Background
Malaria is one of the most important public health problems worldwide. Globally, an estimated 3.3 billion people in 97 countries and territories are at risk of malaria. An estimated 214 million malaria cases occurred globally in 2015 and led to 438,000 deaths [
1]. Malaria was once a major challenge in China, however after large-scale implementation of interventions such as mass drug administration [
2], indoor residual spraying and long-lasting insecticide nets, China has effectively controlled malaria and reduced local malaria to 56 cases in 2014 [
3].
After China began implementing the national malaria elimination action plan (NMEAP) [
4] in 2010, the ‘1-3-7’ approach, which defined targets to guide and monitor case reporting, investigation and response, respectively, was carried out and local malaria infections across the country and in Jiangsu Province decreased significantly [
5]. However, imported
Plasmodium falciparum malaria cases, mostly from overseas migrant workers posed a challenge [
6].
For
Plasmodium ovale sp. and
Plasmodium malariae, only sporadic malaria cases have been reported in China [
7‐
11]. Historically, these two species of
Plasmodium are rare in China. Since 1960, there have been no reported local
P. malariae cases in Jiangsu Province. Given their rarity, local centres for disease control and prevention (CDC) and hospital microscopy examiners commonly misdiagnose
P. ovale and
P. malariae as
Plasmodium vivax and
P. falciparum, respectively [
12,
13]. Due to the similarity in the parasite density and life cycle forms of ovale malaria and vivax malaria,
P. ovale sp. is easily and frequently misdiagnosed as
P. vivax [
14,
15]. If misdiagnosed as
P. falciparum, P. ovale sp. malaria cases could relapse because drug treatments between the two species differ. Furthermore, treatment based on an incorrect diagnosis of
Plasmodium species leads to misuse of anti-malarial drugs as well as drug wastage.
With the substantially increasing number of imported P. ovale and P. malariae cases, it is necessary to understand the difference between these species. At present, there are few epidemiological studies focused on imported P. ovale and P. malariae cases in China. In this work, by collecting and analysing data from the diseases surveillance information system for the period 2011–2014, this study describes P. ovale sp. and P. malariae prevalence trends, population characteristics, latency periods, and geographic distribution patterns to provide a basis for the prevention and control of imported P. ovale sp. and P. malariae malaria in Jiangsu Province.
Discussion
These results show long latency periods and frequent misdiagnosis by microscopy of malariae and ovale malaria cases and highlight a challenge that all levels of CDCs should focus on for accurate diagnosis and surveillance of rare
Plasmodium species imported from sub-Saharan Africa and Southeast Asia. The local malaria situation in China has been effectively controlled, however, as local malaria cases have decreased drastically, imported malaria cases are now the main challenge for China to reach elimination. To address this challenge of misdiagnosing malaria infections, the Chinese Government has held training at different levels, including a national competition for the diagnosis of parasitic diseases [
21]. The training and competitions have helped to maintain the microscopy capabilities for accurate detection and diagnosis of
Plasmodium parasites among professionals at all levels of CDCs and hospitals.
In recent years, the total number of imported malaria cases coming from abroad to Jiangsu Province ranked in the top three provinces in China [
22,
23]. Although imported falciparum malaria cases accounted for a majority of the total cases in this study, the other three
Plasmodium species (
P. ovale sp.
, P. malariae, and
P. vivax) were detected every year during the 2011–2014 period. Ovale and malariae malaria cases increased overall during the study period, increasing the potential risk of re-introducing malaria in Jiangsu Province, an area with historically stable malaria transmission [
18]. Vivax and falciparum malaria outbreaks have been reported in non-endemic areas in 2005 and 2007, respectively [
24,
25] and pose a major challenge for Jiangsu Province to maintain zero incidence of locally transmitted malaria. Given that the transmitting vectors
A. sinensis and
A. anthropophagus are present, as well as having a suitable climate [
17,
18], the potential for local transmission in Jiangsu remains.
Symptoms such as fever, sweating and headache develop on average 7 days after migrant workers return to Jiangsu Province. Of those with
P. ovale sp. and
P. malariae infections, the average number of days before fever onset was almost 2 months and nearly 1 month, respectively. During these long periods some
Plasmodium-infected individuals could have asymptomatic parasitaemia, providing an opportunity for mosquitoes to bite and further contribute to local transmission. Additionally, these asymptomatic individuals may donate their blood through local blood stations without knowing they are infected with malaria. A high rate of antibodies against
P. ovale and
P. malariae were found in asymptomatic blood donors in Western Africa [
26].
