Background: Following the global relaxation of Coronavirus disease 2019 (COVID-19) Non-Pharmaceutical Interventions (NPIs), the epidemiology and immunology of Acute Respiratory Infections (ARIs) are in rapid flux. We aimed to quantify the resurgence patterns of seven major pathogens and to define pathogen-specific host cytokine fingerprints for clinical use.

Methods: From June 1, 2024, to May 31, 2025, we conducted 52-week prospective/retrospective surveillance at Huzhou Central Hospital, China. All febrile (>37.5 °C) out- and in-patients (n = 37,425) were tested by multiplex RT-PCR for SARS-CoV-2, IAV, IBV, RSV, ADV, HRV, and Mycoplasma Pneumoniae (MP). Forty-five serum cytokines/chemokines were quantified using Bio-Plex 48-plex immunoassay in ARI pathogen positive patients and healthy controls.

Results: 18,568 cases (49.6 %) were pathogen positive. IAV dominated (30.2 %), followed by HRV (21.8 %), ADV (17.4 %), SARS-CoV-2 (17.8 %), MP (8.6 %), RSV (3.9 %), and IBV (0.2 %). Three epidemic waves were identified: a midsummer SARSCoV-2 surge (631 cases/week) and two IAV peaks (1,011 and 514 cases/week). Age distribution was bimodal (peaks 0-8 and 24-36 years); RSV, ADV, HRV and MP were pediatric-skewed (>80 % ≤12 y), whereas SARS-CoV-2 and IAV were pan-age. Coinfections occurred in 8.3 %, most commonly ADV+HRV. Serum cytokines segregated into six mechanistic signatures: (1) bFGF uniquely elevated in IAV; (2) IL-3 and MIP-1β uniformly up-regulated; (3) Eotaxin/PDGF-BB pathogen-graded suppression; (4) 19 molecules (e.g., IP-10, IL-6, GM-CSF) pathogen-graded elevation; (5) IL-1Ra, RANTES, VEGF, etc. bidirectional regulation; (6) 13 non-informative analytes. These patter006Es implicate PI3K/Akt, JAK/STAT and MAPK/ERK signaling hubs.

Conclusions: Post-pandemic ARI resurgence is asynchronous and age bimodal. Pathogen-specific cytokine fingerprints allow realtime etiology inference and precision immunomodulation, guiding rapid diagnostics, risk stratification and targeted therapy.