Malaria in China, 2011–2015: an observational study

Abstract Objective To ascertain the trends and burden of malaria in China and the costs of interventions for 2011–2015. Methods We analysed the spatiotemporal and demographic features of locally transmitted and imported malaria cases using disaggregated surveillance data on malaria from 2011 to 2015, covering the range of dominant malaria vectors in China. The total and mean costs for malaria elimination were calculated by funding sources, interventions and population at risk. Findings A total of 17 745 malaria cases, including 123 deaths (0.7%), were reported in mainland China, with 15 840 (89%) being imported cases, mainly from Africa and south-east Asia. Almost all counties of China (2855/2858) had achieved their elimination goals by 2015, and locally transmitted cases dropped from 1469 cases in 2011 to 43 cases in 2015, mainly occurring in the regions bordering Myanmar where Anopheles minimus and An. dirus are the dominant vector species. A total of United States dollars (US$) 134.6 million was spent in efforts to eliminate malaria during 2011–2015, with US$ 57.2 million (43%) from the Global Fund to Fight AIDS, Tuberculosis and Malaria and US$ 77.3 million (57%) from the Chinese central government. The mean annual investment (US$ 27 million) per person at risk (574 million) was US$ 0.05 (standard deviation: 0.03). Conclusion The locally transmitted malaria burden in China has decreased. The key challenge is to address the remaining local transmission, as well as to reduce imported cases from Africa and south-east Asia. Continued efforts and appropriate levels of investment are needed in the 2016–2020 period to achieve elimination.


Introduction
Malaria remains a public health issue, with an estimated 214 million cases and 438 000 deaths globally in 2015. 1,2 Historically, malaria has been widespread in China, with 24 malariaendemic provinces and over 24 million cases being reported in the early 1970s. Plasmodium vivax and P. falciparum are the main parasite species responsible. 3,4 After control efforts were intensified in China in 2007, the incidence of malaria was substantially reduced in the provinces with malaria transmission, with 95% of these counties (2345/2469) having an estimated incidence below 1 per 10 000 persons in 2009. 5 The Chinese government launched a national malaria elimination programme in May 2010, aimed at reducing the number of locally transmitted malaria cases across most of China to zero by 2015 (except in some border areas of Yunnan province where the goal is elimination by 2017), and achieving World Health Organization (WHO) certification of malaria elimination for China by 2020. 3,6 Comprehensive intervention policies and strategies have been adopted, 7,8 and in 2014 indigenous malaria infections were only found in Yunnan and Tibet provinces. 9 Both international and domestic funds have been used to implement the national malaria elimination programme to achieve the goal of malaria elimination. The Global Fund to Fight AIDS, Tuberculosis and Malaria has supported China, with approximately United States dollars (US$) 113 million, to progress from control to elimination between 2003 and 2012. 9,10 Hence the coverage of Global Fund-supported projects expanded from 47 high malaria-burden counties (within 10 provinces) in 2003 to 762 high and lower malaria-burden counties (within 20 provinces) in 2010. 9 The Global Fund accounted for all documented operational malaria funding in China between 2005 and 2010, 11 and the national strategy application project from the Global Fund has been specific for malaria elimination in China since 2010. However, changes to eligibility criteria in November 2011 meant that China was no longer eligible for grant renewals, due to its categorization as an upper-middle-income country and the malaria burden being sufficiently low. 9,10 The national strategy application was closed ahead of schedule on 30 June 2012, and the Chinese central government has since been committed to covering the investment gaps. 9 Few comprehensive analyses of the changing epidemiology of malaria in China have been done. The achievement of the national malaria elimination programme by 2015, the challenges for the halfway point goals and the evidence in favour of these actions has been more descriptive than quantitative. 9,[12][13][14][15] Both donors and policy-makers should ideally have information about the costs and benefits of interventions. [16][17][18] A robust epidemiological and cost analysis is important to support the design and update of national strategies and future needs for malaria elimination. [17][18][19] We conducted an observational analysis to determine (i) the epidemiological trends and burden of malaria; (ii) the areas and populations with residual Objective To ascertain the trends and burden of malaria in China and the costs of interventions for 2011-2015. Methods We analysed the spatiotemporal and demographic features of locally transmitted and imported malaria cases using disaggregated surveillance data on malaria from 2011 to 2015, covering the range of dominant malaria vectors in China. The total and mean costs for malaria elimination were calculated by funding sources, interventions and population at risk. Findings A total of 17 745 malaria cases, including 123 deaths (0.7%), were reported in mainland China, with 15 840 (89%) being imported cases, mainly from Africa and south-east Asia. Almost all counties of China (2855/2858) had achieved their elimination goals by 2015, and locally transmitted cases dropped from 1469 cases in 2011 to 43  This work identifies the achievements and challenges and thereby helps to plan resource allocation for the second half (2016-2020) of the elimination plan and the ultimate goals of the national malaria elimination programme in China.

