Canine rabies control and human exposure 1951–2015, Guangzhou, China

Abstract Objective To describe changes in rabies surveillance and management in Guangzhou, China between 1951 and 2015, and to analyse human rabies cases over that period. Methods Rabies control policies and strategies implemented by the Guangzhou government were reviewed for three periods: 1951 to 1978, 1979 to 2000 and 2001 to 2015. Data on human rabies deaths and exposure were obtained from Guangzhou and national health and disease records. The demographic characteristics of human cases are reported using descriptive statistics. Findings Between 1951 and 2015, the number of organizations cooperating on rabies control increased: there were two between 1951 and 1978, six between 1979 and 2000, and nine between 2001 and 2015. The number of human rabies cases reported in these periods was 331, 422 and 60, respectively. Organizations involved included city and district centres for disease control and prevention, rabies outpatient clinics, medical institutions and police. Overall, 88% (713/813) of cases occurred in rural districts, though, between 1951 and 2015, the distribution shifted from being predominantly rural to being both urban and rural. The number of people exposed to rabies increased annually. The biggest increases were among those injured by a pet dog or other animal: 3.26 and 4.75 times, respectively, between 2005 and 2015. Conclusion Increased cooperation on rabies control between civil organizations in Guangzhou over decades was associated with a marked decrease in the number of human rabies cases. The Guangzhou experience could thereby provide guidance for other cities experiencing similar rabies epidemics.


Introduction
Rabies is a fatal, zoonotic, disease caused by an RNA virus of the genus Lyssavirus. 1 Almost all mammals are susceptible to infection, 2,3 which can occur via bites or scratches from infected animals or through contamination of fresh wounds or mucous membranes by infectious material. 4 In humans, the fatality rate is almost 100%. [5][6][7][8] Worldwide, rabies is a commonly neglected zoonotic disease, especially in developing countries. Mainland China has the second highest rabies incidence in the world, after India 6-8 and the impact on public health is substantial. 9,10 In China, rabies is the third leading cause of death from notifiable diseases, behind acquired immune deficiency syndrome and tuberculosis. 11 The threat of rabies is considerable in many countries around the world. Several of these countries have responded proactively to a proposal by the World Health Organization (WHO) to eliminate rabies transmission from dogs to humans before 2030, by exploring different ways of eradicating endemic rabies. 9 One way is to apply a cooperative effort across multiple disciplines at local, national and global levels that aims to achieve the best results for health by taking into account people, animals and the environment. [12][13][14] The underlying rationale is that disease, particularly zoonotic disease, is influenced by human, animal and environmental factors and can only be tackled through better interdisciplinary and institutional communication, cooperation and collaboration. Applying a cooperative approach reduces health risks to both humans and animals. In practice, this approach involves the combined efforts of public health professionals, doctors and veterinary physicians, as well as staff in related disciplines and institutions. The approach has been applied in Africa, India and Latin America and as a result, the threat of rabies in these areas has decreased. 15 In addition, countries that have successfully eliminated rabies, such as Spain, 16 have adopted a cooperative approach to managing imported cases of rabies.
During the last century, rabies has been endemic in animals in the city of Guangzhou, China and local government has implemented several strategies for controlling the disease and preventing human infection. As techniques for control and prevention have improved and an increasing number of organizations have become involved, human rabies cases have decreased. The aim of this paper was to review the rabies control and prevention strategies implemented in Guangzhou in recent decades to provide guidance for other cities confronting a similar challenge.

