The geography of imported malaria to non-endemic countries: a meta-analysis of nationally reported statistics

Introduction

Tackling malaria remains a high priority internationally, with elimination and eradication back on the global agenda.¹ In the past century, more than 50 countries have succeeded in eliminating the disease. Nevertheless, although malaria is no longer endemic in these nations, increasing travel to endemic areas in recent decades means that the malaria-endemic world is becoming increasingly connected by population movements,² and that imported malaria cases remain common.³ Such cases continue to pose challenges for diagnosis and management, with malaria remaining an infrequently encountered disease for many physicians in non-endemic areas,⁴ where it can be expensive to treat⁵ and result in high mortality.⁶ Moreover, with anopheles vectors still present in many non-endemic countries, imported cases can also cause secondary transmission,⁷ although the chances of resumption of endemic transmission are very small.⁸ Finally, although the effects of imported malaria on malaria-free countries are problematic, data on the features of imported cases can also provide valuable information about both the epidemiology of malaria in endemic regions where surveillance systems are weak, and on how malaria moves around the world.²

The timing, number, and origin of imported malaria cases into non-endemic regions vary by country and are a function of several factors including the transmission intensity of the origin location, the number of people visiting that location, the activities undertaken in the location, and prophylaxis availability and adherence.^{3, 9, 10, 11} Depending on the country, some demographic groups have substantially higher infection rates. For instance, malaria imported to Europe is often reported in travellers returning from (or migrants coming from) endemic areas and migrants living in Europe returning from visiting friends and relatives, with children who are visiting friends and relatives being particularly at risk.¹²

Information about imported malaria is to an extent captured by national authorities where, for most high-income countries, malaria is a notifiable disease. However, under-reporting is probably common; for instance, WHO reported that 6244 cases of malaria were imported to Europe in 2010, but the true number might be six times higher.¹³ Such deficiencies have prompted the initiation of surveillance networks such as GeoSentinel¹⁴ and EuroTravNet,^{15, 16} which now play a key part in the surveillance of imported malaria, in the identification of changing trends in malaria importation, in tracking drug-resistance patterns, and in establishing the changing profile of malaria risk at traveller destinations. Nevertheless, nationally reported data continue to be widely collected and still provide valuable information about the trends, composition, and drivers of imported malaria for most non-endemic countries, with annual data compilations and analyses of statistics providing the main source of information guiding national policies on imported malaria. However, a contemporary global assembly of such nationally reported data, and assessment of patterns and variations has not previously been undertaken.

Here, we describe the first global assembly of nationally reported imported malaria data in 20 years,¹¹ and the geographic analysis of these data from 40 non-endemic countries in the past 10 years. We map the system of transmission from endemic to non-endemic areas to provide insights into the underlying dynamics of the system. Exploration of the driving factors behind these patterns is beyond the scope of this study. We examine the rates of flow of cases from endemic to non-endemic countries and their inherent spatial patterns. Moreover, we map the species composition of cases by sending and receiving regions. Finally, we discuss candidate factors that shape the recorded patterns and likely future trends.

Methods

Full details of the process of constructing a library of imported malaria statistics and data extractions are provided in appendix (pp 2–8). Here we provide brief details of the steps taken in assembly and analysis of the data.

Results

The movement of people with malaria in 2005–15 followed specific routes (figure 1). Of those cases with origin location recorded between 2005 and 2015, more cases were reported in France (2169 cases per year on average) and the UK (n=1898) than any other country (figure 1A), with the USA (n=1511), Italy (n=637), and Germany (n=401) close behind. Most (22 946/24 941 [92%]) exported cases to non-endemic countries originate in west Africa (13 947 [56%]), India (4988 [20%]), east Africa (3242 [13%]), and Papua New Guinea (748 [3%]; figure 1A). Figure 1B shows that the connections between the UK and west Africa, and between France and west Africa are the strongest in terms of annual average numbers of cases moving from endemic to non-endemic countries (2492 cases on average per year, 2005–15), but that many other routes produce an annual average of more than 50 cases reported in non-endemic countries. These include the movements between the USA and India (149 cases per year on average), the USA and west Africa (n=716), the USA and Haiti (n=52), Australia and Papua New Guinea (n=97), and the UK and Pakistan (n=69). By defining the origin–destination pairs of endemic–non-endemic countries and the cases originating and reported in each as a weighted network, the community detection analyses identified sections of this global imported malaria flow matrix that were more strongly connected than others. Although the matrix is incomplete, with country-level imported malaria data unavailable for some non-endemic countries, it is clear that the structure of these mapped network communities is not mainly geographically determined (figure 2), with historical, economic, language, and cultural ties evident. For example, the UK community includes the English-speaking African nations connected to the UK that were its former colonies (including Nigeria, Ghana, Kenya, Uganda, and The Gambia), and French colonial ties are also evident (including Mali, Niger, Chad, CÔte d'Ivoire, Burkina Faso, Benin, Togo, and Madagascar).

