Background
Between 2000 and 2015, malaria incidence declined from an estimated 237 million cases to 211 million cases and mortality decreased by 29% globally. However, these reductions appear to have plateaued, with 2016 and 2017 reporting a slight increase in the number of malaria cases [
1]. The emergence and spread of parasites resistant to anti-malarial drugs and mosquitoes resistant to insecticides significantly hamper the global efforts to control and eliminate malaria [
1]. In addition, reduction in financial support in high-burden countries was also responsible for the slight rebound of the global malaria incidence, despite overall relatively stable funding for malaria. The six countries of the Greater Mekong Subregion (GMS) of Southeast Asia have targeted malaria elimination by 2030 [
2]. A major challenge to achieving this goal in the region is the cross-border movement of people from intensive malaria transmission areas along international borders. In the border regions, public health infrastructure and accessibility are poor, and people often live in extreme poverty [
3]. Furthermore, civil unrests have led to internal displacement of human populations and movement of human populations to border areas from interior malaria-endemic areas, which further exacerbates the malaria problem along the borders [
4,
5]. Among the GMS nations, the malaria burden and progress towards malaria elimination differs drastically by country. Myanmar had the heaviest malaria burden in 2016 [
6], whereas China reported no autochthonous malaria in 2017 [
1]. All reported cases in China were imported from endemic areas outside its borders. Thus, in this elimination phase, close surveillance at malaria transmission hotspots along international borders is critical to prevent cross-border re-introduction of the malaria parasites [
7].
To track the progress of malaria control and elimination at the China–Myanmar border, surveillance using passive case detection (PCD) among febrile patients was implemented at treatment facilities in the Laiza Township, Kachin State, Myanmar.
Methods
Study site and populations
This study reports surveillance data collected between 2011 and 2016 in the Laiza Township (24°45′N, 97°33′E, altitude 263 m), Kachin State, Myanmar. The Laiza Township borders the Nabang Township located in the Yingjiang County of Yunnan Province, China. Laiza has a total population of ~ 20,000 based on the 2012 census. In 2010, as a result of military conflicts between local and central Myanmar governments, a few settlements for internally displaced people (IDP) established themselves at sites ~ 5 km from the Laiza town. Malaria case information was collected through PCD instituted in one hospital and 12 clinics in and around Laiza.
Study design and data collection
Patient enrollment, data, and sample collection were performed by trained nurses. Febrile patients (axillary temperature ≥ 37.5 °C) or patients suspected of having malaria, with a history of fever within the last 24 h, were recruited into the study. Written informed consent, or assent in the case of minors, was obtained from all participants, prior to enrollment into the study. Demographic (ethnicity, age, gender, occupation, education, travel history) and clinical (fever, fever history, symptoms, malaria history, previous treatment) data were obtained using a structured questionnaire. For malaria diagnosis, thick and thin smears were prepared from finger-prick blood samples collected from patients, stained with Giemsa, and examined under a light microscope. Initial diagnosis was performed in the local hospital or clinics by field microscopists on duty. Confirmed malaria patients were treated by the hospital and clinic staff according to the local malaria treatment guidelines [
8]. All blood smears were then shipped to a nearby project field laboratory and re-examined by two experienced microscopists to identify the species. When the results were discrepant, the slides were re-examined to obtain the final diagnosis.
The study protocol was reviewed and approved by the local Bureau of Health at Kachin and institutional review boards at Kunming Medical University, China Medical University, and Pennsylvania State University.
Data analysis
Initial slide microscopy results of the hospitals and clinics were compared to those from the project laboratory using the Cohen’s kappa statistic and the McNemar’s test to evaluate if the discordance was differential. Cases of malaria were compared to febrile non-malaria cases using the χ
2 test for categorical variables. For polytomous variables like occupation, education, and age categories, if there was an overall difference between the two groups, a reference group was chosen, and all subgroups were contrasted with this reference group. The Student’s
t test was used for continuous variables when they were normally distributed or the Wilcoxon rank sum test for non-parametric analyses. Odds ratios were used to quantify the magnitude of association between the factors of interest and outcomes. To adjust for confounding, logistic regression was used to compute odds ratios after adjusting for the effects of age and gender. Test based methods were used to compute 95% confidence intervals (CI) and
P values were interpreted in a two-tailed fashion. The Cochran–Armitage test was used to evaluate the linear trend of malaria burden over time. Seasonal index for a given month was calculated using the 6-year average number of cases observed in that particular month divided by the monthly-mean number of all cases over the six-year study period [
9]. A value close to 1.0 indicates no significant shift from expectation for a particular month from the overall monthly mean [
10]. Climate data were obtained from a nearby meteorological station in Yingjiang County, China, for the period between 2011 and 2016 (the highest and lowest monthly temperatures) and monthly precipitation for 2016.