Methods
Guangzhou, the capital city of Guangdong, is located in the south of China (Fig. 1). The city covers an area of 7473.4 km 2 , which includes two satellite towns (Zengcheng and Conghua), six urban administrative districts (Huangpu, Tianhe, Yuexiu, Liwan, Haizhu and Luogan) and four rural administrative districts (Panyu, Huadu, Baiyun and Nansha). The population was around 1.38 million in 1951 and 13.5 million in 2015. In 1990, the annual per capita disposable income in rural and urban areas was 1539 yuan (221 United States dollars, US$) and 2749 yuan (US$ 395), respectively and in 2015, it was 17 663 yuan (US$ 2543) and 42 955 yuan (US$ 6185), respectively.
The current system of rabies surveillance and management in Guangzhou has been developed and improved over the decades and comprises two parts: human prevention and monitoring; and dog management (Fig. 2). The Guangzhou Objective To describe changes in rabies surveillance and management in Guangzhou, China between 1951 and 2015, and to analyse human rabies cases over that period. Methods Rabies control policies and strategies implemented by the Guangzhou government were reviewed for three periods: 1951 to 1978, 1979 to 2000 and 2001 to 2015. Data on human rabies deaths and exposure were obtained from Guangzhou and national health and disease records. The demographic characteristics of human cases are reported using descriptive statistics. Findings Between 1951 and 2015, the number of organizations cooperating on rabies control increased: there were two between 1951 and 1978, six between 1979 and 2000, and nine between 2001 and 2015. The number of human rabies cases reported in these periods was 331, 422 and 60, respectively. Organizations involved included city and district centres for disease control and prevention, rabies outpatient clinics, medical institutions and police. Overall, 88% (713/813) of cases occurred in rural districts, though, between 1951 and 2015, the distribution shifted from being predominantly rural to being both urban and rural. The number of people exposed to rabies increased annually. The biggest increases were among those injured by a pet dog or other animal: 3.26 and 4.75 times, respectively, between 2005 and 2015. Conclusion Increased cooperation on rabies control between civil organizations in Guangzhou over decades was associated with a marked decrease in the number of human rabies cases. The Guangzhou experience could thereby provide guidance for other cities experiencing similar rabies epidemics.

Research
Rabies control in Guangzhou, China Yuehong Wei et al.
Center for Disease Control and Prevention is primarily in charge of confirming the diagnosis of rabies in humans and of carrying out epidemiological investigations of rabies cases, leaving other institutions responsible for rabies control work. Medical facilities at every level and rabies outpatient clinics are responsible for identifying cases and offering postexposure prophylaxis (i.e. four doses of rabies vaccine and rabies immunoglobulin) to people who have been bitten or scratched by dogs, cats or other animals. These institutions also record the details of exposed people when they seek medical help. Local centres for disease control and prevention, schools and village committees are responsible for educating people susceptible to rabies infection, the local police are responsible for licensing dogs, the Guangzhou agriculture and veterinary bureau is responsible for vaccinating dogs and the Guangzhou industry and commerce bureau is responsible for regulating the dog and dog meat trade. There is extensive, regular cooperation and communication between these organizations.

Data analysis
All   Data on patients with confirmed rabies who received postexposure prophylaxis between 2005 and 2015 were obtained from surveillance sites located at rabies outpatient clinics. Human rabies was diagnosed according to WHO's expert consultation on rabies. 17 The criteria for a probable case of rabies were a history of exposure (i.e. contact with a suspected rabid animal) and the presence of a clinical syndrome characterized by excitability, hydrophobia, fear of drafts and pharyngeal muscle spasms.
In addition to meeting these criteria, confirmed rabies cases also had to have at least one of the following laboratory findings: (i) the presence of rabies virus antigens; (ii) isolation of virus in cell culture or a laboratory animal; (iii) the presence of viral-specific antibodies in the cerebrospinal fluid or serum of an unvaccinated person; or (iv) the detection of viral nucleic acids by molecular methods in a postmortem or intra vitam sample of, for example, brain tissue, skin, saliva or concentrated urine. In some cases, there was no clinical suspicion of encephalitis or no history of animal exposure, but the case was confirmed by laboratory diagnostic tests. Initial data were entered into a database using EpiData Entry v. 3.1 (EpiData, Odense, Denmark), then analysed and depicted using R v. 3.31 (The R Foundation, Vienna, Austria). The demographic characteristics of human cases are presented using descriptive statistics.

