We combined records of 6,656 plague outbreak cases in historical Europe and North Africa and the trade route database that geo-referenced the major overland and maritime trade routes during the early modern period (Fig. 1). To examine whether trade routes were related to the plague outbreak patterns during our study period, we started by checking whether plague hotspots were also key trade nodes. According to a recent study by Schmid et al.30, there was never any permanent plague reservoir in pre-industrial Europe. This implied that a plague outbreak at any given place in our study area was transmitted from a nearby outbreak. If human movements and the circulation of goods provided an ideal channel for the spread of plague, a city’s proximity to key trade nodes would determine its likelihood to become a plague hotspot.

Figure 1 Spatial distribution of plague outbreak in Europe, and Northern Africa, AD1347–1760. Plague outbreaks are related to the patterns of trade routes, both overland and maritime, and also major trade ports in pre-industrial Europe. Cities with recorded plague outbreaks are marked with red dots, with the size of dots referring to the number of plague outbreak during the study period (See legends). The blue lines indicate the major trade route in early modern Europe. The black dots identify the locations of major trade ports with plague outbreak over the study period. Major trade ports without plague outbreak over the study period are labeled in grey dots. Trade routes and trade ports at countries with no plague record are omitted. From our results, more plague outbreaks happened in the periphery of trade routes and trade ports. The map is generated in ArcGIS version 10.1 (www.esri.com/software/arcgis). Full size image

The top 20 cities with the highest year count of plague outbreaks between AD1347 and 1760 are listed in Table 1. Thirteen of these cities were key trade nodes that linked trade routes together. These cities were geographically dispersed and spread in seven countries. As stated by Vogler et al.31, maritime ports were common plague outbreak centers when “plague ships” introduced infected rodent hosts and flea vectors to the cities. In addition, even though half of the trade nodes as documented in our dataset are port cities, only six port cities (in six countries) are listed in Table 1. The same result was also obtained with a sensitivity test (Table S2). Briefly, plague hotspots were mostly trade nodes. Yet, there seemed to be no evidence to support that those hotspots were necessarily port cities. We dissimilated this pattern by searching for the relationship between plague outbreak and its distance to trade route and trade port.

Table 1 List of top 20 plague hotspot cities and their role in old world trade route in Europe, AD1347–1760. Key trade node refers to the major transportation node connecting medieval Europe as indicated by Evans and Brooke41 and Spufford42. Major port city indicates whether it also functioned in maritime trade route. Full size table

If plague was spread along trade routes, the closer one got to a trade route, the easier it would be to become infected. Therefore, we calculated the distance between each plague outbreak and its closest trade route and estimated its relationship with the accumulated count of each plague outbreak point. Several control variables were included in our Ordinary Least Square (OLS) regressions to investigate the robustness of the relationship. Our results are summarized in Table 2. Model 1 was the base model for estimating the relationship between logged distance to trade route and plague count. The association was negative, which supported our hypothesis. In Model 2, the regression was run with both the time fixed-effects and the region fixed-effects to control the influence of any observable or unobservable predictors over the dependent variable. Hence, bias on omitted variables was greatly reduced. The relationship between logged distance to trade route and plague count remained negatively significant. In Model 3, the regression was run with additional geographical controls. As climate is one of the most dominant factors in determining the prevalence of plague13,15,16,32,33, we controlled the effect of temperature on plague reoccurrence by incorporating the elevation and the latitude of plague location into the regression. In addition, the longitude variable also helped to capture the difference in plague distribution between the eastern part and the western part of Europe34. The association continued to remain negatively significant. Further control on climatic zone did not affect the negative correlation between plague count and its distance from trade route (Table S1). As there might be difference between North Africa and Europe, as well as between coastal city and inland city, in terms of their plague recurrence, we included a North Africa dummy and a coastal city dummy in Model 4. Our results showed that no significant difference is seen between North Africa and Europe. In parallel, although coastal cities were more prone to plague outbreak, it did not distort the negative correlation between plague count and its distance to trade route. In Model 5, we included vegetation cover and normalized population density, which symbolizes the degree of urban development over different plague outbreak points, as control variables in the regression. In Model 6, we included per capita Gross Domestic Product (GDP), Consumer Price Index (CPI), and normal laborer wages as control variables in the regression. The specifications in Models 5 and 6 were set according to the practices of traditional public health studies. The rapid and unplanned urbanization process would promote the spread of epidemics35, while landscape contexts were associated with plague occurrence36. On the other hand, accumulated wealth and improvements in the living standard in early modern Europe might dampen plague reoccurrence. Nevertheless, the inclusion of these control variables did not alter the significance and robustness of our estimated relationship.

