 severity (q-values < 0.05, Jonckheere-Terpstra trend test). Increases in EGF, MIP-1β, and RANTES concentration and decreases in MIP-1α concentration over time were associated with mild rather than moderate or severe disease. Increases in MIP-1β and RANTES concentration and decreases in Eotaxin concentration over time were associated with the absence of long-term symptoms.

Conclusions: Worse COVID-19 severity by 30 days was associated with higher early and post-acute period cytokine concentrations. Participants with long-term symptoms did not see resolution of cytokine responses over time.

Source: Mendall C, Li X, Pakanati V, Liu C, Wang T, Morelli D, Korpak A, Baraff A, Isaacs SN, Chang KM, Le E, Holodniy M, Sugimoto JD, Smith NL, Lee JS, Ross JM, Shah JA. Peripheral blood cytokines during early and post-acute stages of SARS-CoV-2 infection are associated with disease severity and long-term symptoms. Front Immunol. 2026 Jul 15;17:1870109. doi: 10.3389/fimmu.2026.1870109. PMID: 42528778; PMCID: PMC13415590. https://pmc.ncbi.nlm.nih.gov/articles/PMC13415590/ (Full text)

Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles

Abstract:

While there are many postulates for the etiology of post-viral chronic fatigue and other symptomatology, little is known. We draw on our past experience of these syndromes to devise means which can expose the primary players of this malady in terms of a panoply participating biomolecules and the state of the stool microbiome.
Using databases established from a large dataset of patients at risk of colorectal cancer who were followed longitudinally over 3 decades, and a smaller database dedicated to building a Long PASC cohort (Post-Acute Sequelae of COVID-19), we were able to ascertain factors that predisposed patients to (and resulted in) significant changes in various biomarkers, i.e., the stool microbiome and serum cytokine levels, which we verified by collecting stool and serum samples.
There were significant changes in the stool microbiome with an inversion from the usual Bacillota and Bacteroidota species. Serum cytokines showed significant differences in MIP-1β versus TARC (CC chemokine ligand 17) in patients with either PASC or COVID-19 (p < 0.02); IL10 versus IL-12p70a (p < 0.02); IL-1b versus IL-6 (p < 0.01); MCP1 versus TARC (p < 0.03); IL-8 versus TARC (p < 0.002); and Eotaxin3 versus TARC (p < 0.004) in PASC. Some changes were seen solely in COVID-19, including MDC versus MIP-1α (p < 0.01); TNF-α versus IL-1-β (p < 0.06); MCP4 versus TARC (p < 0.0001). We also show correlates with chronic fatigue where an etiology was not identified.
These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology.
Source: Tobi, M., Chaudhari, D., Ryan, E. P., Rossi, N. F., Koka, O., Baxter, B., Tipton, M., Dutt, T. S., Tobi, Y., McVicker, B., & Angoa-Perez, M. (2025). Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles. Biomolecules15(7), 928. https://doi.org/10.3390/biom15070928 https://www.mdpi.com/2218-273X/15/7/928 (Full text)

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay.

Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1β, suggesting a disturbance in interleukin 1 signaling.

Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

 

Source: Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. 2016 Feb;21(2):261-9. doi: 10.1038/mp.2015.29. Epub 2015 Mar 31. https://www.ncbi.nlm.nih.gov/pubmed/25824300