Risk Factors for Border Malaria in a Malaria Elimination Setting: A Retrospective Case-Control Study in Yunnan, China

Introduction

Remarkable progress has been achieved in reducing malaria burden globally over the past 10 years.1,2 Nowadays, there are 99 endemic countries; of these, 65 are controlling malaria and 34 are pursuing elimination. The 34 eliminating countries have declared a national policy for malaria elimination or are pursuing spatially progressive elimination within their borders.2–4 Countries in the Asia Pacific region are making particularly strong progress toward eliminating malaria.5 As one of countries with a great reduction in malaria incidence, China aims to eliminate malaria by 2020.6

In low transmission settings, malaria is increasingly imported, caused by Plasmodium vivax, and clustered demographically in adult men with shared epidemiological risk factors. Current malaria control interventions and strategies are not likely to be optimal, and novel strategies targeting high-risk groups are urgently needed. In high endemic, control settings, risk factors can be established through nationally representative cross-sectional surveys, such as malaria indicator surveys. However, in areas where transmission is very low and malaria infections are rare, these surveys are unlikely to adequately detect cases or identify risk factors. Furthermore, such large-scale surveys require substantial financial and operational resources.7,8 Case-control analysis is a well-established method to study rare diseases and identify associated demographic, behavioral, and clinical risk factors, being particularly appropriate for rare diseases. As yet, this epidemiological tool has not to be extensively applied to malaria, which has traditionally been studied in high-endemic settings.7,9–11

In China, malaria has been eliminated from large parts of the country. The remaining at-risk areas can be characterized as low endemic and they are clustered in parts of central China, southern China, and Tibet. The southern province of Yunnan will be particularly challenging for elimination as it shares a 4,061 km border with malarious countries including Myanmar, Laos, and Vietnam.12,13 The epidemiology of malaria in this area is presumed to be similar to other parts of Southeast Asia, where reported malaria incidence and parasite species have been identified. Malaria tends to concentrate among migrant workers on border regions and in forest areas. For example, men who travel into the deep forest for work become infected with bites from Anopheles dirus (the primary vector in the deep forest of Southeast Asia) and return to their home villages on the forest fringe where they become reservoirs for transmission of the parasites by Anopheles minimus (the primary vector on the forest fringe of Southeast Asia) to their young children.14 However, these risk factors have not been evaluated in a controlled study. To improve understanding of risk factors of border malaria infection in Yunnan and to support the design and implementation of targeted interventions, we conducted a retrospective case-control study.

Methods

Study site.

The study was conducted in Tengchong and Yingjiang, two border counties at the Yunnan-Myanmar border (Figure 1). There are 39 health facilities that are required to report all suspected and laboratory-confirmed malaria cases through the China Information System for Disease Control and Prevention (CISDCP), the national internet-based disease reporting system. Basic demographic data and contact information are included in the reports. The epidemiology of malaria in this area has been described.14–16 Briefly, these sites were selected because they are formerly hyper-endemic areas and the current hot spots of border malaria in China, as a result there were enough cases for the study.

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Study Site, Yingjing and Tengchong, Yunnan Province, China.

Citation: The American Society of Tropical Medicine and Hygiene 92, 3; 10.4269/ajtmh.14-0321

Results

There were 214 malaria cases and 428 matched controls recruited to participate in the study. Of the 214 confirmed malaria case patients, 176 (82.2%) were vivax malaria and 38 (17.8%) were falciparum malaria. There were no mixed infections. Based on the CISDCP, 201 (93.9%) cases were imported from other countries, 12 (8.0%) locally acquired, and 1 could not be confirmed as imported or local. Among the 12 local cases, 4 were < 15 years of age, and the youngest one was only 3 years of age.

