Multi-scale analysis of the HIF1A hypoxia-inflammation axis in severe COVID-19

Abstract

Objective and designTo test whether the hypoxia-inducible factor 1-alpha (HIF1A) axis links transcriptional, cellular, biomarker and host-genetic features of severe COVID-19, in a retrospective multi-scale observational study of public cohorts and one hospital cohort.

Material or subjects35,268 hospitalized patients (Mexican national registry); 1,100 samples from five bulk RNA-seq cohorts; 25,773 peripheral neutrophils from six individuals; 326 hospitalized patients (Sao Paulo, Brazil); 93 hospitalized patients (University Clinical Center Kragujevac, Serbia).

TreatmentNone.

MethodsWithin-cohort effect sizes for a 10-gene HIF1A panel; single-cell pathway scoring; logistic regression and gradient boosting with SHAP; TaqMan genotyping of HIF1A rs11549465 and rs41508050; cross-validation with bootstrap confidence intervals.

ResultsHIF1A (mean Cohens d +0.39) and LDHA (+0.76) were higher in severe disease in all five cohorts. Neutrophils of all three patients who failed extubation scored higher than those of both weaned patients and over-expressed S100A8/A9. C-reactive protein dominated ICU prediction; laboratory variables raised the AUC from 0.636 to 0.794. In Kragujevac, a clinical model predicted severe outcome (AUC 0.84, 95% CI 0.75-0.92). rs11549465 CT/TT carriers had lower mortality (1/11 vs 28/78; p = 0.095).

ConclusionsHIF1A pathway activation is reproducible across cohorts and localizes to an alarmin-rich neutrophil state; host-genetic effects require larger cohorts.

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BibTeX RIS

BibTeX

@misc{zivanovic2026multiscale,
  title = {{Multi-scale analysis of the HIF1A hypoxia-inflammation axis in severe COVID-19}},
  author = {M. N. Zivanovic and I. Rakovic and A. Miric and M. Z. Milosavljevic and N. Milivojevic Dimitrijevic and N. Filipovic and J. Kosaric and K. Virijevic and M. Brankovic and T. Mladenovic and B. Popovska Jovicic},
  howpublished = {medRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.23.26366304},
  url = {https://www.medrxiv.org/content/10.64898/2026.10.23.26366304v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Multi-scale analysis of the HIF1A hypoxia-inflammation axis in severe COVID-19
AU  - M. N. Zivanovic
AU  - I. Rakovic
AU  - A. Miric
AU  - M. Z. Milosavljevic
AU  - N. Milivojevic Dimitrijevic
AU  - N. Filipovic
AU  - J. Kosaric
AU  - K. Virijevic
AU  - M. Brankovic
AU  - T. Mladenovic
AU  - B. Popovska Jovicic
PY  - 2026
DA  - 2026/10/23
PB  - medRxiv
DO  - 10.64898/2026.10.23.26366304
UR  - https://www.medrxiv.org/content/10.64898/2026.10.23.26366304v1
AB  - Objective and designTo test whether the hypoxia-inducible factor 1-alpha (HIF1A) axis links transcriptional, cellular, biomarker and host-genetic features of severe COVID-19, in a retrospective multi-scale observational study of public cohorts and one hospital cohort.  Material or subjects35,268 hospitalized patients (Mexican national registry); 1,100 samples from five bulk RNA-seq cohorts; 25,773 peripheral neutrophils from six individuals; 326 hospitalized patients (Sao Paulo, Brazil); 93 hospitalized patients (University Clinical Center Kragujevac, Serbia).  TreatmentNone.  MethodsWithin-cohort effect sizes for a 10-gene HIF1A panel; single-cell pathway scoring; logistic regression and gradient boosting with SHAP; TaqMan genotyping of HIF1A rs11549465 and rs41508050; cross-validation with bootstrap confidence intervals.  ResultsHIF1A (mean Cohens d +0.39) and LDHA (+0.76) were higher in severe disease in all five cohorts. Neutrophils of all three patients who failed extubation scored higher than those of both weaned patients and over-expressed S100A8/A9. C-reactive protein dominated ICU prediction; laboratory variables raised the AUC from 0.636 to 0.794. In Kragujevac, a clinical model predicted severe outcome (AUC 0.84, 95% CI 0.75-0.92). rs11549465 CT/TT carriers had lower mortality (1/11 vs 28/78; p = 0.095).  ConclusionsHIF1A pathway activation is reproducible across cohorts and localizes to an alarmin-rich neutrophil state; host-genetic effects require larger cohorts.
ER  -

Abstract

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