Echinococcosis control in China: Progress on humans and dogs population intervention


 Background A national control program for echinococcosis has been in effect since 2005 in China. This program has applied a comprehensive strategy, and good control results have been achieved. The objective of this study is focusing on the effectiveness of the programme with two indices, including patients treatment and registered dogs deworming, in endemic areas of echincoccosis control over the period of 10 years (2004-2014) in China. Methods 10 provinces and autonomous regions of China were chosen for this study and a database was established that included demography at county and township levels, grouping available patients into those subjected to surgery and those receiving drug treatment after population screening. All statistical analyses were performed using Microsoft Excel software and SPSS software and the results are shown as percentages with the corresponding 95% confidence intervals (95% CIs). Results The study showed that over this period, the coverage rate (the grant total average rate) of surgical patient (after surgical operation) treatment had increased with 32.4% and with 81.3% for medical treatment with albendazole. Meanwhile, it increased by 58.6% for the deworming of registered dog since 2007. The accumulated costs amounted to US$ 27.03 million after discount for patients and registered dog treatment, which is 1/4 (27.03/110.67) of the total accumulated financial inputs (US$ 110.67 million from the Chinese Government. Since the implementation of the national program, it has increased 57 times (1705.9/30.1=57) with respect to the annual financial inputs (costs) and 368 times (11,067.9/30.1=368) with respect to all accumulated financial inputs (costs). Conclusions As found through this study, it is suggested that more attention should be paid to controlling wild canines during the ongoing program period and sustainable follow-up evaluations are crucial for success and continued implementation of the national program, which will be necessary until the disease is under control and has been eliminated in all endemic areas of China.

China has a high prevalence of human CE and one of the highest prevalence levels of human AE, accounting for 40% of global DALYs lost worldwide [4,[6][7][8]. Both diseases are widely endemic in the pastoral and farming-pastoral regions of Inner Mongolia, Sichuan, Yunnan, Tibet, Shaanxi, Gansu, Qinghai, Ningxia, and Xinjiang provinces (autonomous regions) covering 350 counties, with120,000 people infected and 50 million people estimated at risk according to the national prevalence survey of echinococcosis initiated by the National Health and Family Planning Commission in 2012 [9]. Notably, canine infectious sources in wild environments in the above endemic areas play important roles in the transmission dynamics of both diseases [10][11][12][13].
A national program for echinococcosis control with comprehensive approaches was launched in 2005. This program has developed well, particularly thanks to the national control action plan (2010)(2011)(2012)(2013)(2014)(2015) implemented by the Chinese Central Government, as evidenced by the human echinococcosis prevalence rate, which has shown a remarkable decrease from 1.08% in 2004 to 0.24% in 2012 [9,14]. The key measures were monthly praziquantel oral treatment (reported to have 99.9% e cacy by WHO) of registered dogs in addition to large-scale human surgical interventions and oral treatment in the endemic regions [15]. Clearly, control of CE and AE will have important economic consequences. An evaluation of the costs of the human intervention and deworming of the dog population is essential and should be part of any program aimed at the control of parasitic zoonoses [16]. The objective of this study was to assess progress and costs for the national echinococcosis control program at the central government level over Due to the limitation of data con dentiality, we only collected data approved by the National Health and Family Planning Commission up to 2014, so the four years data after that were not covered. Moreover, although the national control programme was led by National Health and Family Planning Commission, the livestock management and vaccination were the responsibility of the Ministry of Agriculture and the outcomes will depend on their reports. In addition, the national surveillance system for echinococcosis was established in 2016, as there were hardly any historical data for analysis to fully re ect the prevalence for patients and dogs, except for the two national surveys in 2004 and 2012.

Study area
The study was conducted in the pastoral and farming-pastoral regions of project counties in 10 provinces and autonomous regions (Inner Mongolia, Sichuan, Yunnan, Tibet, Shaanxi, Gansu, Qinhai, Ningxia, Xinjiang and the Xinjiang Production and Construction Corps (XPCC)) where the echinococcosis control measures were implemented and supported by budgeted annual nancial requirements by the Chinese Central Government covering the period 2004-2014 ( Fig. 1, Fig. 2).

Data collection
All data were obtained in the form of echinococcosis control statistics from the disease-endemic areas approved by the National Health and Family Planning Commission for each year of the 10-year period. Data involving patient privacy were not involved. Based on the collected information, a database was established that included demography at county and township levels, grouping available patients into those subjected to surgery and those receiving drug treatment after population screening. Information was given regarding the diagnosis (CE, AE, co-infection or unclassi ed) and the number of registered dogs and that of those dewormed. The situation with respect to humans and dogs were described using epidemiological descriptive analyses and the direct costs calculated after discount.