Due to the rare occurrence of indigenous ovale and malariae malaria cases in China, these
Plasmodium species have been largely neglected. Nevertheless, severe cases of
P. ovale sp. pertaining to acute respiratory symptoms and renal failure have been reported [
27‐
29].
Plasmodium ovale cases have the potential to relapse if misdiagnosed as
P. falciparum and incorrect treatment provided. Furthermore, treatment based on an incorrect diagnosis leads to misuse of anti-malarial drugs as well as drug wastage. Also,
P. ovale infections have been misidentified in clinical laboratories settings as
P. vivax among malaria cases imported to Singapore over the last 3 years. Misidentified
P. ovale infections are reported for the first time among imported malaria cases in Singapore [
15]. Although both
P. ovale sp. and
P. malariae cause mild symptoms,
P. malariae can cause chronic nephritic syndrome, leading to adverse reactions during treatment and a high rate of mortality [
30]. In Hunan Province, China,
P. malariae infections can cause sudden attacks in the following years when patients go without proper anti-malarial treatment [
7]. As countries reduce their malaria burden, strategies that address the changing epidemiology to increasing proportions of infections from non-falciparum species need to be developed, validated and adopted [
31]. Ensuring a high capacity potential for the diagnosis of falciparum and vivax malaria, as well as for
P. ovale sp. and
P. malariae infections, remains a challenge to all levels of CDCs and hospitals in Jiangsu Province and China.
Both
P. ovale and
P. malariae species were reported across the south, central and north parts of Jiangsu Province. In Changzhou, Lianyungang, Yangzhou and Nantong prefectures, which accounted for more than half of all reported malaria cases, the prefecture CDCs should strengthen management of personnel at entry-exit inspection and quarantine department to obtain more information about migrant workers returning from high malaria-endemic areas such as sub-Saharan Africa and Southeast Asia. These cities have many construction enterprises and local migrant labourers frequently travel to Africa for work, and return to China infected with malaria [
32,
33]. At the provincial level, since 2012, the JIPD has established a dynamic information platform for local CDCs to collect and input information on migrant workers returning from abroad. Through the platform, timely and accurate information on migrant workers is collected and analysed. Furthermore, local CDCs should also strengthen early malaria detection, standardized treatment and follow-up of those individuals who have travelled with confirmed imported malaria cases. Local hospitals should improve clinical diagnosis and treatment of imported malaria and reduce incidence of severe cases and death cases.
The geographical distribution of imported
P. ovale sp. and
P. malariae within Africa were mainly concentrated in western Africa. The top three countries that contributed most numbers of
P. ovale sp. and
P. malariae cases were Equatorial Guinea, Nigeria, and Angola. Given the large economic investment from Jiangsu to Africa, exported migrant workers for construction and labour is increasing as more Chinese companies support infrastructure projects and development [
34]. Unexpectedly high sero prevalence of
P. ovale and
P. malariae was found in healthy West African populations [
26]. Isolation and characterization of the
msp1 genes from
P. ovale and
P. malariae has also been reported in a significant number of blood donors in Cameron [
35]. That suggested why a greater proportion of imported malaria cases originate from western Africa. In Southeast Asia, this study found Pakistan and Brunei where
P. ovale sp. still exist and
P. malariae was only found from Pakistan.
Sutherland considered that the weight of evidence favors the proposition that the two
P. ovale sp. types are actually two distinct species [
36]. For
P. ovale curtisi, this study found that Nigeria was the most commonly identified place of origin, which is consistent with observational study [
37]. For
P. ovale wallikeri, imported infections were mainly clustered in Angola. This is largely because Nigeria and Angola are major economic investment locations for China and Chinese migrant labourers [
38]. In Nolder et al.,
P. ovale sp. interspecies differences in the latency period were significant [
37]. However, this study did not find a statistically significant difference in the latency period analysis between
P. ovale curtisi and
P. ovale wallikeri infections. One possible reason is that this study used patients’ symptoms onset time to calculate latency period instead of diagnostic time, which was introduced by Nolder et al. [
37].
Authors’ contributions
YYC, WMW, YBL, and JC conceived the study, YYC collected, analysed and mapped the data and drafted the manuscript. CC contributed to data analysis and manuscript writing. HYZ and GDZ contributed to the data interpretation and coordination. WMW contributed to data collection and interpretation. JXT, FT, FL, SX, YPG, CZ, and JLL contributed to parasitic species confirmation. JC provided guidance and coordination throughout the entire process. All authors read and approved the final manuscript.