Table 2 OLS estimates of relationship between plague outbreak and trade route in Europe, AD1347–1760. Full size table

The OLS estimates revealed that distance to trade route has a high explanatory power to the distribution of plague outbreak. Despite its large sample size (n = 6,656), the R2 ranged from 0.41 to 0.44 in Models 2 to 6. The negativity of the association implies that cities closer to trade routes were more vulnerable to plague reoccurrence. On the other hand, being further away from trade routes was a good way to escape from plague.

We performed several sensitivity tests to further check the robustness of our OLS regression results (Table S3). It was shown that the relationship between plague outbreak and trade route was highly significant and remained negative in different temporal domains of our study period (AD 1347–1449, AD1450–1549, AD1550–1649, and AD1650–1760). In addition, the relationship was robust in our different specification of spatial domains, in which the cases in Russia and Africa were excluded, or only the cases in continental Europe and the six major plague outbreak countries were included (see SI for more details). The above results implied that the pattern of plague outbreak was determined by the trade route patterns for the entire study area, which was consistent over the study period. Hence, the relationship should be independent of cultural, demographic, economic factors or the possible spatial bias of plague database as suggested by Alfani37. Otherwise, the relationship over different regions and time periods should differ.

The pattern of plague outbreak in historical Europe was related to the distribution of major trade routes at that time. However, was plague circulating within villages and cities and being retained as a reservoir, as suggested by Ell38? Or was plague repeatedly introduced from major trade ports to inland areas, as suggested by Schmid et al.30? Here we used the distance to major trade ports as an indicator to determine whether there was a permanent plague focus in historical Europe (Fig. 1). A few plausible scenarios should be considered. If there was a permanent plague focus in historical Europe, plague would circulate between cities and villages, and not necessarily be transmitted through trade ports. Therefore, we should not detect any significant relationship between plague outbreak and distance to trade port. However, there might also be a scenario in which the permanent plague focus was so strong that it kept on exporting plague from inland to other parts of Europe. In this case, the relationship being examined in this section might become positively significant. At the same time, it might be possible that trade ports were always the entrance point or starting point for plague transmission, which moved inland until that wave of plague outbreak was no longer able to sustain itself and faded. In such a case, we should detect a negatively significant correlation between distance to trade port and plague outbreak. The OLS estimation results for the above scenarios were reported in Table S4. It was clear that distance to major trade ports was negatively correlated to plague outbreak (p = 0.000, F = 114.38). The negative relationship highlights that more plague outbreaks were recorded when distance to trade port decreased, suggesting that there should not be any permanent plague reservoir in the inland part of Europe. We also conducted a detailed robustness check on how the pattern of plague outbreak was controlled by the distance to trade ports over different specifications in spatial and temporal domains (Table S5). Overall, the results showed a constantly highly significant and negative relationship between distance to trade port and plague. The relationship was robust and did not vary in any timespan or region that we singled out from the database. This further confirmed the estimation that plague was repeatedly introduced to the inland of Europe through maritime trade ports in our study period. Plague was introduced to Europe mainly by maritime trade routes and entered overland trade routes until that wave of plague outbreak faded away or strengthened again by a new introduction of plague supply. Or it was possible that any of the major ports could be a strong permanent plague reservoir. As Davis39 has suggested, in the “upper half” of Europe, the climate was a disadvantage to black rat reproduction. The population of black and brown rats could never be sustained as an epidemic focus without a continuous supply of new rats by ships40.