Development of rabies control
Between 1951 and 1978, human rabies was a nationally notifiable infectious disease in China and doctors at every level of medical institutions in Guangzhou had to report suspected or confirmed cases to the Guangzhou Center for Disease Control and Prevention within 24 to 48 hours. Subsequently, patients were given a second and confirmatory diagnosis by the Center for Disease Control and Prevention. During this time period, only two types of organization were involved in the management of rabies: medical institutions and the Guangzhou Center for Disease Control and Prevention (Fig. 2). Rabies control involved killing the infected dog, epidemiological investigation, postexposure prophylaxis and rabies education in the local area.
Between 1979 and 2000, after a human rabies case had been reported, everyone closely connected to the patient would be immunized, all dogs within 2.5 km of the place where the case occurred would be killed and it would be forbidden to be keep or sell dogs in that area for 1 year. At the same time, an extensive educational programme about rabies would be conducted in schools, communities and villages. Moreover, in the late 1980s, the Chinese government established rabies outpatient clinics, where exposed people could get postexposure prophylaxis much more easily (Fig. 2). These clinics dealt only with rabies and were located in district centres for disease control and prevention, hospitals and community health centres. During this time period, six types of organization were involved in the management and surveillance of rabies: district centres for disease control and prevention, schools, village committees and rabies outpatient clinics, as well as medical institutions and the Guangzhou Center for Disease Control and Prevention. In addition, since the Cultural Revolution between 1966 and 1976, many health workers, so called barefoot doctors, have been introduced into the countryside and public health services have been provided with more doctors, medicines and medical equipment. Barefoot doctors raised awareness of rabies prevention and treatment among the population and helped increase treatment and reporting rates after rabies exposure. As a result of these improvements, rabies diagnostic and monitoring capacity improved markedly. Moreover, since economic reforms started in 1978, people's living standards have risen continuously and awareness of disease prevention has increased. Together with rabies prevention measures, these changes have had a considerable effect: only one human rabies case was reported in 1991 and none was reported between 1993 and 1996 (Fig. 3).
Between 2001 and 2015, almost all of the 125 rabies outpatient clinics in Guangzhou started to be used as monitoring points for a rabies monitoring system. The local police started to restrict dog density through dog licensing. The Guangzhou agriculture and veterinary bureau started to immunize dogs by injection at regular intervals and the Guangzhou industry and commerce bureau started to limit the trade in dogs and dog meat products, especially in rabies endemic areas (Fig. 2). In addition, in response to a rabies epidemic in 2005, a dog management regulation and a code of practice for the prevention and treatment of rabies exposure were introduced in Guangzhou. 18,19 In 2016, the Chinese health ministry issued a rabies control and prevention guide, 20 according to which the Guangzhou Center for Disease Control and Prevention  Implementation period  Improvement period   1951  1953  1955  1957  1959  1961  1963  1965  1967  1969  1971  1973  1975  1977  1979  1981  1983  1985  1987  1989  1991  1993  1995  1997  1999  2001  2003  2005  2007  2009  2011

Human rabies cases
Between 1951 and 2015, 813 human rabies cases were recorded in Guangzhou (Fig. 3). The geographical distribution of human rabies cases in Guangzhou was analysed over the decades between 1951 and 2015 (Fig. 4). Cases occurring in rural areas accounted for 88% (713/813) of all human cases. In the 1950s, the highest number of cases were in Baiyun and Panyu districts: 20 and 12 cases, respectively. In later decades, the highest numbers of human rabies cases tended to occur in northern rural areas, especially in the 1980s. In the 1960s and 1970s, the largest number of cases were found in Zengcheng district: 43 and 34 cases occurred in these two decades, respectively. In the most severe epidemic in the 1980s, the total number of cases in all northern rural areas was 70, less than in Conghua district alone, where there were 90 cases. After this epidemic, only 8 cases were reported in the whole of Guangzhou throughout the entire 1990s and there was no case in any of the six urban districts or in one of the two satellite towns. However, between 2000 and 2015, particularly during the late 2000s, another rabies outbreak occurred. At that time, the number of cases in Zengcheng district equalled that in all other districts combined. In the six urban districts, a total of 13 cases were reported between 2000 and 2015, almost equal to the total reported between the 1960s and 1980s in these districts.
The number of people exposed to rabies between 2005 and 2015 was 1 050 553, according to data from monitoring sites at rabies outpatient clinics collected by the Guangzhou Center for Disease Control and Prevention (Fig. 5). The number of cases of exposure reported increased annually, such that, by 2015, it was almost double (61 983/116 776) that in 2005. In more than 90% of cases (57 216/61 983), exposure occurred in the upper or lower limbs. In 2005, the ratio of males to females exposed to rabies was 1.39:1; this ratio decreased over a decade to 1.13:1 in 2015. The proportion of exposed individuals who were younger than 15 years decreased from 26% (16 341 The biggest change was in the number of exposed people who were injured by a pet dog or other animal: between 2005 and 2015, the number increased 3.26 and 4.75 times, respectively. Rabies exposure from guard dogs remained stable over time.