Characteristics of the cases versus controls are shown in Table 1. The cases were predominantly male (194 of 214 or 90.7%) and the 428 controls were matched by gender. Median age of cases and controls were 33.6 (range 3 to 62) and 33.8 (range 4 to 64) years. The case and control groups were similar in terms of ethnicity, household wealth index, main cash sources, education, housing structure, presence of screened windows and doors, hill zone, proximity to breeding sites and vegetation, and awareness on malaria prevention (P > 0.25). According to answers of participants to a specific knowledge question on methods for malaria prevention, 115 (54.0%) cases versus 196 (46.0%) controls knew of chemoprophylaxis, and 60 (28.2%) cases versus 140 (32.9%) controls knew of using bed nets or repellents for malaria prevention (P < 0.25). Cases were more likely to own bed nets including insecticide-treated nets (ITNs) or long-lasting insecticide nets (LLINs) and other measures against mosquito bites in the home than control group (P < 0.05). Most of the cases (93.9%) stayed overnight in Myanmar within 1 month of the malaria episode.

Characteristics of cases and controls that stayed at least 1 night in Myanmar in the 1 month before the malaria attack in the case are shown in Table 2. In Myanmar, lumbering activities, housing conditions, use of measures against mosquito bites, and local ecology were significantly different between case and control groups (P < 0.05). The hill zones of their staying sites were similar (P = 0.464).

Table 3 shows the results of matched univariate and multivariate logistic regression analyses. Independent risk factors associated with malaria infection were overnight in the hyperendemic areas of Myanmar, especially staying in lowland, foothill, and mid hill, and proximity of potential mosquito breeding sites such as streamlets and paddy fields or pools nearby their staying site. In both China and Myanmar, ownership of bed nets including ITNs or LLINs, using measures against mosquito bites including sleeping under a net did not differ significantly between case patients and matched controls. In Myanmar, activities and housing conditions of Chinese migrants, and vegetation nearby the staying site did not differ significantly between case patients and matched controls too.

Discussion

The study revealed that most case-patients were imported from the neighboring districts of Myanmar (93.9%), male (90.7%) and 16–50 years of age (90.7%), and vivax malaria (82.2%). Independent risk factors associated with malaria infection were overnight in the lowland, foothill, and half-hill areas of Myanmar. This coincides with comments in the literature: malaria cases are increasingly male, adult, clustered geographically, imported among migrant and other hard-to-reach groups, and caused by P. vivax in eliminating settings.7 This is also similar in Cambodia, the males and adults had an increased risk of Plasmodium spp. infection.24 However, local malaria infection still exists, especially for patients < 15 years of age, and the youngest one only 3 years of age, who had never been in the neighboring districts of Myanmar, showed that local malaria transmission has not been interrupted completely.

In the Greater Mekong Subregion (GMS), forests are commonly considered as a major determinant of malaria risk.14,25–29 In Vietnam a large proportion of all malaria cases and deaths occurred in the central mountainous and forested areas.28 In Myanmar, about 60% of the total malaria cases occurred in forest or forest fringe areas; forest workers (loggers, gem miners, etc.) were at high risk of malaria.29 The explanation is that forests and forest fringes are mountainous and hilly areas, difficult of access, sparsely inhabited by the ethnic minorities, and limited economic development and infrastructure. Men who travel into the deep forest for work become infected with bites from An. dirus and return to their home villages on the forest fringe where they become reservoirs for transmission of the parasites by An. minimus to their young children.14,29 However, the study found that malaria was associated with Chinese migrants staying in the lowland and foothill or mid-hill areas, especially along the waterside. The study results showed that the border crossers of the control group reported staying in forests more often than that of the case group, and the percentage of loggers among controls (86.5%) was higher than that among case patients (68.2%). One of the reasons might be that the study site was next to Kachin State of Myanmar, where malaria burden is particularly high and malaria outbreaks occur frequently, the malaria-related mortality rate was as high as 7.8 deaths per 1,000 people in 200529–31; Liu and others32 reported a mean parasite rate 16.3% (95% confidence interval [CI]: 12.9–20.1%) among residents of Kachin State in 2010. In most parts of Southeast Asia, the year-round high rainfall and temperatures, and malaria vectors lead to persistent and intense malaria transmission.25 However, in northern Myanmar the mountainous areas border with China, the high altitude leads to its difference from most parts of Southeast Asia; the hilly forested areas have low temperatures, fewer mosquito breeding sites, less malaria vector, and less parasite reservoirs caused by sparse population.