Data sources
We obtained data on individual malaria cases, including clinically diagnosed and laboratory-confirmed cases reported in all 31 provinces of mainland China during 2011-2015, from the Chinese malaria enhanced surveillance information system. This system was developed as a part of the national malaria elimination programme to actively collect demographic and epidemiological information, using the unified form for case investigation required by the Chinese technical scheme of malaria elimination. 7,20 Laboratory-confirmed malaria cases refer to patients with a positive result from one type of laboratory test. 21 Rapid diagnostic tests were the primary diagnostic tools in the remote villages, townships and counties. Microscopy was used in county, prefectural and provincial levels as the gold standard method for case verification. Polymerase chain reaction was mainly used for case verification at provincial levels because of its higher sensitivity than microscopy and rapid diagnostic tests. Clinically diagnosed cases were defined as patients with malaria-like symptoms but no parasites detected in blood examination. Imported cases were malaria patients who had travelled to any malaria-endemic areas outside China within the month before illness onset; the last country visited was taken as the potential origin of infection. Locally transmitted cases were patients who had contracted malaria within China. 7 We extracted data on the costs of malaria control and the estimated annual population at risk in 2011-2015 from the WHO annual world malaria reports for 2012-2016, 1,22-25 the annual report of malaria elimination in China, the national programme office for malaria of the Global Fund in China, and information publicly available through the Global Fund website. 10 This study included the costs from the Global Fund (2011-2012) and Chinese central government (2011)(2012)(2013)(2014)(2015). Other sources of international malaria funding (e.g. the President's Malaria Initiative, the United Nations International Children's Emergency Fund and The World Bank) were checked but excluded because no funding for malaria was allocated to China from these sources in 2011-2015. The costs incurred by the governments at sub-national levels are also not included here because the Chinese central government plays a major role in domestic funding to the national malaria elimination programme. From the world malaria reports 1,22-25 and the China annual reports of malaria elimination, 26-30 we also collected data on actions supported using these funds: the number of long-lasting insecticidal nets and insecticide-treated nets distributed; the number of people protected by indoor residual spraying; and the number of blood samples collected and tested for malaria. All the funds documented in Chinese yuan were converted into US$ (the conversion rates were US$ 100 to The geographical distributions of dominant Anopheles species vectors of human malaria in China were obtained from the Malaria Atlas project 32 to define high-risk areas for malaria residual transmission. The population data at national and sub-national level for each year were obtained from the national statistical bureau of China, 31 to estimate the incidence rate and population living in counties with malaria transmission by different dominant Anopheles mosquitoes.

Data analyses
For this analysis we included all cases reported in all 2858 counties of 333 prefectures in 31 provinces of mainland China, with illness onset from 1 January 2011 to 31 December 2015. We summarized the epidemiological characteristics of malaria cases. We estimated the incidence for each year at national and county levels, and calculated the malaria case-fatality rate (number of deaths divided by number of probable and confirmed cases), both overall and stratified by locally transmitted and imported cases. All counties in mainland China have been classified into four categories with different goals for malaria elimination in the national malaria elimination programme (Table 1). We defined the achievement of the national malaria elimination programme for 2011-2015 by comparing the incidence of malaria with the midway goals of the four categories of counties by 2015. The population living in the counties with locally transmitted P. falciparum and P. vivax each year were stratified by the different dominant Anopheles vectors.
We calculated the values of funds disbursed for malaria elimination by the Global Fund and the Chinese central government in 2011-2015. The costs of different interventions and management (e.g. insecticidal nets, diagnostic testing, insecticide and spraying materials, antimalarial medicines, monitoring and evaluation, human resources and technical assistance, management, and other costs) were summarized for each year and stratified by sources of funding. We estimated the coverage of nets (long-lasting insecticidal nets and insecticide-treated nets) and indoor residual spraying, using the corresponding at-risk population in China. The proportion of positive cases was calculated by dividing the total number of laboratoryconfirmed malaria cases by the number of blood samples tested, multiplied by 100 (and expressed as a percentage).
We used R statistical software version 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria) for statistical analyses.

Ethical approval
The National Health and Family Planning Commission of China determined that the collection of malaria case reports was part of continuing public health surveillance of a notifiable infectious disease and was exempt from institutional review board assessment. Ethical clearance for collecting and using second-hand data was also granted by the institutional review board of the University of Southampton, England (No. 18152). All data were supplied and analysed in an anonymous format, without access to personal identifying information. Compared with the goals set for different counties in the national malaria elimination programme by 2015, almost all counties (2855/2858) had achieved their goals by 2015. All 25 counties in the border areas of Yunnan had an annual incidence below the target of one case per 10 000 persons since 2013. However, Motuo county in Tibet, Sanya city in Hainan Island and Donggang city in Liaoning province failed to achieve their goal (reducing locally transmitted cases to zero) by 2015 ( Table 1).

