Spatial heterogeneity in the temperature–hand, foot, and mouth disease association among children: A multicounty time-series study in western China

While meteorological and socioeconomic factors are well-documented modifiers of spatial heterogeneity in temperature-hand, foot, and mouth disease (HFMD) associations, substantial unexplained heterogeneity remains. This study investigates underexplored environmental modifiers-including extreme temperature events (heat waves and cold spells), air pollution, and normalized difference vegetation index (NDVI)-by analyzing 484,928 HFMD cases among children under six years old in western China (2013-2019) using distributed lag nonlinear models and meta-regression. We found that cold spells (accounted for 3.84% of the spatial heterogeneity attributable above the baseline level), PM2.5 (3.06%), heat waves (2.72%), PM10 (2.08%), NDVI (1.57%) and O3 (0.78%) were statistically significant modifiers of spatial heterogeneity in the temperature-HFMD associations. Further analysis of PM2.5 components identified nitrate (1.78%) and ammonium (1.58%) as additional modifiers. Among these, cold spells, heat waves, PM2.5, and NDVI were the primary contributors. Specifically, the relative risk (RR) of HFMD at the 95th temperature percentile reached 3.17 (95% CI: 2.39-4.19) in frequent heat waves regions and 3.05 (2.35-3.95) in high-PM2.5 areas. Conversely, regions with low cold-spell frequency also exhibited increased temperature-related risk (RR = 3.13, 2.40-4.07) at the same temperature, as did low NDVI regions (RR = 2.16, 1.79-2.59). Spatial cluster analysis further revealed that the central and northeastern regions exhibited higher temperature-related HFMD risks compared to the southwestern region. These pronounced spatial modification effects challenge the generalizability of single-site study and highlight the importance of region-specific public health strategies that integrate early warning systems for extreme temperatures, air pollution mitigation, and locally adapted greening interventions.