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.Author summary: Hand, foot, and mouth disease (HFMD) is a common illness among young children, especially in Asia. Although temperature is known to influence the risk of HFMD, the relationship between temperature and disease varies from place to place. In this study, we analyzed over 480,000 HFMD cases in children under six years old across 88 counties in western China. We explored how regional environmental conditions—such as heat waves, cold spells, air pollution, and green space—might explain these differences. We found that areas with more heat waves or higher levels of air pollution had greater HFMD risk during hot weather. In contrast, regions with more green space or frequent cold spells showed weaker temperature effects. We also used clustering methods to group regions with similar environmental patterns and found that some areas were more vulnerable to temperature-related HFMD than others. These results show that local environmental conditions play an important role in shaping disease risk and suggest that region-specific prevention strategies may help reduce HFMD in children.