Discussion
As malaria control along porous international borders is critical to achieve the goal of malaria elimination, this study conducted surveillance in a malaria-endemic border region with high-risk mobile populations. Consistent with the WHO reports on rising trends of malaria cases for years 2016 and 2017, the China–Myanmar border area also showed a worrisome increase in the burden of malaria with vivax malaria accounting for most of the clinical cases.
Despite intensified malaria control efforts with large bed net coverage and availability of appropriate recommended anti-malarial treatment, the annual malaria incidence for vivax malaria steadily increased over the 6 years of the study (2011–2016). While the cause for this increase is not obvious, population genetic analysis from the Laiza area between 2011 and 2013 revealed reduced genotypic evenness of the parasite population [
13], suggesting that the expansion of certain parasite genotypes may be responsible for the outbreaks.
Alternatively, drug resistance may also be partially responsible, as the efficacy chloroquine in the treatment of vivax malaria in this region was shown to be deteriorating [
14]. Other contributing factors to this rising trend of vivax malaria could be the significant increase in
Anopheles vector density, as observed in 2013 [
12].
Increased risk of malaria in school-aged children and their potential to be a reservoir of transmission has been observed in many parts of the world [
15‐
17]. Consistent with these and other findings from the area [
8,
18], students accounted for the largest proportion (47%) of clinical malaria cases. Though not fully understood, one reason for the age bias could be related to the developing immunity against clinical malaria in this age group. Soldiers were another high-risk group in the area and accounted for approximately 14% of all malaria cases. Since soldiers constitute a very small proportion of the total population, this would translate to a very high incidence rate in this group. Most border malaria surveillance reports focus on migrant workers and mobile populations. This study shows that soldiers who patrol border and forested areas, especially in unstable areas, may be an important source of malaria transmission and control efforts should target this group for interventions. Strikingly, soldiers also accounted for about 34% of all falciparum malaria cases, suggesting that they might be an important source for low-level maintenance of falciparum malaria in the region.
People with a travel history in the study area also carried significantly increased odds of having acute malaria infections. On the China side, adult men and travel history to Myanmar were major risk factors for malaria acquisition, which highlights the contribution of human cross-border movement as an important source of malaria introduction [
19]. This one-directional cross-border movement of parasites was further implied from genetic evidence, which showed that migration of the parasites from the neighbouring sites in Myanmar to Yunnan in China was asymmetrical [
20]. To realize the regional goal of malaria elimination and prevent parasite re-introduction, heightened border inspection on migrant population is necessary, as removal of the last transmission foci on both sides of the border is critical.
Falciparum and vivax malaria differed significantly in their clinical symptoms and characteristics. The large difference in the odds ratios for protection from bed net use (0.19 vs 0.67) and risk with travel history (12.2 vs 1.8) might suggest that a large fraction of the vivax malaria might be due to relapses, since bed nets should be equally effective in protection against exposure to Anopheles mosquitoes carrying P. vivax or P. falciparum. Vivax malaria is often described as ‘benign tertian’ malaria. In our study, approximately 300 vivax patients presented with symptoms of severe malaria, including coma, febrile convulsions, respiratory distress, acute pulmonary edema, renal failure and severe anemia, further emphasizing the need for improved clinical management of this parasite.
An important finding from the PCD study is that field diagnosis missed a substantial number (22%) of malaria cases. As a result, more than a fifth of the cases did not receive antimalarial treatment. Surveillance data from routine surveillance hence significantly under-estimates the true burden of malaria. Because 8% of falciparum cases was wrongly classified as vivax, these P. falciparum cases received inappropriate treatment with chloroquine and could have been treatment failures because of chloroquine resistance in the area. This could also be a contributing factor to the low-level persistence of falciparum malaria observed throughout the study period. Strengthened training of field microscopists and the deployment of ultrasensitive rapid diagnosis tests are needed to improve the diagnostic accuracy.
Conclusions
Malaria incidence in the China–Myanmar border area has experienced an overall upward trend in recent years, amidst the continuous decline of malaria cases in the entire GMS. Plasmodium vivax has become a major obstacle for malaria elimination, and it was responsible for an increasing proportion of the clinical malaria incidence as well as the two outbreaks. Thus, improved case management and more effective treatment of vivax malaria are needed, especially with the evidence of reduced efficacy of chloroquine-primaquine for the treatment of vivax malaria. In addition, the presence of a substantial number of cases missed or misdiagnosed in the field highlights the need for strengthened training of field microscopists and deployment of more reliable diagnostic methods. Targeted control measures need to focus on vulnerable populations such as soldiers, children, and migrants. Altogether, this study highlights the need for effective strategies to shrink the large parasite reservoir in this region. Elimination of border malaria is also essential to avoid malaria re-introduction into neighbouring countries, and to achieve the goal of regional malaria elimination.
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