In theory, people who have a better knowledge of malaria transmission and methods of prevention, awareness and using measures for malaria prevention, should have reduced malaria infection. The reported investigation in the literature documented that use of bed nets provide useful protection against malaria infection.33,34 However, the results of the study did not show that the knowledge of malaria transmission and prevention was associated with the reduced risk of malaria infection; furthermore, it was not documented that the ownership and the use of bed nets or repellents was related to the reduced risk of malaria infection. On the contrary, the percentage of case patients (54.0%) who knew chemoprophylaxis was higher than that of controls (46.0%); and the percentage of case patients (43.1%) who used measures of bed nets or repellents against mosquito bites in Myanmar was higher than that of controls (13.9%). When malaria is rare to see in the eliminating setting of China, the better knowledge and behavior might be attributable to malaria infection. People who had malaria attacks might have more experience with malaria and they might actively seek knowledge and take action for malaria prevention and control.

Overmatching may be one of the main limitations in this study. In the eliminating setting, malaria cases cluster on border areas, are increasingly male, adult, imported, among migrant and other hard-to-reach groups.7 Li and Fan reported that 97.5% (2,556 of 3,646) of malaria patients were imported from Myanmar and most of them were male adults in the study site.15 To exclude the confounding effect of age and sex, controls were matched by age and sex. The goal of malaria elimination was to interrupt local mosquito-borne malaria transmission in a defined geographical area, i.e., zero incidence of locally contracted cases; but imported cases will continue to occur, and continued intervention measures are required to prevent reintroduction.17,18 Therefore, community of residence was also selected as one of the matching criteria to identify the risk factors of local malaria infection. One of the purposes of using age, gender, and community of residence as matching criteria was to explore methods for reduction of the confounding effect from age and gender, and to identify risk factors of local malaria infection. However, we could not ensure whether this design might lead to overmatching and limiting assessment on these as independent risk factors. The study results did not identify any risk factors of local malaria infection because of only 12 (8.0%) locally acquired cases, therefore the purpose has not been achieved by using residence as one of the matching criteria. This failure showed that use of residence as a matching criterion may be inappropriate in a malaria elimination setting. Despite among 214 case-patients, 194 (90.7%) were male and 210 (98.1%) adult (≥ 16 years), this study could not identify whether they are an independent risk or confounding factors because of using age and gender as the matching criteria.

The study also had several other limitations. The first was the potential bias in capture of case patients. The cases were from records of public health facilities. The malaria patients who sought treatment from the private sector were excluded from this study. Some Chinese migrants carry anti-malarial drugs with them for self-saving during staying in Myanmar; however, the case-patients were from parasite-based diagnosis in China. In cases where the self-medication cured their malaria infection, they might not seek diagnosis and treatment from the public health service in China, which led to exclusion of them from the study too. These might lead to selection bias. The second is that some people declined to answer certain questions that they thought of as sensitive, and might cause responding bias. The third is that the financial support for this study only permitted an operation period of < 1 year, unable to recruit enough case patients in such a short period, therefore a design of retrospective case-control study was used. A weakness of this design was that the data were collected after the fact, and there are major challenges with recall bias, particularly in the control subjects who would have a hard time remembering the time before a date that is not relevant to them.

In conclusion, imported malaria is particularly prominent, and most malaria patients are male, adult, and infection of P. vivax in the malaria elimination setting of Yunnan, China. The independent risk factors for malaria infection were staying in the lowland, foothill, and half hill, and availability of streamlets and paddy fields or pools nearby their staying sites of Myanmar. However, the study identified neither forest exposure nor use of vector control measures to be independently associated with malaria infection. In considering the limitations of the study, further research is needed to identify the major determinants of malaria risk on the China-Myanmar border, and to develop new strategies for malaria elimination; for example, how to promptly find and treat imported malaria infection in China, reduce malaria transmission and incidence in Myanmar through effective cooperation mechanism between China and Myanmar, and promote vigilance and use of personal protection among Chinese border crossers through effective behavior change in communication.