The epidemiology of Plasmodium vivax and Plasmodium falciparum malaria in China, 2004–2012: from intensified control to elimination

Background In China, the national malaria elimination programme has been operating since 2010. This study aimed to explore the epidemiological changes in patterns of malaria in China from intensified control to elimination stages. Methods Data on nationwide malaria cases from 2004 to 2012 were extracted from the Chinese national malaria surveillance system. The secular trend, gender and age features, seasonality, and spatial distribution by Plasmodium species were analysed. Results In total, 238,443 malaria cases were reported, and the proportion of Plasmodium falciparum increased drastically from <10% before 2010 to 55.2% in 2012. From 2004 to 2006, malaria showed a significantly increasing trend and with the highest incidence peak in 2006 (4.6/100,000), while from 2007 onwards, malaria decreased sharply to only 0.18/100,000 in 2012. Males and young age groups became the predominantly affected population. The areas affected by Plasmodium vivax malaria shrunk, while areas affected by P. falciparum malaria expanded from 294 counties in 2004 to 600 counties in 2012. Conclusions This study demonstrated that malaria has decreased dramatically in the last five years, especially since the Chinese government launched a malaria elimination programme in 2010, and areas with reported falciparum malaria cases have expanded over recent years. These findings suggest that elimination efforts should be improved to meet these changes, so as to achieve the nationwide malaria elimination goal in China in 2020.


Background
Malaria, transmitted via the bites of Anopheles mosquitoes, is one of the most important parasitic diseases affecting mankind [1]. More than 3.4 billion people were exposed to the risk of malaria in 2012, and there were an estimated 207 million cases and 627,000 malaria deaths [2,3]. Much effort and progress to control and eliminate malaria has been made by the World Health Organization, affected countries as well as many other cooperative partners [4]. By 2010, 108 countries in the world are malaria free and 99 countries have continuing malaria transmission [5].
Malaria had a wide geographical distribution in China. Both Plasmodium falciparum and Plasmodium vivax malaria have been historically present, with a high incidence. Before the foundation of the People's Republic of China in 1949, it was estimated that 30 million malaria cases occurred yearly and 70% of the counties were endemic for malaria [6,7]. Since then, organizations for control and scientific malaria research have been established and large-scale surveys and anti-malarial campaigns carried out among the regions with high transmission of malaria. These initiatives included strengthening the case reporting system, improving access to treatment, preventive anti-malarial administration for the high-risk groups, environmental improvement, vector control, and social mobilization [8,9]. More recently, annual numbers of reported malaria cases have declined significantly through years of effort, to less than 26,000 by 2000 [10]. The Chinese government implemented intensive interventions between 2000 and 2010, and the national malaria elimination programme was launched from 2010, with the National Action Plan for Malaria Elimination being issued officially in 2010 [11]. An unprecedented fall in numbers of malaria cases was observed subsequently [12][13][14]. Currently, little research has been conducted on the changes of malaria epidemiologic features from the control stage (pre-2010) to the elimination stage (2010 onwards) in China [15]. In this paper, the epidemiological characteristics of both P. vivax and P. falciparum malaria in China were described during this transition period, so as to help prioritize current and future resource allocation for malaria elimination.

Data collection
In this study, the nationwide data on malaria cases were obtained from 2004 to 2012 from the national malaria surveillance system, hosted by the Chinese Center for Disease Control and Prevention. In China, malaria is a statutory notifiable infectious disease, and cases are identified according to the unified diagnostic criteria issued by the Chinese Ministry of Health, which includes the definitions of clinically diagnosed and laboratoryconfirmed cases. Clinically diagnosed cases were defined as a patient with malaria-like symptoms, having lived in or recently travelled to areas with known malaria transmission. Laboratory-confirmed cases were defined as clinically diagnosed cases with any of the following lab test results relating to malaria: malaria parasites confirmed by microscopy, rapid diagnostic tests (RDTs), or polymerase chain reaction test [16,17]. Health workers in both the public and private medical sectors were required to report malaria cases. Both clinically diagnosed and laboratory-confirmed cases were included in this study. The species P. falciparum and P. vivax were further identified.
A standard form was adopted by local physicians and epidemiologist to collect individual information on each malaria case, including age, gender, address, date of onset, diagnosis, and laboratory test result. Routine case and malaria-associated death reporting is done by hospitals. Population data for every province in China from 2004 to 2012 were retrieved from the National Bureau of Statistics of China.

