Distinct Inflammatory Immune Signature in Acute Mpox Associated With Proctitis.

The immunopathogenesis of clade IIb monkeypox virus (MPXV) infection and its relationship with clinical severity remain poorly defined. We characterized cytokine responses in acute and convalescent mpox to delineate inflammatory profiles. In a multicenter cohort, we quantified 45 plasma protein biomarkers in 3 adult groups: acute mpox (polymerase chain reaction-confirmed clade IIb MPXV infection sampled <14 days from symptom onset); convalescent mpox (>30 days postinfection); and uninfected controls matched for age, sex, race, and HIV status. Biomarkers spanned innate and adaptive immune activation, systemic inflammation, and tissue repair. Principal component analysis and unsupervised hierarchical clustering defined immune profiles. Associations with clinical features were explored via logistic regression. Sixteen participants with acute mpox (median [IQR], 6 days [4-8] from symptom onset; 13% vaccinated) were compared with 16 controls. Three immune clusters were identified. Cluster 1 comprised only unvaccinated acute mpox and exhibited a broad inflammatory signature (IFN-γ, CXCL9/10/11, CCL 7/8, IL-6/10, OSM). Cluster 2 displayed elevated TNFSF12 and FLT3LG, suggestive of tissue remodeling. Cluster 3 demonstrated lower cytokine expression. Mucosal involvement was associated with the inflammatory cluster 1 (odds ratio, 7.85; 95% CI, 1.02-102.40; P = .048). Among 25 participants who were convalescent (median [IQR], 405 days [225-450] postinfection; 12% vaccinated), clustering did not distinguish cases from controls. However, targeted comparisons demonstrated persistent low-grade immune activation (IL-6, OSM) and tissue-remodeling signatures (TGF-α, VEGF-A). Acute clade IIb mpox displays distinct inflammatory profiles, with systemic inflammation concentrated among those with mucosal disease. Convalescence shows partial resolution but persistent tissue repair activity. These pathways may support risk stratification and targeted therapeutic interventions.