{
  "abstract": "A cytokine storm drives critical COVID-19, yet the determinants and long-term consequences of this exaggerated inflammatory response remain unclear. We investigated whether cytokine responsiveness remains altered 2 years after recovery from critical disease. In a cohort of 117 individuals with mild, severe, or critical COVID-19, acute-phase clinical and laboratory parameters were analyzed in moderate–severe and critical cases. Long-term immune function was assessed by ex vivo stimulation of whole blood with PMA/ionomycin, lipopolysaccharide (LPS), and phytohemagglutinin (PHA), followed by cytokine quantification and correlation with clinical parameters. A biobank of 76 patient-derived lymphoblastoid cell lines (LCL cells) was established to evaluate the stability of cytokine responses. During acute illness, critically ill patients exhibited marked inflammatory dysregulation, including lymphopenia (72%), neutrophilia (51%), elevated neutrophil-to-lymphocyte ratios, and increased C-reactive protein (median 91 mg/L) and ferritin (median 1,153 μg/L), consistent with a hyperinflammatory–hypercoagulable phenotype. Two years post-infection, individuals with prior critical disease showed more than threefold higher secretion of IL-1β, IL-6, TNF-α, and IL-8 following PMA/ionomycin (p < 0.0001) and LPS stimulation (p < 0.05) compared with younger mild cases, whereas PHA-induced responses remained comparable. PBMC counts were also higher in the moderate–severe and critical groups 2 years post-infection (p < 0.001), highlighting differences in cellular composition. LCL cells from critically ill donors secreted 79% more IL-8 and TNF-α than those from mild cases (p < 0.05). Collectively, these findings indicate differences in cytokine responsiveness 2 years after COVID-19 which correspond to prior disease severity and are associated particularly with age and innate immune activation.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "Luka Hiti",
      "orcid": "0009-0007-8254-6259"
    },
    {
      "name": "Maša Kandušer",
      "orcid": "0000-0001-7854-0750"
    },
    {
      "name": "Tilen Burnik",
      "orcid": "0009-0004-4566-3796"
    },
    {
      "name": "Nataša Karas Kuželički",
      "orcid": "0000-0002-7662-8481"
    },
    {
      "name": "Jerneja Farkaš Lainščak"
    },
    {
      "name": "Mojca Miholič"
    },
    {
      "name": "Emil Pal"
    },
    {
      "name": "Mitja Lainscak",
      "orcid": "0000-0002-5922-4098"
    },
    {
      "name": "Irena Mlinarič-Raščan",
      "orcid": "0000-0002-7459-3502"
    },
    {
      "name": "Tijana Markovič",
      "orcid": "0000-0002-2397-5009"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/617e6sksqfhmv.bib",
  "cited_by": 0,
  "doi": "10.1038/s41598-026-76481-1",
  "fulltext_url": null,
  "id": "617e6sksqfhmv",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://www.nature.com/articles/s41598-026-76481-1",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2725|COVID-19 Clinical Research Studies"
    ]
  ],
  "openalex": "W7223468079",
  "pdf_url": "https://www.nature.com/articles/s41598-026-76481-1_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-24",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/617e6sksqfhmv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:33Z",
      "native_id": "10.1038/s41598-026-76481-1",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41598-026-76481-1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2725|COVID-19 Clinical Research Studies",
      "subfield": "infectious-disease"
    }
  ],
  "title": "Ex vivo IL-1β, IL-6, TNF-α, and IL-8 responses 2 years after critical COVID-19 are associated with age and innate immune activation",
  "title_text": "Ex vivo IL-1β, IL-6, TNF-α, and IL-8 responses 2 years after critical COVID-19 are associated with age and innate immune activation",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:33Z",
  "url": "https://research.draconitic.com/paper/617e6sksqfhmv",
  "venue": "Scientific Reports",
  "versions": []
}