Seasonal feature analysis
Seasonal index was used to understand seasonal patterns of malaria incidence. The index was calculated by month, and it was the average case number for a given month (i.e. May) divided by the mean of case number in that corresponding month (i.e. May) during the whole nine years of 2004-2012 [18]. No obvious seasonal pattern was expected if the seasonal index of each month was close to 1.0 [18].

Geographic distribution of disease incidence
Annual malaria incidence rate for P. vivax and P. falciparum was calculated by dividing the number of annual cases by the corresponding population, and multiplying by 100,000. The incidence rate of every year by province was mapped to present the geographic distribution of malaria. Numbers of total counties and newly affected counties for each species of malaria were calculated separately every year. The total counties were defined as the cumulative number of counties where malaria had been detected by year, and the counties with malaria cases occurring for the first time since 2004 were considered as newly affected counties in the corresponding year. These counties were then regarded as existing affected areas in the following years. The software ArcGIS version 9.1 was used to describe the spatial distribution of malaria using a county-level polygon map.
Overall, 215 deaths from malaria were reported, most of which (92.1%) were caused by P. falciparum (Table 1). One hundred and ninety-one fatal cases (88.9%) were male, and the mean age of deaths was 35.4 years (range: 4-85 years). The crude fatality rate of all cases was 0.09%, with the lowest being 0.03% in 2007 and the highest being 0.73% in 2011. The overall fatality rate of P. falciparum was 1.11% with the lowest recorded in 2007 (0.61%) and the peak in 2011 (2.10%). The overall fatality rate of P. vivax was 0.01%, and no deaths from P. vivax were reported since 2009.
The average annual incidence rate was 2.0 cases/ 100,000 during the whole nine years. Annual incidence rate presented striking variation by year, with the highest recorded in 2006 (4.6/100,000) and the lowest level in

Demographic features
There was a male predominance among cases of both P. vivax and P. falciparum malaria, with male-to-female ratios of 1.9:1 and 5.7:1 respectively. The proportion of male patients had risen significantly during recent years (Figure 2A and B). For P. falciparum malaria, the maleto-female ratio reached 23.6:1 in 2012. Figure 2C and D showed that the proportion of malaria cases among the 0-19 age group decreased during the study period, with the proportion of P. vivax malaria occurring among this age group dropping from 30% in 2004 to 7.5% in 2012, and for P. falciparum malaria from 21% in 2004 to 2% in 2012. By contrast, the proportion of cases among 20-59 year-olds increased for P. vivax (from 62% in 2004 to 89% in 2012) and P. falciparum (from 76% in 2004 to 97% in 2012).

Seasonal features
Plasmodium vivax and P. falciparum malaria presented obvious seasonal characteristics during the study period ( Figure 1B). Plasmodium falciparum malaria occurred most frequently in May-June, during which 28% of cases were reported. The seasonal index was the highest (1.8) and the average monthly incidence rate was 0.022/ 100,000 in May. A relatively high incidence rate of P. vivax malaria was observed during July-October, during which 66% of cases were reported. The average monthly incidence rate reached the peak in August (0.29/ 100,000) and the seasonal index was 2.  Figure 1A). Figure 3 shows the geographical distribution of malaria incidence rate, including the proportion of cases infected with P. vivax and P. falciparum, by province. All 31 provinces in mainland China reported malaria cases. The number of provinces with malaria incidence rate of ≥10/

