Background
Malaria is a life-threatening infectious disease severely affecting vulnerable communities in tropical and subtropical regions where the environment is suitable for transmission [
1,
2] Although malaria transmission appears to be declining worldwide as a result of control interventions [
2,
3], the 2015 estimation indicates that there are 214 million cases and 438,000 malaria deaths [
4]. Malaria is caused by five species of
Plasmodium:
Plasmodium falciparum, Plasmodium vivax,
Plasmodium ovale,
Plasmodium malariae and
Plasmodium knowlesi [
1]. In China,
P. vivax and
P. falciparum are the main malaria parasites, with the former being the most dominant species [
5].
Anopheles sinensis,
Anopheles minimus,
Anopheles dirus, and
Anopheles lesteri are common malaria vectors in China [
6].
Prior to 1949, the annual number of malaria cases in China was estimated to be 30 million. Owing to its substantial public health importance, a Malaria Control Programme was initiated in 1955 [
7]. Since then, the malaria burden has greatly declined [
8,
9], but it has remained a serious public health problem in China with periodic outbreaks [
10]. Following an epidemic peak in 2006 [
11], control efforts were consolidated with the formulation of the National Malaria Control Programme (NMCP) in 2006 [
12]. Overall, malaria cases have sharply declined with only 14,491 malaria cases reported in 2009 [
13]. The National Malaria Elimination Programme (NMEP) was launched in 2010 [
12]. Since then, substantial progress has been made.
P. vivax malaria cases were reduced by 57.7% in one year [
14], followed by a decline in geographical coverage [
5]. However,
P. falciparum greatly increased dominating the overall confirmed malaria cases since 2007. The proportion of
P. falciparum malaria increased from 7.1% in 2009 [
13] to 71.2% in 2013 [
15]. Areas affected by
P. falciparum have consistently increased from 17 provinces in 2006 to 20 in 2010, 22 in 2011 [
14], and to 30 provinces in 2013 [
14‐
16], involving formerly non-endemic provinces [
17].
The distribution of malaria in China shows considerable variation at fine spatial resolution such as county [
18,
19]. A better understanding of the spatiotemporal change in disease distribution is crucial for improving control interventions and health resource allocation. Several studies have used the spatial and space–time scan statistics to detect clustering of malaria [
18‐
22] and other public health problems [
23] in space and time. These techniques detect disease clusters while adjusting for varying population size among spatial and temporal scales under study. In China, these have been used to identify high-risk areas and periods of malaria in some endemic provinces [
18‐
22,
24,
25]. However, few studies have analysed the spatial and space–time distribution of both
P. vivax and
P. falciparum malaria at the national level. The purpose of the present study is to fill this gap in the understanding of the spatial and spatiotemporal distribution malaria in China during 2005–2014.
Discussion
Using a surveillance dataset of 10 years, the present study demonstrated substantial changes occurring with respect to annual trends and the geographical distribution of malaria in China. The annual number of
P. vivax malaria cases showed a considerable decrease, especially after 2006 when the NMCP was launched [
12]. However, the number of
P. falciparum cases remained relatively stable at a higher level.
P. falciparum cases malaria peaked in 2005, fell until 2008, then slightly increased, and has dominated cases since 2012. The steady decline in
P. vivax cases and increase in
P. falciparum cases was similar to that noted previously [
5].
The present study also indicated a shrinking in the geographical distribution of
P. vivax malaria and a substantial expansion in areas with
P. falciparum. These findings coincide with previous research [
15,
35]. Different interventions have been formulated with the aim of controlling malaria in China. These have been effectively implemented with support from the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) [
36]. This may have increased the ability of counties to effectively control local malaria transmission dominated by
P. vivax [
15,
16]. A possible reason for the geographical expansion of
P. falciparum malaria could be the rising number of overseas imported malaria cases in recent years [
14,
37]. As of 2013, 97.9% of the national malaria cases reported came from overseas [
15]. Most overseas-imported malaria in recent years was
P. falciparum. One study conducted in Jiangsu province showed that
P. falciparum accounted for 79.8% of the total malaria cases imported to the province during 2001–2011 [
38]. In recent years, a dramatic increase in overseas investments increased the number of Chinese persons working abroad and paved the way for international travel to and from countries where
P. falciparum is highly endemic. In 2012, about 0.5 million people left the country for work and 83.2 million for other reasons. Compared to 2010, an increase of 24.6 and 44.9% were observed, respectively [
39]. Available evidence indicated that
P. falciparum was mostly imported via Chinese people returning from Africa [
17,
38,
40‐
44].