In the previous analysis, we verified that plagues were repeatedly introduced to Europe through major trade ports, following the trade route to various trade nodes as well as to the cities around the trade routes. This, however, gave rise to another question regarding the extent of the impact of trade route to plague outbreak. Is trade route responsible for shaping all the plague outbreak patterns in historical Europe? To answer this question, we narrowed down our investigation to the sporadic plague outbreak points that had four or fewer outbreaks during our study period (Fig. 2). As shown in Fig. 2, sporadic plague outbreaks (frequency ≤ 4) are scattered around on the map. These sporadic cases did not follow the pattern as described in our previous analysis. The associated statistical result also indicated the relationship between trade routes and plague outbreak to be insignificant (Table S6).

Figure 2 Sporadic plague outbreak (N < 5) did not follow the pattern of major trade routes. The red spots represent the locations of sporadic outbreak of plague (856 locations). The blue lines indicate the major trade route within our study period. The black dots identify the major trade ports with plague outbreak. The trade ports with no reported plague outbreak within our study period are labeled in grey dots. The map is generated in ArcGIS version 10.1 (www.esri.com/software/arcgis). Full size image

However, there must be certain ways for animal hosts to cause these sporadic outbreaks scattered around the European continent. It might be attributable to some less active transportation routes (e.g., navigable rivers) that connected these sporadic cases with the plague hotspots. We calculated the correlation between distance to the closest navigable river and plague outbreak for these sporadic cases (Table S7). We found that although navigable rivers were not as capable as major trade routes in influencing the total plague transmission (Table S8), they did account for the pattern of sporadic plague distribution in historical Europe (p < 0.005; F = 6.13). There were more outbreaks of plague in those cities located closer to the navigable rivers. The result was also verified by robustness checks in various geographical specifications. It confirmed that local river channels, instead of major trade routes, were more significant in determining the distribution of sporadic plague outbreak cases in early modern Europe.

The major trade route database by Evans and Brooke41 and Spufford42 might have neglected the trade route-plague relationship at the local level, as they primarily address the major trade routes and trade ports at the continental scale. Here, we employed a very fine-gained trade route database in Germany, which consists of both major and local trade routes (Fig. 3), to see whether our findings about the trade route-plague relationship could be supported. Our results showed that the parts of Germany that were closer to trade routes, measured by logged distance, tended to be the areas suffering repeated plague occurrence (Model 2 in Table 3). Also, we repeated our analysis by using the major trade route data (in Germany only) complied by Evans and Brooke41 and Spufford42 (Model 1 in Table 3) for cross-validation (Model 2 in Table 3). The same conclusion was reached. In addition, we tested for the role of navigable rivers in plague transmission in Germany (Model 3 in Table 3), and the navigable rivers were shown to be less influential than trade routes (Models 1 and 2) in plague transmission, which is consistent with our results for the whole of Europe (Table 2 and Table S8). The above findings indicated that local trade routes, which are linked with and nested within the major trade routes networks, also contributed to plague distribution significantly. Yet, the absence of fine-grained local trade route databases constrained our investigation on the topic in Germany only.

Figure 3 Distribution and frequency of plague outbreak in relation to the local Holy Roman Empire trade route in Germany, AD1347–1760. It can be seen that locations with more plague recurrence (as referred by the size of red dots) are closer to the local Holy Roman Empire trade route (blue lines). The strength of recurrence fades in according to the distance away from these trade routes as suggested by the statistical analysis (Table 3). The map is generated in ArcGIS version 10.1 (www.esri.com/software/arcgis). Full size image