Statistical analysis
All statistical analyses were performed using Microsoft Excel software, version 2010 (Microsoft O ce, CA, USA) and SPSS software version 18 (SPSS Institute, Chicago, IL, USA). The maps were generated using ArcGIS software, version 10 (ESRI, Redlands, CA, USA). The results are shown as percentages with the corresponding 95% con dence intervals (95% CIs). The annual numbers of dewormed dogs were not directly acquired for the period 2012-2014 due to a change in the statistical criterion adjustment in these years; instead the expectation-maximization (EM) method for missing value lling (https://en.wikipedia.org/wiki/Expectatio-maximization_algorithm) was used to estimate the number of dewormed dogs statistically with reference to the annual total of the registered dog variable and the human prevalence rate for 2004-2011.
Additionally, the direct costs after discount of each documented surgical and treatment patient was in accordance with the national available direct nancial inputs approved by the State Ministry of Finance as follows (using the exchange rate of 1 US$=6.5 RMB Yuan): the annual nancial inputs calculated with bank discount average changes of 2.3-3.3%: US$1,230 per surgical case; and US$1.20 per treatment case at the beginning of 2006. All costs data were statistically analyzed and calculated after the corresponding discount in accordance with annual bank interest rates during the years used for the costs analysis. [17] 3. Results (95% CI, 56.8-82.0%) in 2007, while the total coverage rate was 76.7% (95% CI, 67.5-87.9%) in 2014; these rates were stable over the whole study period (Table. 1).

Humans intervention
Additionally, the number of surgical cases changed from 318 (1,749*18.2%) to 2,379 (31,507*7.55%) from 2004 to 2014 (Table 1) (Table 3). Because disease surveillance was not performed in the endemic regions due to the uneven development of disease control, the actual and accurate data of the dogs in which infection was not reported until 2012, with the exception of large-scale treatment schemes of the dog population using praziquantel tablets, whereas unpublished data based on Echioncoccus coproantigen ELISA tests (fecal antigen detection) for the average dog infection rates (available via the national pilot surveillance system) ranged between 2.89% (15317/530135) in 2013 and 3.35% (3944/117671) in 2014 in the endemic areas.
Dogs are de nitive hosts in the semi-domestic life cycle of E. multilocularis and play a key role due to their close association with E. granulosus throughout parasite transmission in the endemic areas of western China [11,13;18-19] Additionally, monthly anthelmintic treatment for dogs was more effective compared to previous studies [20][21].

Economics Analysis
The national echinococcosis control program led by National Ministry of Health was implemented in sectoral collaboration with 13 other ministries, e.g., the Ministry of Agriculture and the Ministry of Water Resources. The activities consisted of health education, sanitation improving, ultrasound screening of the human population, surgical interventions and treatment with albendazole, including management and deworming of the dog population(8 times above per year). In addition, a pilot study on comprehensive measures, capacity building for the local CDC and other approaches was carried out [22][23]. The annual nancial outlays for the control activities were allocated at the province and county level by the Chinese Central Government. Over the 10-year period, a total costs of US$110.7 million after discount was estimated for the national program by the National Health and Family Planning Commission, a sum that was veri ed by the health administration departments of the endemic areas. The direct costs, ranging from albendazole treatment and surgical operations to deworming the dog population with oral praziquantel, were calculated at US$ 12.  (Table 4).

Estimated Gaps
We carried out a nancial input gap estimate for patient treatments and dogs deworming by for the 2006-2014 period at the national level. The formulas were expressed as follows:  The table 5 shows that although the current nancial inputs did not fully adapt to the emerging number of patients and dogs in need of treatment and deworming, the gap narrowed by 68% in 2014, while it narrowed by 66% with respect to the accumulated costs in comparison to 2006, which is in accordance with the annual increases by China's Central Government.