Identifying a high-risk area is crucial for spatial targeting of interventions against malaria transmission. Spatial cluster analysis identified most likely clusters of
P. vivax malaria located in North Anhui province from 2005 to 2009. The area where most likely clusters of
P. vivax were identified in this study was similar to the previous transmission foci detected in the northern part of Anhui province [
18], where
An. sinensis is a principal vector. A study suggested that increased vector capacity of
An. sinensis related with the mosquito host reduction (livestock), and human behavioural change contributed to
P. vivax malaria outbreak in Huaiyuan county of Anhui province [
45]. This area, especially north of the Huai River, is one of the high-risk areas with unstable malaria transmission [
46], possibly due to environmental conditions associated with geographical location [
11,
14,
18]. Malaria transmission in this province has been an important issue in China, responsible for the outbreak in 2006 which was dominated by
P. vivax [
11]. From 2006 to 2009, Anhui had been the number one province in China in terms of number of malaria cases [
11,
13,
47].
The present study also identified most likely spatial clusters of
P. vivax malaria in western Yunnan province, along the China–Myanmar border after 2009. The cluster persisted for five years (2010–2014), contributing more than half the total number of
P. vivax cases reported each year. Although the high-risk area identified in this area agrees with previous studies [
20,
48,
49], a shift of the geographical location from Anhui to Yunnan province after 2009 is new. The reduction in Anhui may be explained by intensive malaria control in the central China provinces [
50]. Since the initiation of the NMEP in 2010 [
12,
51], national malaria, especially local cases greatly declined [
8,
15]. One study showed that overall malaria cases in Anhui province decreased by 65.5% (in 2011) compared to those in 2010 [
9]. The total number of
P. vivax cases in the country, therefore, decreased by 57.7% in one year, with most of the local cases in Yunnan province [
16]. The province remained endemic, ranking first in the country in terms of an overall number of malaria cases [
8,
9,
15,
52], particularly
P. vivax [
16]. For example, 73.1% (171/234) of the national
P. vivax malaria cases in 2012 were contributed by Yunnan [
16], and
P. vivax malaria appeared to be dominant along the China–Myanmar border [
53]. Malaria transmission in this area is a major concern in the disease elimination stage. This could be attributed to environmental conditions conducive for transmission and efficiency of the dominant
An. minimus vectors in this area [
17]. Unlike
An. sinensis [
54,
55],
An. minimus shows a strong attraction to human than other hosts [
56] and has a high human blood index [
57] which has an implication for vector control interventions even though
An. minimus is endophilic, endophagic, and susceptible to insecticides [
55,
58]. Human behavioural factors [
59] could be another reason for malaria transmission and control in this area. For example, some counties of Yunnan province along the international border have been recognized as high-risk areas in China because of sharing a boundary with malaria endemic countries which put them at risk of reintroduction [
20,
60]. One study revealed that imported
P. vivax to China had increased between 2004 and 2012, most of which were from malaria endemic countries of South East Asia (Myanmar, Cambodia and Laos) [
16]. 59.3% of the total
P. vivax malaria cases imported from South East Asia (n = 697) were introduced from Myanmar, and 56.7% (n = 6832) of the total introduced
P. vivax cases (n = 12, 060) were in Yunnan [
17]. However, other evidence shows lack of significant association between travel to Myanmar and transmission of
P. vivax along the China–Myanmar border [
53]. Residents in this area have a relatively low educational level, limited knowledge of malaria transmission and utilization of personal protection, especially during outdoor activities [
61,
62], and exhibit poor treatment-seeking behaviour [
62]. These factors could contribute to sustained malaria transmission in this area [
17].
