Zoonotic diseases are capable of infecting humans from animals by direct contact, or via food, water and environment, representing a significant public health problem. Brucellosis, caused by multiple species of the genera Brucella, is a textbook example of zoonotic disease prevalent all over the world. Brucellosis, recognized as the leading neglected zoonotic diseases by World Health Organization (WHO), remains a major epidemic, particularly in low- and middle-income countries, including China (1–4). During the past decades, it was observed a significant increase in human brucellosis in China (5, 6). Given a broad range of animal reservoirs, and humans serving as an accidental host, the exact relationship between human brucellosis and its animal reservoirs remains elusive. This is one of the most pressing knowledge gaps to understand the dynamics of zoonotic Brucella in China.

The Brucella pathogens infect and invade the host via the mucous membranes, gastrointestinal tract, respiratory tract or abraded skin. In China, human infections are more often related to the occupation and consumption of foods of animal origin (7). Veterinary personnel, animal-farmers, and slaughterhouse workers are at the highest risk, usually acquiring infections through the mucous or abraded skin (8, 9). Respiratory tract infections are common in people inhaling contaminated air-borne droplets or dust, for example, those working in the fur processing environment (10). People with no exposure to farm animals or animal-products are usually infected by contaminated food or water via gastrointestinal tract infections (11). The disease burden of human brucellosis infections is dynamic with respect to the endemic areas and time. Despite this dynamism, the only static component in the transmission chain is that the human incidences of brucellosis are always linked to certain animal reservoirs. Here, for the first time, we can address these key questions by using a “One Health” approach in an interconnected manner (6).

Farm animals, companion animals, and wild animals are well-known reservoirs for human Brucella infections (10). Farm animal brucellosis, with a wide range of clinical signs, is dependent on the infected animal hosts, age, sex, routes of exposure and organs involved (12). The hallmarks of infection include spontaneous abortion, undulant fever, and sometimes mastitis. Generally, animal brucellosis is sub-clinical but causes significant economic losses in the livestock industry. In companion animals, most of the infection cases are usually asymptomatic or mild (13). Therefore, farm and companion animal brucellosis are usually underappreciated due to their obscure syndrome and clinical presentations. Nevertheless, a systematic understanding the burden of animal brucellosis is largely lacking in China.

In this study, we conducted a systematic review and meta-analysis of the spatiotemporal epidemiological feature of brucellosis in animals and humans from a nationwide One Health approach. A comprehensive review of animal brucellosis in China, with an integrated evidence-based result analysis of human brucellosis to address the parameters for potential transboundary infections, was also undertaken.

Brucellosis is one of the most common zoonotic diseases worldwide, with a bioweapon potential, posing a significant public health concern (16). It not only causes considerable damages to public health but also significantly impairs veterinary public health and animal welfare. For example, reduced milk yield and contaminated dairy products due to animal brucellosis in America alone worth ~400 million US dollars (17), and the annual economic losses of brucellosis in two counties in Jilin province, China was more than 2.3 million US dollars (18). Brucellosis had been well-controlled last century in China by a nationwide program for brucellosis control, as well as by a national campaign for preventing and controlling brucellosis (19). In China, it had been well-controlled by a national campaign for preventing and controlling brucellosis in the last century. However, the disease has reemerged during the last two decades (20). In certain regions of China, the number of cases of brucellosis reported is higher than that in the 1990s (21). Recently, a study on the epidemiology of human brucellosis was carried out with official data (6). Moreover, Ran and his group applied a meta-analysis on seroprevalence in dairy cows in China (22). Despite these interesting and novel studies, information on the dominant biotype of Brucella in multiple kinds of hosts and prevalence within other animals is ambiguous. To a general extension, our unique One Health approach, combined with evidence-based meta-analysis, could be readily scaled to other zoonotic agents with significant public health importance.

In China, brucellosis was first recorded as Malta fever in two foreigners in Shanghai in 1905 (6). Until the 1990s, there was a high incidence of animal brucellosis, with relatively few human incidence (Supplemental Figure 1). Then after the 1990s, it started an uphill climb in most of the regions of mainland China. Brucellosis, previously thought to be frequently detected in northern China, is now increasingly seen in highly cosmopolitan parts of southern China (23). Our findings are in line with an earlier study which, using the notifiable reporting data for 1955–2014 based on the magnitude and distribution of human brucellosis in mainland China, had emphasized its recent re-emergence (6). Similar to the findings of our analysis, a previous study focusing only on the human incidence of brucellosis, showed some distinct temporal patterns, such as high incidence during 1955–1978, low incidence during 1979–1994, and dramatic accumulation incidences from 1995 onwards is consistent with the trend in Brucella seroprevalence from animal and human sero-surveys conducted in China during 1950–2014 (6). In general, where human prevalence of brucellosis is higher than prevalence of brucellosis in animals are mainly in southern China, including Hainan, Guangxi, Guangdong, Fujian, Jiangxi, Zhejiang, and Hubei (Figure 4). This might be because (1) a lack of animal surveillance capabilities in southern regions as a result of small population of large livestock; (2) the imported animal food contaminated with Brucella are responsible for the infections, which further support the multiple routes for disease transmission (24–28). These reasons might be lead to extreme cases in particular years and places where there is only human brucellosis without an indication of animal brucellosis (Supplemental Figure 1).