Discussion
This study, utilizing a longitudinal surveillance dataset spanning 9 years, demonstrated the great changes occurring with respect to the epidemiological characteristics of malaria in China during a period of transition from intensified control to elimination. The incidence rate of P. vivax and P. falciparum both decreased dramatically in the past decade, especially from 2010 when the Chinese government launched a national malaria elimination programme.   However, the number of areas with P. falciparum malaria has increased dramatically during the study period.
Three epidemiologic stages were observed during the study period: malaria cases increased from 2004-2006, decreased from 2007-2009, and kept at a very low, stable level from 2010-2012. A total of 60,193 malaria cases were reported in 2006, which was the highest number of malaria cases in the 21 st century. This was mainly caused by the re-emergence of malaria in the region along the Huanghuai River of central China, especially in Anhui and Henan Provinces. Changing meteorological factors, resulting in increasing vectorial capacity and basic reproductive rate of Anopheles sinensis may lead to further malaria reemergence in these areas [19][20][21][22]. Malaria in these affected areas was effectively controlled by the strengthened Anti-Malaria Programme in 2007, which included several intensified anti-malaria measures, including active screening for malaria cases in high-risk villages, providing greater access to treatment for P. vivax malaria cases facilitated by case tracing and recording of treatment history, preventive administration of anti-malarial medicines in highrisk populations, including people who lived in the same household as malaria cases, and conducting vector control in the high transmission areas [23][24][25].
The demographic characteristics of malaria cases changed markedly, with the predominance of males and young adults increasing during the study period. Migration from the economically backward areas to developed areas, as well as going abroad for business, has exploded since the last decade. It has been suggested that young migrant workers, who leave their original community to another place for work, likely comprise a high-risk group for malaria in China [26]. Most young migrant workers live in the suburbs of the cities. Poor living conditions and a lack of anti-mosquito facilities likely increase opportunities to be exposed to the vector mosquitoes [26]. A total of 215 deaths from malaria were reported, which maintained at a relatively low level during nine years. The fatality rate increased slightly in recent years, which could possibly be attributed to the sharp decrease of cases occurring and the delayed diagnosis of imported malaria cases, as more and more cases existed in the previously non-epidemic areas and the clinicians lacked awareness of malaria diagnosis. The research on malaria fatalities in China and its determinants should be further conducted.
The seasonal analysis demonstrated that peak activity of P. vivax malaria occurred later (July-October) than P. falciparum (May-June). China is a country with a vast territory and contains several climatic zones, and the two types of malaria had different epidemic areas, where meteorological factors and dominate vectors vary greatly, which may explain the difference of seasonal features of the two types of malaria. Along with the rapid reduction in malaria incidence and more sporadic cases among the returners from overseas countries, seasonal variation of cases also lessened [27,28]. It may be a reason for weakened seasonal fluctuation of these two types of malaria epidemics during recent years.
Although incidence rate of P. vivax malaria declined significantly after the strengthened anti-malaria programme in 2007, incidence rate of P. falciparum malaria stabilized, albeit at a lower level, becoming the dominant subtype in 2012. More than 50% of all malaria cases were caused by P. falciparum. What is more, the areas affected by P. falciparum malaria expanded greatly over recent years. The increasing trend of imported malaria from overseas during recent years was the probable reason for the geographic expansion of P. falciparum malaria. One study revealed that many malaria cases were imported in 2011, most of which were caused by P. falciparum [13]. In recent years, with the sharp increase in overseas financial investment, global travel and export of labour, more and more people travelled to Africa and Southeast Asia, where P. falciparum malaria is highly endemic. According to the statistics from the Chinese Bureau of Immigration, the number of international travellers has grown steadily over the decade, and more than 80 million people left the country to seek job opportunities, travel or study in Africa and Southeast Asia in 2012 [29]. Due to a lack of awareness and poor implementation of measures to prevent malaria infection, many travellers suffer from a high risk of malaria infection [30][31][32]. Most recent imported cases returned from African countries (i.e. Ghana and Angola) or Southeast Asian countries (i.e. Myanmar) [33,34]. Therefore, intensive surveillance and management of exported labour, with timely detection, diagnosis and appropriate treatment, should be prioritized [35]. Training of local epidemiologists and physicians on malaria case diagnosis and investigation, especially in the non-epidemic areas, needs to be enhanced. The epidemiological features of imported malaria cases and its impact on malaria elimination in China should also be explored with long-term data in future research.
This study has two possible limitations. First, not every case could be distinguished as being indigenous or imported during the earlier part of the study period, because the data were not available. Only since the national malaria elimination programme launched in 2010, each malaria cases was then required to be investigated and identified as indigenous or imported. Second, the existence of the untyped cases before 2007 might impact the observed distribution of malaria by plasmodium species. However, the proportion of the untyped cases had decreased sharply with the improvement of capacity of malaria testing after 2007.

Conclusions
The incidence of malaria in China has decreased dramatically in the past few years, especially after 2010 when the Chinese government launched a national malaria elimination program. However, areas with P. falciparum malaria have expanded. Many sporadic cases appeared in the non-epidemic areas, which has brought new challenges for malaria diagnosis and treatment at a local level. Malaria elimination efforts should be further improved to meet these new challenges, so as to effectively allocate public health resources to achieve the goal of national malaria elimination in 2020.