Similarly, the current study identified the most likely spatial clusters of
P. falciparum malaria in the western Yunnan province along the China
–Myanmar border every year from 2005 to 2011. This is consistent with previous studies [
20,
48,
49]. This is the only area where the local
P. falciparum cases were reported by several studies [
9,
15]. It implies that these counties are at high-risk of achieving stable
falciparum malaria transmission. Most of the national
P. falciparum cases during 2005–2011 were reported from Yunnan province, although counties were not frequently specified [
9,
11,
47,
52]. In addition to behavioural and lifestyle factors for malaria transmission [
61], travel to Myanmar was significantly associated with acquiring
P. falciparum infection, indicating cross-border movement is a key factor for the stable transmission of
P. falciparum in the China–Myanmar border [
17,
53,
61,
62]. However, 84.5% of the imported
P. falciparum cases were imported from Africa. Climatic factors have also been found to be an important factor for malaria transmission in this area [
48]. According to one study [
20], temperature was significantly associated with vivax malaria in clustered areas of Yunnan province. Further research is required to better understand the importance of climatic factors in the spatial distribution of malaria in China.
The present study also identified high-risk areas for
P. falciparum in central Anhui province from 2013 to 2014. This foci (Feidong county) is different from the previously identified high-risk area in the Northern Anhui province [
18], indicating spatial variation in foci of
P. falciparum cases, was and its less importance in this area than
P. vivax [
11]. In the present study, the most likely spatial cluster of
P. falciparum was not detected in Anhui province until 2012. However, a spatial cluster of
P. vivax was observed consistently in the northern Anhui province from 2005 to 2009. This result verified that
P. falciparum played a relatively insignificant role in the previously identified high-risk area in Anhui province [
18].
The high-risk area for
P. falciparum malaria shifted from Yunnan to Anhui province, and very large secondary clusters were detected in some counties of the northern and eastern provinces, especially after 2011. This could be attributed to the increased proportion of overseas imported malaria from the parasite endemic countries in recent years [
14,
46].
P. falciparum dominates overseas imported malaria cases, which are distributed in different parts of China, including non-endemic provinces. Nevertheless, the study of disease clustering focused only on local malaria cases. Spatial variations among
P. vivax and
P. falciparum malaria followed different patterns indicating differences in the biological features of parasites, which might have facilitated their transmission. Climatic factors are associated with an increased risk of malaria because of their impact on vector activities and the parasite incubation period [
63]. Compared to
P. vivax,
P. falciparum requires a slightly higher temperature for parasite development. The minimum threshold temperature for
P. falciparum and
P. vivax are approximately 18 and 15 °C, respectively [
64], indicating increased opportunity for
P. falciparum to spread to previously cooler areas, following global climate change. Further studies are required to fully understand the risk factors driving spatial shifting and geographic expansion of
P. falciparum across mainland China.
The most likely space–time cluster of
P. vivax malaria was detected in the northern Anhui province. These areas coincided with results of the purely spatial analysis in this study as well those of previous studies [
18]. The time frame for all significant space–time clusters of
P. vivax malaria was 2005–2009. This implies a declining burden of
P. vivax malaria in China since 2010. Control interventions, especially those following the establishment of the Chinese NMEP [
12,
51] are a likely factor in this substantial reduction of this malaria.
For
P. falciparum, the most likely space–time cluster was detected in western Yunnan province during 2005–2009. Although this is consistent with the previous study [
65], the secondary space–time cluster was scattered mostly in the eastern and north-eastern provinces after 2012 (Fig.
4b). This could imply the spreading of
P. falciparum malaria to previously non-endemic areas, probably due to an increased number of overseas-imported
P. falciparum [
8,
15,
35]. Although an imported case can be distributed randomly to any provinces, the present study showed a greater expansion of
P. falciparum to the east and northeast of China than to any other parts of the country. A better understanding of the direction of malaria expansion or spatial change and underlying risk factors for the malaria transmission in these formerly non-endemic areas is important for the malaria elimination goal of China.
This study is the first to identify the spatial and spatiotemporal distribution of
P. vivax and
P. falciparum at the national level in China. A separate analysis was conducted for both important malaria parasites in the country. The study identified high-risk areas and the spatial extent of both
P. vivax and
P. falciparum. Spatial and space–time scan statistics were performed using SaTScan software [
66]. These techniques were designed particularly to perform spatial clustering of disease or health related events, and to test the statistical significance of clustering under the null hypothesis of a random distribution of the diseases in space, time and space–time [
66,
67]. These techniques are most effective at identifying disease clusters [
68], and have been widely used in fields of epidemiology for similar purpose [
18,
19,
21,
24,
25].
Although purely spatial scan statistics are most effective at identifying a cluster of malaria with a circular shape [
68], the spatial distribution of the disease may not always assume this shape and some irregularly shaped clusters might have been undetected.