Discussion
After decades of battling with rabies, the Guangzhou government has achieved remarkable results and, in 2014 and 2015, there were no cases in the city. The rabies surveillance and management system has been improved and the Guangzhou government has issued strict regulations to reduce canine density, improve postexposure prophylaxis and increase public awareness of rabies prevention. Over the years, the establishment of this system involved the cooperation of an increasing number of organizations, which illustrates the importance of multisectoral collaboration. 21,22 Multidisciplinary collaboration is an important step towards the elimination of rabies. 15 The disease has already been eliminated in many developed countries and even in developing Latin American countries, the incidence of both human and canine rabies has fallen by 90% thanks to help from international organizations and the establishment of governmental committees. 23 In those countries, rabies control was based on the core strategies of: (i) annual mass vaccination of dogs; (ii) easy access to free postexposure prophylaxis; (iii) disease surveillance; and (iv) education and communication. 21 In Guangzhou, maintaining the number of rabies cases at zero involves addressing several persistent potential threats. Rabies is mainly caused by dogs in developing countries and by wild animals in developed countries. 24 However, the main source of infection in rural areas is free-roaming dogs, which may be either guard dogs or pets. 25 In Guangzhou, efforts to prevent the spread of the rabies virus must consider the changing distribution of rabies cases from predominantly rural areas to both urban and rural areas. According to WHO's recommendations on the prevention of rabies, the vaccination rate in dogs should be at least 70% but, if this cannot be achieved, postexposure prophylaxis should be used as a last defence against human rabies. 26,27 Consequently, despite the usefulness of mass dog vaccination for eliminating rabies, 28 investment in strategies that reduce the health burden of the disease in humans is also important. 29,30 Two other potential threats to rabies control in Guangzhou are a lack of awareness of the disease among the population and limited access to postexposure prophylaxis. In recent years, the number of people exposed to rabies has increased dramatically, particularly the number injured by pets. Some people exposed to infection after being injured by an animal did nothing, because they were not aware that rabies is fatal. One important policy introduced in the 1980s that helped control rabies successfully, aimed at increasing public knowledge about protection against rabies and about the behaviour of rabid dogs. This strategy was particularly beneficial for high-risk sectors of the population, especially children and people living in rural areas. [31][32][33] Research has demonstrated that income plays an important role in gaining access to postexposure prophylaxis. Even in 2010, the annual per capita disposable income of rural residents in Guangzhou was under 18 000 yuan (US$ 2591), whereas the cost of rabies postexposure prophylaxis was approximately 1000 yuan (US$ 144), which made treatment a substantial financial burden for rural residents. 34 Consequently, new policies should be introduced to make it easier for people exposed to rabies, particularly those living in rural areas, to obtain postexposure prophylaxis. One limitation of our study was that the number of cases of rabies exposure was probably underestimated, especially in rural areas. Studies have shown that around 50% of exposed people do not seek medical treatment. Consequently, promoting knowledge of rabies among the general population is still very important. 35 The current rabies control system in Guangzhou took decades to establish and is now very mature and costs around 120 000 yuan (US$ 17 279) per annum to operate. The control effort has had a clear effect on the incidence of rabies. Moreover, the approach demonstrates to other countries and regions with a similar rabies problem that multisectoral collaboration is vital. ■ Acknowledgements Zhicong Yang and Yuehong Wei are the principal co-authors of this paper.  Задействованные организации включали городские и районные центры эпиднадзора и профилактики заболеваний, амбулаторные поликлиники, медицинские учреждения и полицию. В целом 88% случаев (713/813) были зарегистрированы в сельских районах, хотя между 1951 и 2015 годами их распространение изменилось с преимущественно сельских районов на городские и сельские. Количество инфицированных бешенством людей ежегодно увеличивалось. Наибольший рост был среди людей, укушенных домашней собакой или другим животным: в 3,26 и 4,75 раза соответственно в период с 2005 по 2015 год. Вывод Расширение сотрудничества между гражданскими организациями по контролю над бешенством в Гуанчжоу на протяжении десятилетий привело к заметному сокращению количества случаев заболевания бешенством. Таким образом, опыт Гуанчжоу может служить руководством для других городов со сходной эпидемической ситуацией по бешенству.