**1. Introduction**

Arguably, there is an increasing consensus in academia showing that climate change is a dominant driving force of plague outbreak in the intricate pattern of disease complexity. For example, climatic fluctuations have been found associated with the recurrent introduction of *Yersinia pestis*, the bacterium responsible for causing the plague, from Asia into Europe during the Black Death era [1,2]. Stenseth, et al. [3] pointed out that warmer springs and wetter summers favored the prevalence of plague dynamics at its natural reservoir in Kazakhstan. In China, the modeling results by Xu, et al. [4] demonstrated that historical plague intensities in Northern and Southern China were positively correlated to wetness and dryness, respectively. However, according to more updated findings from Xu, et al. [5], wetness accelerated the spread of the plague during the third plague pandemic in China. Apparently, some of these climate-plague nexuses are related to climatic phenomena at a larger scale. Plague outbreak is quantitatively known to be associated with El Nino Southern Oscillation [6–8], Indian Ocean Dipole [7], Pacific Decadal Oscillation [8], and Southern Oscillation Index [9].

Although the above studies help us understand the connection between climate change and plague outbreaks, they are all grounded on the same assumption: climatic variables have a direct and one-step impact on plague dynamics. In those studies, the investigated climatic variables and the plague-indicating variables are simply correlated for measuring their first-order relationship. However, is the association between climate and plague straightforward in nature? According to a series of studies by Zhang et al. [10–12], climatic variations might have worked through a specific set of economic systems to cause the outbreak of epidemics. Hence, the climate-plague association is unlikely to be direct in nature, as there should be a medium in human societies translating climatic forcing to plague outbreaks.

If there is indeed a direct relationship between the climatic variables and plague dynamics, then the investigations of the climate-plague nexus would remain convincing that the nexus normally requires a lesser likelihood to include a third variable in explaining the correlation. If there is not such a relationship, although it cannot overturn the previous observations and computational results, it may somehow indicate that many scholars may have oversimplified the necessary pathways between climate change and plague outbreak. As Zhang et al. [12] indicated, climate change could generate chronic undernourishment in China through the shrinkage of agricultural production, which further weakened immunity to infectious diseases. Lee and Zhang [13] associated the causality of climate-induced famine on epidemics outbreak in historical China. Tian, et al. [14] worked further to reveal that cold and dry climate conditions, in large part, indirectly increased the frequency of epidemics outbreak through generating the prevalence of locusts and famines in China over the last two millennia. Dunca and Scott [15] also emphasized the crucial role of nutrition and immunity in the spread of infectious diseases in pre-industrial European societies. The study by Pei, et al. [16] outlined the dependence on climate of the macroeconomic structure in Europe, and further indicated that such dependence would be imperative in pulling human societies into the Malthusian trap, which includes epidemics outbreak, in pre-industrial Europe. Specifically, we also provided a hypothetical explanation of the climate-plague relationship and highlighted the possibility that climate change a ffected plague dynamics via economic systems. Hence, the influence of temperature/precipitation on plague dynamics appeared to have inconsistent time lags at the multi-decadal to centennial timescales [2]. However, despite e fforts to demonstrate the climate-economic-epidemics relationship in the past decades, there exists little empirical understanding of how climatic variations and plague dynamics are integrated via economic systems.

In this study, we tried to fill in the research gap in the climate-economic-epidemic relationship by examining the direct and indirect e ffects of climatic fluctuations on the frequency of plague outbreak in pre-industrial Europe at the continental scale. In our study region over the course of AD1347–1760, there have been documented long-term counts of human plague outbreak; the economic trend has been described in fine resolution; and climatic variables have been reconstructed through widespread dendrochronology records. We used such long-term data on plague, climate, and economic attributes to answer the following questions: (1) whether the investigated climatic variable exhibited a direct and/or indirect influence (through economic systems) on human plague dynamics in Europe at the continental scale; (2) whether economic attributes deliver their influence to human plague activities in Europe at the continental scale; and (3) whether both climatic variables and economic factors maintain a long-term trend with human plague dynamics over the study period in Europe at the continental scale. To address the above issues, we applied structural equation modeling (SEM) to disentangle that direct and/or indirect importance of climatic fluctuations on historical plague activities in human societies. We showed all the hypothetical pathways being tested in our analysis in Figure 1. Our findings sugges<sup>t</sup> that climate-driven economic fluctuations played a crucial role in translating climate change into plague outbreak.

**Figure 1.** Path diagram showing all hypothesized direct and indirect links amongs<sup>t</sup> climate change, economic fluctuations (including wheat price, CPI, and real wage), and plague outbreak. Climate change and economic fluctuations may directly cause the plague outbreak. Also, climate change may indirectly cause the plague outbreak by influencing the wheat price, and then the wheat price will a ffect CPI and the real wage.

#### **2. Materials and Methods**