In China, 90% of brucellosis occurs in six northern agricultural provinces including Inner Mongolia, Shanxi, Heilongjiang, Hebei, Jilin, and Shaanxi. The Inner Mongolia Autonomous Region has the highest incidence rate of human and animal brucellosis throughout China (29). Human cases have been observed in those regions where animal farming is prevalent, particularly in areas with many poor rural farms and pastures in northwest China (30). However, it is suggested that there is a change in the epidemiology of brucellosis in China (23). Recent publications show that the areas of brucellosis endemicity gradually shifted from pasturing areas, i.e., Inner Mongolia, Xinjiang, Tibet, Qinghai, and Ningxia, to grassland and agricultural areas, i.e., Shanxi, Liaoning, Hebei, Shandong, and Jilin provinces, and the southern provinces became increasingly affected (6). Some analyses further revealed that patients from Guangdong province were more likely to have consumption of apparently exotic foods such as goat placenta (23), thereby manifesting as increased incidence of brucellosis. Although incidence appeared to increase in every province, Tibet seems to follow an inverse pattern and reported a few cases during the past 10 years (6). These hint on the probable movement of infected animals or contaminated food from northern to southern China and thus may explain the current change in the epidemiology of brucellosis in China (23).

Sheep and goats are the major herbivores in northwest China, and they are primarily kept by poor rural farmers in pastoral areas. In general, a considerable number of sheep and yaks are raised on the same grazing land on the Tibetan plateau, and these animals are considered to be the main hosts of Brucella (30). Brucellosis was recognized in Tibet in the 1980s as a disease of both livestock and humans. Some study indicates that bovine brucellosis is endemic among the yak population in the plateau region of China (31).

In the last 12 years, brucellosis has re-emerged in most regions of China, showing an annual accumulation in animal and human infections during this period (29). This is also evident in our meta-analysis which shows a general increasing trend in the prevalence, particularly for the recent past years. With regard to the geographic distribution, our investigation confirmed that sero-prevalence in eastern regions was higher than the central and western regions. This conclusion is also supported by the localized and dense clusters of small ruminants in those regions.

Our analysis has shown that most of the human cases of brucellosis were caused by B. melitensis. It is well-known that B. melitensis is a dominant epidemic strain in animal and B. abortus and B. suis can also infect sheep; B. suis biovar 3, especially emerged in Inner Mongolia (32). B. melitensis genotype ST8 was not only the predominant genotype in sheep but also responsible for human brucellosis (33). The results of seroprevalence assays have confirmed that Brucella spp. was mainly epidemic in sheep and dairy cows, whereas other animals had a very low incidence. These results also showed a strong host preference for certain Brucella species. Furthermore, this also indicates that small ruminants or cattle are the primary risk factors for human contagion. Human brucellosis in northwest China is closely related to infectious sheep. From an epidemiological perspective, the major causes of brucellosis in animals in China have been sheep infected by B. melitensis (34). Sheep and dairy cows with Brucella had higher infection trends, although the positive rates in dairy cows dipped to a downward trend between 2013 and 2014. Compared with this, in sheep and dairy cows, brucellosis in yellow cattle and dogs maintained sporadic onset, and no cases were found in swine (34).

A notable feature in our analysis is the presence of B. canis in all other hosts except for pig and yak. Human brucellosis caused by B. suis and B. canis in Guangxi, China (35) have also been reported earlier. An earlier study reports that B. canis is a rare source of human brucellosis in China (36), where B. melitensis has been the major pathogen associated with human brucellosis outbreaks. B. canis infection was first reported in China in 1983 (13), but now our data indicates that this has become the leading reservoir for emerging brucellosis. This scenario will be even more challenging, considering a significantly growing population in canine market. In a less frequent situation, B. suis can also be directly or indirectly transferred from swine to sheep, which could act as reservoirs for B. suis infection and later transmitted to humans (37). Therefore, an enhanced surveillance system for companion animals in the densely populated cities is urgently needed.