Results
The residual transmission by 2015 might reflect the spatial variability and complexity of Anopheles vectors in China. Among the counties with only An. sinensis and/or An. lesteri as dominant vectors, the number of P. vivax and P. falciparum cases decreased substantially, with only one county reporting the occurrence of locally transmitted P. vivax in 2015 (Table 2). However, among the counties with other dominant vectors (e.g. An. minimus, sensu lato (s.l.), An. dirus s.l., An. stephensis, and An. maculatus), there were still more than 10  A total of 15 840 (89%) imported malaria cases were reported from 2011 to 2015 (Fig. 2)   The expenditure by intervention varied between international and domestic funding ( Table 3). In 2011, the expenditure on management and other costs (e.g. vehicle, small refrigerators and computers) accounted for US$ 13.8 million (57%) of the US$ 24.4 million from the Global Fund. The next highest cost was human resources and technical assistance (US$ 6.3 million; 26%) for providing township hospitals and village clinics with incentives to improve case management and reporting. However, over 2013-2015 the total financing for interventions from the Chinese central government (US$ 51.6 million) was predominantly allocated for diagnostic testing (US$ 29.7 million; 58%) and management and other costs (US$ 14.7 million; 28%). The costs of insecticide-treated nets and long-lasting insecticidal nets, insecticide and spraying materials and antimalarial medicines accounted for small proportions of both international (US$ 0.9 million; 4%) and domestic (US$ 6.6 million; 13%) funding.  (Table 3). Of the total of 30 119 108 blood samples collected for testing 16 579 (0.06%) were positive for malaria parasites (Table 3).

Discussion
The incidence of locally transmitted malaria has decreased in mainland China following the first five years of elimination efforts which began in May 2010. The geographical range of endemic areas with P. falciparum and P. vivax transmission has shrunk, with most counties having achieved their national malaria elimination programme goals by 2015. Malaria is on the verge of elimination in central China. This reduction corresponded with the implementation of the national malaria elimination programme and continuous investments from international and domestic funders to support diagnosis and treatment, indoor residual spraying and the distribution of insecticidal nets. 11,33 This success could also be attributed, at least in part, to robust surveillance systems that rapidly detected and responded to individual cases. 8 This study also suggests that the greatest threats to successful elimination efforts in China are residual malaria transmission in the regions with dominant vectors of An. minimus s.l. and An. dirus s.l.
In areas where malaria transmission has been interrupted, the challenge is to maintain malaria-free status and prevent reintroduction. In contrast, in areas with ongoing local transmission two main challenges exist. First is the higher malaria burden and lack of health care and malaria control services in the malaria-endemic areas of Myanmar and India which border China. Second is the importation of cases from mobile and migrant populations. 34 A high incidence of clinical malaria has been reported from the villages in Yunnan along the border with Myanmar, and the risk increases closer to the international border. 32,[35][36][37] Malaria parasites could be carried across the borders by infected mosquitoes due to the very close proximity of villages along the border on both sides. 35,36 Additionally, malaria importation from beyond neighbouring countries in Africa and south-east Asia also remains a challenge, 38 because only a few countries in these regions are expected to eliminate malaria by 2020. Therefore, addressing cross-border malaria carried by travellers, especially Chinese migrant workers, to and from Africa and nearby countries in southeast Asia is crucial to eliminate malaria and maintain the gains that have been achieved by China so far. 14,[39][40][41][42][43][44] The cost per person at risk in China was low compared with other countries. 17,23 Among 87 malaria-endemic countries that received financial support from international donors to control malaria from 2008 to 2012, China (with more than 56 million people living in endemic districts) ranked second in terms of the size of population at risk of malaria, but 82nd in terms of the amount of international funding invested per person. 17,23  For the second half of the elimination programme and post-elimination era in China, the central and local governments will continue to fund malaria elimination activities and ensure that the universal coverage of interventions is maintained. Resurgence of malaria may occur if control and surveillance measures are scaled back too early following elimination; consistent financing is necessary to avoid this. 5,45,46 Malaria elimination in China may be currently underfunded relative to the frequency of parasite importation and the size of the population living in areas at risk of malaria. Increased funding could be crucial for elimination efforts.  This study had some limitations. First, it is possible that not all improvements in the malaria situation were attributable to the elimination activities. For example, it is known that socioeconomic development can be associated with reduced malaria risk in urban areas, 47 and China has undergone substantial socioeconomic growth and urbanization since the 1980s. 48 These changes could have contributed to a decrease in malaria prevalence, irrespective of malaria control and elimination activities. Second, the number of malaria cases identified in the present study might be an underestimate if some people did not seek treatment. Also, imported cases of malaria may have been misdiagnosed in malaria-free or hard-to-reach areas, even though the individual case-based malaria surveillance system in China operated well during the malaria elimination stage. 20 Third, the cost calculations did not include funding from governments at national and sub-national levels to support the salaries of health department staff at county level or above. These staff members were responsible for most of the malaria elimination activities (e.g. surveillance, data collection, vector control and diagnosis). We also did not include the direct costs of eliminating malaria incurred by the governments at sub-national levels. Because of difficulties in obtaining adequate data, we did not include the costs of malaria treatment provided by physicians and the costs to patients.