Temporal cytokine profiling of acute dengue, Zika, Chikungunya, and Mayaro virus infections in Northern Peru

Background: Arboviruses such as Dengue virus (DENV), Chikungunya virus (CHIKV), Zika virus (ZIKV), and Mayaro virus (MAYV) are major causes of acute febrile illness (AFI) in Peru. However, their overlapping clinical symptoms complicate differential diagnosis. Identifying immunological markers like cytokine profiles could facilitate differential diagnosis and improve understanding of their immunopathogenesis. This study aimed to describe the cytokine responses (IL-2, IL-6, IL-10, TNF-α, IFN-γ) associated with each infection. Methods: A cross-sectional study was conducted from June 2020 to April 2022 in Cajamarca, Peru, including 20 patients each with DENV, CHIKV, ZIKV, or MAYV infection, and 20 healthy controls. Infections were confirmed by RT-PCR and virus-specific IgM ELISAs. Serum cytokine levels (IL-2, IL-6, IL-10, TNF-α, IFN-γ) were measured by ELISA. Cytokine profiles were compared across the four infections and controls, and cytokine kinetics were analyzed by stratifying patients by days post-symptom onset. Results: All four infections presented with overlapping acute symptoms (e.g., fever, headache, myalgia, arthralgia). Despite these clinical similarities, each infection presented a different cytokine profile. IL-2 levels were comparable among the arbovirus groups (though higher in DENV and patients with ZIKV infection than in controls). IL-6 was elevated predominantly in CHIKV and ZIKV; IL-10 was highest in DENV; and TNF-α and IFN-γ were significantly elevated in DENV and ZIKV (with DENV levels exceeding those in MAYV). Analysis of cytokine dynamics showed that levels of all five cytokines generally peaked early (days 1–4 post-symptom onset) and declined thereafter, with the timing and magnitude of peak responses varying by virus. Conclusion: Each arboviral infection analyzed presented a distinct cytokine profile, with elevated IL-6 levels in CHIKV and ZIKV. IL-2, IL-10, TNF-α, and IFN-γ levels were elevated among the flaviviruses studied, with a delayed increase in IL-2 observed in ZIKV patients. Clinical trial number: Not applicable.