Discussion
Echinococcosis transmission mainly occurs in the pastoral and farming-pastoral regions of western China due to the complex animal populations and Echinococcus spp., which involve a wide range of intermediate and de nitive hosts, Human epidemiological surveys may be carried out by serology, and ultrasonography is regarded as a simple, safe and reliable diagnostic tool for screening for internal cysts. Importantly, relatively safe and effective chemotherapy is available [24][25][34][35][36][37][38][39][40][41].
The data in this study demonstrate that the grand total person-hours spent on surgical interventions and treatment (including postoperative treatment) was 76.6% of the corresponding grand total proportion for the year of 2014, which was 1. According to the mean prevalence rate at the county and township level, more diagnosed patients will be reported with a higher prevalence following a large-scale population screening; however, the characteristics of the co-infection cases and the unclassi ed cases treated during an additional 3-year period decreased by one-half. The results indicate that patients with co-infection and unclassi ed cases display an annual decreasing trend. Moreover, the patient treatments varied widely due to improvement of the diagnostic accuracy through ultrasound screening for the entire exposed population in high-risk areas. Therefore, patient diagnosis and management, including surgery and treatment with albendazole in endemic areas, are sustainable, whereas established surveillance systems for population prevalence and relevant factors need improvement at different levels, including compliance with respect to albendazole treatment, clinical follow-up, personal information and timely treatment updates of record.
Data for the annual number of dogs deworming with dog-time calculated for large-scale deworming for the registered dogs increased 1.7-times in 2014 compared to 2012 and was estimated at 12 times per dog per year for 2014. In conclusion, the estimation of dog management and treatment over this period was performed at completely different levels on an annual timeline and helped reduce the parasite load to control the disease.
The national echinococcosis control program demonstrates that mass human population screening of echinococcosis, early detection and prompt treatment of human cases and large-scale dog deworming are valuable (particularly with respect to coverage) based on the cost proportion changes, with the exception of limitations of minor values based on the estimation. The results of the simple cost analysis show that over the 10-year period, a total cost of US$ 27.0 million after discount on patients treatment and registered dogs deworming was accumulated. It reached 24.4% accounting for 1/4 of the total nancial input, though currently they have not adapted to the emerging numbers of patients in need of treatment and dogs that should be dewormed. The annual and the accumulated costs increased 57-fold and 368-fold compared to those in 2005 respectively, and the grand total proportion narrowed by 70% with respect to annual or accumulated gaps, which is in accordance with the annual increase of the cost for patients and anti-parasite treatment of registered dogs.
Notably, a strong relationship exists between patients and dogs, which means that there is a high risk that humans ingest parasite eggs directly through contact with infectious dogs or indirectly from contaminated environments. Studies also reveal that E. granulosus eggs remain viable and infective after 41 months that include warm summer and cold winter conditions [1,2,[12][13].
In this study, we found that a positive correlation (R=0.97, P <0.01) between registered dogs with the available patients after Spearman's correlation analysis of the present data. Currently, the management of stray dogs is particularly di cult in some regions where cultural acceptance is prevalent, several studies indicate that distribution of anthelmintic baits against wild and stray de nitive hosts results in signi cant reductions in AE prevalence, particularly if innovative bait delivery is used [26][27][28][31][32]. According to WHO reports regarding endemic regions, the human prevalence rates for CE can reach more than 50 per 100,000 person-years with prevalence levels as high as 5%-10% worldwide; similar rates have been reported in regions of western China [1,6,15,[29][30].
Lastly, though we were unable to include the distribution of wild canines(stray dogs and etc.) through the national program, which is a critical for blocking parasitic egg transmission( . Based on the results obtained through this study, we recommend that more attention should be paid to controlling wild canines during the ongoing program period and with increased focus on patients and dog interventions by the Chinese Government.

Conclusion
The national program for echinococcosis control in China has applied a comprehensive strategy and good control results have been achieved, particularly on the patients and dog interventions. As found through this study, it is suggested that sustainable follow-up evaluations are crucial for success and continued implementation of the national program, which will be necessary until the disease is under control and has been eliminated in all endemic areas of China.

Declarations
The authors declare that they have no competing interests.
Ethics approval and consent to participate Not applicable as the study does not involve the use of any animal or human samples.

Consent for publication
Agreement for publication.

Availability of data and materials
The supporting data in this paper are included in the context. Authors' contributions QY and NX designed the study and QY was the principal writer of the proposals, SH and TT did data management and quality control, X-NZ supervised the study. All authors read and approved the nal manuscript.

Figure 1
Geographic distribution of human cases of cystic echinococcosis (CE) reported by the Chinese system for infectious diseases. Note: The designations employed and the presentation of the material on this map do not imply the expression of any opinion whatsoever on the part of Research Square concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. This map has been provided by the authors.

Figure 2
Geographic distribution of human cases of alveolar echinococcosis (AE) reported by the Chinese system for infectious diseases. Note: The designations employed and the presentation of the material on this map do not imply the expression of any opinion whatsoever on the part of Research Square concerning