Clear associations exist between the average annual number of outgoing P falciparum cases from endemic to non-endemic countries, P falciparum prevalence in the endemic countries, and the migration flows to non-endemic countries (figure 3). Moreover, the countries with the most migrants residing in non-endemic countries (eg, India, Pakistan, and Nigeria) typically fall further towards the upper-left side of the plot, as larger numbers of travellers (particularly those visiting friends and relatives in endemic countries) are related to larger numbers of imported cases to non-endemic countries. Although there are associations between the numbers of cases and both malaria prevalence in endemic countries and numbers of migrants in non-endemic countries, many other factors play a part, including demographics, levels of prophylaxis and protection use, and travel activities.

We analysed the species compositions of cases reported in non-endemic countries by region (figure 4) and nation (figure 5 and table). Reports of cases in non-endemic countries often present species type broken down by origin region rather than country, thus initially we did the species composition analyses at pooled regional level to ensure larger and more stable sample sizes (figure 4). The results emphasise the large variation in the species composition of malaria cases travelling between the different regions of the world. Although these outputs represent a pooling of data of varying numbers, time periods, treatment-seeking behaviours, and diagnostic capacities, the clear and geographically consistent patterns suggest a robustness in the outputs. The dominance of P falciparum from African and Caribbean sources (mean percentage of cases across regions 74·4%) compared with those originating in Central and South America (13·1%) and Asia and Oceania (17·6%) is clear, although no single species in any region has total dominance. This finding is also reflected at national levels (figure 5), with strong geographically coherent patterns recorded, but also a mixed picture in many places, especially in southeast Asia and central America. The species compositions of cases received in each non-endemic country (figure 4 and table) are indicative of each country's connections to endemic regions. For example, the high P falciparum percentage for France results from its strong ties to west Africa (figure 1). European proximity and ties to Africa result in more cases of P falciparum (mean percentage of cases of 65·8%) than in the Americas (41·7%) or the Asia-Pacific region (32·9%), although a divide is clear, with higher proportions of P vivax in eastern compared with western Europe evident (figure 4). Finally, analyses of diagnostic capacities in European countries (appendix pp 9, 10) highlight the growth in capacities in the past decade, with an increasing use of PCR and rapid tests. However, substantial geographical differences remain, with the range of methods and their reporting higher in western Europe than eastern Europe.

Discussion

The substantial growth in the reach and rates of human travel, in particular the air traffic network, in recent decades, has had a major effect on global disease epidemiology, including malaria.⁹ Rising rates of travel to and from endemic areas has resulted in imported malaria being frequently reported in malaria-free countries, with occasional secondary transmission.⁷ However, this travel expansion has not been ubiquitous, with historical and economic ties driving growth along certain routes far more than others, and resulting in uneven malaria movement.² Moreover, substantial investment in malaria control in recent decades has resulted in overall decreased prevalence in endemic areas, with some areas noting especially large decreases,²² further contributing to variations in importation to non-endemic countries. Here, we have presented unique analyses of a global assembly of publicly available contemporary data for the national reporting of imported malaria to capture these variations and quantify the broad geographic features.

We noted clear and consistent patterns despite differences in data quality, completeness, and temporality, and data being indicative of the different surveillance systems and diagnostic capacities of the reporting countries (appendix pp 9, 10). Our results underline the substantial geographical heterogeneities that exist in reported malaria case numbers and compositions in non-endemic countries. Moreover, certain routes from endemic to non-endemic countries carry substantially more infections than others, with evidence of tight couplings that reflect historical ties. These communities of countries can serve to guide surveillance, develop mitigation strategies, and highlight likely routes of drug-resistant malaria movement.²³ The tight coupling of locations also highlights risks for secondary transmission following imported cases, such as through immigrant labour in the Middle East²⁴ or Chinese labourers returning from Africa.²⁵ Further, the species compositions highlight P vivax, P ovale, and Plasmodium malariae as potential malaria parasites in areas of the world where they are rarely considered, such as much of Africa. Coupled with policy shifts towards species-specific diagnostics and reporting, this finding could prompt a robust assessment of the more neglected non-falciparum parasites that can still cause severe clinical illness and require specific control interventions.

