Pre-pandemic blood profiles predict COVID-19 hospitalization and death a decade later

COVID-19 risk scores developed during the pandemic relied on measurements contemporaneous with infection, leaving unresolved whether the metabolic and inflammatory vulnerability they capture pre-existed as a stable trait or was triggered by acute illness. Here, using 501,946 UK Biobank participants whose blood was drawn between 2006 and 2010—at least ten years before SARS-CoV-2 emerged—we show that baseline proteomic and metabolic profiles predict both COVID-19 hospitalization (2,783 events; C* = 0.676 [0.666–0.686]) and COVID-19 mortality (1,564 deaths; C* = 0.730 [0.701–0.760]) from parsimonious, regularized feature sets. The IL-1 pathway index (xIL1, +0.093) was independently selected for hospitalization but not mortality, while the IL-6 trans-signaling index (xIL6, +0.040) was selected for mortality but not hospitalization—a differential pathway weighting corroborated by independent Light-GBM/SHAP analysis and mirroring the subsequent success of tocilizumab (anti-IL-6R) and the limited efficacy of anakinra (anti-IL-1R) in reducing COVID-19 mortality in randomized trials conducted years later. The mortality model was additionally characterized by central adiposity (waist-hip ratio, +0.386), a respiratory compromise index (xRSP, +0.149), and prodromal cardiovascular disease (pCVD, +0.246). These findings establish that vulnerability to a novel pathogen is, in substantial part, a pre-existing and measurable prodromal state, with implications for pandemic preparedness and population-level risk stratification.