Our data and subsequent analysis have thus revealed that brucellosis was a major concern for study and research in Northern China as compared to Southern China over time, for around three-quarters publications on brucellosis were carried out in North China. However, the meta-analysis showed that some areas in Southern China had even higher prevalence rates than northern ones, suggesting that brucellosis in the south is as severe as the north. It can be inferred from these analyses that human is likely to get infected with Brucella from all available transmission pathways, and various kinds of animals, among which the sheep and goat are possibly the highest risks because the formation of Brucella species in sheep and goat is similar with that of human. More alarmingly, canine brucellosis could be a top public health concern imposing a greater threat to human because pet dogs are playing a more and more important role in the current days of Chinese life. According to statistics, there have been over 740 million domestic dogs in China in 2019 (38), relationships between pet dogs and human are getting more and more close, which emphasizes that canine brucellosis is a pressing concern. An earlier study had shown that Chinese isolates of B. suis strains had unique genetic lineages at the global level whereas the isolates of B. canis were closely homologous to strains from Korea (35). Despite this disease being the most widespread zoonosis globally, it is also true that it remains severely neglected as a potential cause for chronic, debilitating maladies for multiple reasons such as its non-descript clinical presentation in human populations and its varying degree of clinical presentations (11).

Despite our updated largest analysis, there are some limitations to our analysis. Firstly, we only used two databases for bilingual publication research, so we might have missed some literatures. Second, most publications chose RBPT and SAT to detect positive blood samples, which have lower specificity and sensitivity than other recommended methods such as ELISA. Only 24 provinces in China had sufficient qualified data and thus were eligible for meta-analysis, leaving a quite large leak of animal brucellosis in remaining regions in China. Despite these, owing to a large number in the examined dataset, we believe that our meta-analysis is able to unravel a general situation and trend of animal brucellosis in China over time, thus attracting more attention to prevention and control of brucellosis in China.

Brucellosis is an important zoonosis in China, which was controlled well in the late twentieth century but re-emerged in the past two decades. Human may get infected from various domesticated animals, and most possibly sheep and goat. Canine brucellosis deserves more attention for the prevalence rate in dogs are quite high and the relationship between human and dogs is more and more close. Studies on brucellosis and Brucella were gaining more attention at northern provinces than those of southern region. However, our findings suggests that brucellosis among animals in the south is as equally serious as that in the north. Therefore, a nationwide comprehensive monitoring program must be reinitiated for both human and animals. In this perspective, brucellosis being a zoonotic disease, the One Health approach would be an ideal tool for alleviating the other diseases impacts on both humans and animals with the public health concerns.

Brucellosis is a worldwide zoonosis caused by Brucella posing significant damage to both public health and agriculture. However, the report about animal brucellosis in China is scattered, unintegrated, and dominant species among each kind of animals remains unknown. Here, we aimed to present the nationwide evidence-based results by using the systematic review and meta-analytic approach.

After over 100 years in discovery of the agent of Malta fever by David Bruce, brucellosis remains one of the important zoonotic infections causing huge reproductive failure in livestock, and economic losses of the dairy industry in low and middle-income countries. Brucellosis is also a serious public health problem for humans, due to food-chain, and/or occupational exposure. It is estimated that over one-fifth of the 1.4 billion worldwide cattle population is currently infected by Brucella, and results in over half-million new human cases annually, representing the most common systemic bacterial zoonosis. As the world largest population (1.4 billion people and 500 million livestock units), even though numerous studies reported significant accumulation of human brucellosis in China, only scattered and unintegrated animal brucellosis datasets are available, leaving huge knowledge gap for the zoonotic control and measurement.

We used the evidence-based studies, a meta-analysis, to build the most updated and comprehensive picture of brucellosis in China, including humans, livestock, and companion animals. The One Health approach indicates that the trend of human and animal brucellosis are closely associated with each other in China, with significant expansion from traditional northern farming areas to southern China. Importantly, we found that canine and yak could serve as the emerging reservoirs for human infections in China.

The surveillance measurement for human brucellosis should be shifted from traditional northern China to southern regions. Policymakers should consider regional epidemiological data and risk factors to mitigate the zoonotic transmission from animals to humans. Our unique One Health approach, combined with evidence-based meta-analysis, could be readily scaled to other zoonotic agents with significant public health importance.

All datasets generated for this study are included in the article/Supplementary Material.

MY: conceptualization. KZ and BW: data curation. KZ and NP: formal analysis and visualization. MY, NP, and HP: methodology. MY and YL: project administration, and writing—review and editing. NP, HP, and JJ: software. MY, YL, and LZ: supervision. KZ: writing—original draft. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.