We have endeavoured to minimise the uncertainties and errors that arise through the analysis of data from such a large range of sources. However, many factors, including the opportunistic and highly varied nature of the available data, affect our ability to compare between countries and draw precise conclusions. First, the data represent a small proportion of a possibly larger pool of cases, with some estimates suggesting that national statistics might capture just one-sixth of all imported cases.¹³ Variations in health system reporting mechanisms and diagnostic capacities between countries also probably mean that some countries capture more cases than others, some cities and regions within countries capture more than others, and some countries have a greater capacity to undertake reliable speciation through using PCR or having more experienced and well trained microscopists. Microscopic examination is widely available in most non-endemic countries (appendix pp 9, 10); however, misdiagnoses or late diagnoses can still be common because of the failure of medical personnel to relate the febrile symptoms to a disease that is rarely reported in their region. Malaria symptoms are non-specific and cannot easily be distinguished from other febrile disorders on clinical grounds alone. Moreover, changes in reporting standards, practices, and capacity over time within nations can affect the comparability of data over time, and affect outcomes and representativeness when data are pooled over many years. Microscopic diagnosis is often slow and inaccurate in non-specialised laboratories.^{26, 27} In some cases, molecular assays can become insufficient to make a correct diagnosis, especially to detect all species in mixed infections or in cases when parasitaemia is low, which is often the case in non-immune patients who complied with chemoprophylaxis.

Moreover, one or more species in mixed species infections are easily overlooked, and some species are more difficult to classify than others, with, for example, morphological similarities between P vivax and P ovale potentially a source of misclassification.²⁸ In relation to these classification challenges, the confidence in the reports regarding imported malaria varies between studies depending on the method used to detect the infection. The large percentages of unknown malaria types for some countries are likely to be indicative of a lack of diagnostic capacity. National health statistics often do not report the techniques used, and therefore it is necessary to refer to the academic publications describing the summarised national data in which this information is provided to assess the overall precision of the diagnosis at the country level. Finally, intervention scale-up,²² urbanisation,²⁹ changing wealth,³⁰ and improved health systems are all likely to have affected the prevalence and species composition of malaria in endemic regions in the past decade, subsequently affecting the comparability of imported case data in non-endemic regions between years. Nevertheless, the clear, consistent, and coherent patterns we recorded within regions and between countries and the congruence with results through dedicated surveillance networks,^{3, 14, 15, 16} suggest that the data presented here form a representative sample.

Second, several factors relating to differences in traveller type and activity between countries contribute to the representativeness, comparability between nations, and uncertainties in outputs. Rates of chemoprophylaxis, prescription, use, and antimalarial adherence vary by country and by demographic group,^{31, 32} as does the use of protective measures while travelling.³³ Further, the demographics and ethnic composition of traveller groups vary by country; for example, nations that have large migrant populations originating from endemic countries probably contribute to more cases arising from those visiting friends and relatives.⁶ The proportion of imported malaria cases due to migrants in Europe has increased in the past 15 years,³⁴ with those visiting friends and relatives travelling to endemic areas of Africa more than eight times more likely to be diagnosed with malaria compared with tourists,³⁵ and their children being especially at risk.³⁶ Activities in endemic regions might also contribute to differences recorded; for instance, people travelling to urban areas and staying in hotels are likely to be at lower risk. Differences in demographics and health systems also translate to differences in treatment seeking as well as whether case importation occurs principally through visitors or travelling residents. Some demographic groups are more likely to seek treatment than others for travel-related health issues.³⁴

Our study is an ongoing effort. Summaries of national malaria surveillance data are not made publicly available for all countries and years and many additional relevant datasets probably remain unpublished, so we welcome input from those who have access to datasets not included here to enable continual updates. Our study provides a global picture of malaria importation to non-endemic countries, but does not extend to exploration of the driving factors behind these patterns. However, our future work will focus on building datasets and a modelling framework for understanding what drives the patterns noted here.

The associations with malaria endemicity and migration flows suggest two key drivers, but further data for travel patterns and volumes, malaria transmission, demographics, health system efficiency, diagnostic capacities, treatment-seeking behaviours, and prophylaxis compliance and availability, among other factors, need to be collated to better explain and model the malaria importation patterns recorded, with a goal of predictive modelling. Further, such analyses could be extended to other commonly imported infectious diseases^{3, 9, 37} and the effects of seasonal variations in these drivers could be incorporated.^{38, 39} We have focused on broad comparisons through pooling across years to provide sufficient data. This approach has probably ignored changes that have occurred across time, and future work will have to focus on augmenting and breaking these data down to explore temporal trends. Finally, our results match closely those found through analysis of data collected by surveillance networks such as GeoSentinel¹⁴ and EuroTravNet,^{15, 16} but future work should focus on undertaking quantitative comparisons.

As many countries move towards national malaria elimination, global eradication moves up the international agenda,¹ and the threat of spreading drug resistance grows,²³ there is an increasing focus on malaria importation and the vulnerability of countries to resurgence.⁴⁰ This study forms part of wider efforts to understand patterns of human and malaria parasite movement and how such information can guide control and elimination efforts. Malaria parasites do not respect national borders, and with human mobility continuing to increase in its volumes and reach, increasing global connectivity,² control, and treatment strategies should account for the continued globalisation of malaria.

Supplementary Material