Progress on the national echinococcosis control programme in China: analysis of humans and dogs population intervention during 2004–2014

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. Human echinococcosis prevalence rate decrease from 1.08% in 2004 to 0.24% in 2012. The objective of this study is focusing on assessment of the programme with two indices, including patient treatment and registered dogs deworming, in endemic areas of echincoccosis control over the period of 10 years (2004–2014) in China. Methods We established the database including demography at county and township levels with coverage for ten provinces and autonomous regions of China in this study. We using methods of epidemiological descriptive, instead the expectation-maximization for missing value filling for grouping available patients into those subjected to surgery and those receiving drug treatment after population screening and the dogs population after registered by deworming. We performed Microsoft Excel software and SPSS software on the results as percentages with the corresponding 95% confidence intervals (95% CIs). We also statistically analyzed the economics data on patient treatment and dogs deworming after the corresponding discount with annual bank interest rates (USD 1 = CNY 6.5, bank discount average changes of 2.3–3.3%). Results During 2004–2014, 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 USD 27.03 million after discount for patients and registered dog treatment, which is 1/4 of the total accumulated financial inputs (USD 110.67 million from the Chinese Government). Since the implementation of the national program, it has increased 57 times with respect to the annual financial inputs (costs) and 368 times with respect to all accumulated financial inputs (costs). Conclusions This study showed that in endemic areas, patient diagnosis and management, dog management and treatment over this period helped reduce the parasite load to control the disease. 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.


Background
Echinococcosis (hydatid disease) is one of the 17 neglected tropical diseases recognized by the World Health Organization (WHO) and its continued spread is a severe public health concern [1]. Echinococcosis is mainly endemic in areas of central, eastern and western Asia, South America, Oceania and southern, northern and eastern Africa. Infection in humans/livestock/small mammals is caused by the larval stage of the parasite. Canines (i.e. dogs, foxes, and wolves) are the definitive hosts and play a key role in the transmission and dissemination of the adult stage of this tapeworms belonging to genus Echinococcus. The two most important zoonotic species, E. granulosus (the causative agent of cystic echinococcosis -CE) and E. multilocularis (the causative agent of alveolar echinococcosis -AE), are a serious threat to over 1 million people and responsible for over USD 3 billion in expenses every year. Expressed in global disability-adjusted life years (DALYs), losses of 0.3-1 million DALYs for CE and 0.65 million DALYs for AE, respectively, have been reported [2][3][4][5].
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 farmingpastoral regions of Inner Mongolia, Sichuan, Yunnan, Tibet, Shaanxi, Gansu, Qinghai, Ningxia, and Xinjiang provinces/autonomous regions covering 350 counties, with 120 000 people infected and 50 million people estimated at risk according to the national prevalence survey of echinococcosis initiated by the National Ministry of Health 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, that 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). This program has developed well, particularly thanks to the national control action plan (2010-2015) implemented by the Chinese 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][15][16]. The key measures were monthly praziquantel oral treatment (reported to have 99.9% efficacy by WHO) of registered dogs in addition to large-scale human surgical interventions and oral treatment in the endemic regions [17]. Clearly, control of CE and AE will have important economic consequences. An evaluation of the outlays 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 [18]. The objective of this study was to assess progress and outlays for the national echinococcosis control program at the central government level over a 10-year period up to 2014. This assessment includes a comprehensive, epidemiological description and economics analysis with estimates for human and dog interventions in the endemic areas of China for the period 2004-2014.

Study area
Based on the National Control Plan on the Prevention and Control of Key Parasitic Diseases (2006-2015) [15], the study was conducted in the pastoral and farmingpastoral regions of project counties in ten provinces and autonomous regions (Inner Mongolia, Sichuan, Yunnan, Tibet, Shaanxi, Gansu, Qinhai, Ningxia, Xinjiang and the Xinjiang Production and Construction Corps) where the echinococcosis control measures were implemented and supported by budgeted annual financial requirements by the Chinese Central Government covering the period 2004-2014 (Figs. 1 and 2).

Data collection
All data were obtained in the form of echinococcosis control statistics from the disease-endemic areas approved by the National Ministry of Health 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 unclassified) 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. The results are shown as percentages with the corresponding 95% confidence 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 filling (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. Statistical analysis on the outlays

Data analysis Statistical analysis on human and dog intervention
The annual financial outlays for the control activities were allocated at the province and county level by the Chinese Central Government. The methods of economics deviations and proportion comparison were used for the outlays of patients' treatment and dogs deworming statistics and analyzed. The outlays after discount of each documented surgical and treatment patient was in accordance with the national available direct financial inputs approved by the State Ministry of Finance as follows (using the exchange rate of USD 1 = CNY 6.5): the annual financial inputs calculated with bank discount average changes of 2.3-3.3%: USD 1230 per surgical case; and USD 1.20 per treatment case at the beginning of 2006 [19]. Additionally, six formulas were expressed as follows for the estimated gap analysis between estimated and actual needs on available patients and registered dogs population calculated and analysis.

Ethical statement
The database is original from National Institute of Parasitic Diseases, China CDC that authorized by National Ministry of Health, China.

Humans intervention
During period 2011-2012 when the accumulated total person-hours were greater than 10 000. During these years, the mean prevalence for surgical patients after diagnosis as the patients at the county level (the project county) were 2.7 (CE), 0.1 (AE), 0.02 (co-infection) and 0.1 (unclassified) per 100 000 persons, respectively, while those at the township level were 2.9, 0.2, 0.04 and 0.13 per 100 000 persons, respectively. It should be noted that some patients were not suitable for surgery. The person-hours for the patients having received treatment were 10.   (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

Economics analysis
Over the 10-year period, a total costs of USD 110.7 million after discount was estimated for the national program by the National Ministry of Health, a sum that was verified by the health administration departments of the endemic areas.  (Table 4).

Estimated gaps
Although the current financial 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 (Table 5).

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 definitive 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 [20][21][22][23][24][25][26][27][28][29].
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 unclassified cases treated during an additional 3-year period decreased by onehalf. The results indicate that patients with co-infection and unclassified 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.
Dogs are definitive 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 [11,13,30,31]. Since 2005, the echinococcosis control initiative in China provides complete data for the management of registered dogs including deworming of infected dogs. Over the 7-year period of 2005-2011, the number of registered dogs increased 9-fold, but the deworming coverage rate only increased 8-fold in 2011 compared to the rate in 2005. However, according to the complete data records of registered dogs   [32,33]. Data for the annual number of dogs deworming with dog-time calculated for large-scale deworming for the registered dogs increased 1.7-time 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. 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]. We also 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 difficult in some regions where cultural acceptance is prevalent, several studies indicate that distribution of anthelmintic baits against wild and stray definitive hosts results in significant reductions in AE prevalence, particularly if innovative bait delivery is used [13,[34][35][36][37]. 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 [1,6,17,38,39].
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 USD 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 financial 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. In this study, due to the limitation of data confidentiality, we only collected data approved by the National Ministry of Health up to 2014, so the 4 years data after that were not covered and 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. Moreover, although the national control programme was led by National Ministry of Health, 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 reflect the prevalence for patients and dogs, except for the two national surveys in 2004 and 2012.
All in all, based on the results obtained through this study, we recommend that it will be more effectively on the national programme evaluation by multi-sectoral joints in the future, 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.

Conclusions
This study showed that in endemic areas, patient diagnosis and management, dog management and treatment over this period helped reduce the parasite load to control the disease. Meanwile, it is suggested that more attention should be paid to controlling wild canines during the ongoing program period and sustainable follow-up evaluations by multi-sectoral joints are crucial for success and continued implementation of the national program.