Imported Malaria in Finland 1995 to 2008: An Overview of Surveillance, Travel Trends, and Antimalarial Drug Sales

I S T M 400 Imported Malaria in Finland 1995 to 2008: An Overview of Surveillance, Travel Trends, and Antimalarial Drug Sales Sandra Guedes, PharmD MSc, Heli Siikamäki, MD, Anu Kantele, MD, PhD, and Outi Lyytikäinen, MD, PhD European Programme for Intervention Epidemiology Training, European Centre for Disease Prevention and Control, Stockholm, Sweden; National Institute for Health and Welfare (THL), Helsinki, Finland; Division of Infectious Diseases, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland DOI: 10.1111/j.1708-8305.2010.00456.x Background. To improve pre-travel advice, we analyzed nationwide population-based surveillance data on malaria cases reported to the National Infectious Disease Register of Finland (population 5.3 million) during 1995 to 2008 and related it to data on traveling and antimalarial drug sales. Methods. Surveillance data comprised information on malaria cases reported to the National Infectious Disease Register during 1995 to 2008. Traveling data were obtained from Statistics Finland (SF) and the Association of Finnish Travel Agents (AFTA). SF data included information on overnight leisure trips to malaria-endemic countries during 2000 to 2008. AFTA data included annual number of organized trips during 1999 to 2007. Quarterly numbers of antimalarial drug sales were obtained from the Finnish Medicines Agency. Descriptive and time series analyses were performed. Results. A total of 484 malaria cases (average annual incidence 0.7/100,000 population) were reported; 283 patients were Finnishand 201 foreign-born. In all, 15% of all cases were children; 72% foreign- and 28% Finnish-born. Malaria infections were mostly acquired in Africa (76%). Among foreign-born cases, 89% of the infections were acquired in the region of birth. The most common species were Plasmodium falciparum (61%) and Plasmodium vivax (22%). Although traveling to malaria-endemic areas increased, no increase occurred in malaria cases, and a decreasing trend was present in antimalarial drug sales. Traveling to malaria-endemic countries and drug sales followed the same seasonal pattern, with peaks in the first and last quarter of the year. Conclusions. More efforts should be focused on disseminating pre-travel advice to immigrants planning to visit friends and relatives and travelers on self-organized trips. Malaria is a major international public health problem, causing annually 350 to 500 million infections and approximately 1 million deaths worldwide; 90% of cases occur in Africa. 1 Malaria risk may change over time, with shifts in the global epidemiology of malaria, changes in travel habits and patterns Presented in part at the third Northern European Conference on Travel Medicine, Hamburg, Germany, May 26 to 29, 2010 (oral communication), at the sixth European Congress on Tropical Medicine and International Health, Verona, Italy, September 6 to 10, 2009 (poster), and at the European Scientific Conference on Applied Infectious Disease Epidemiology (ESCAIDE), Stockholm, Sweden, October 26 to 28, 2009 (poster). Corresponding Author: Sandra Guedes, PharmD MSc, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare (THL), Mannerheimintie 166, 00330 Helsinki, Finland. E-mail: guedesandra@gmail.com of migration, and development of drug resistance. 2,3 Travelers risk of infection can be reduced by preventing mosquito bites with clothing, insect repellents, and bed nets, and by taking appropriate chemoprophylaxis. 4,5 Adopting these measures depends on how well the traveler recognizes and understands the risks. 6 In Finland, the National Infectious Disease Register (NIDR) was established in 1995, and malaria became a notifiable disease. All clinical microbiology laboratories performing malaria diagnostics report positive tests to the NIDR and confirmation is performed by the national reference laboratory. To identify trends and risk groups, we analyzed the surveillance data on malaria cases in Finland during 1995 to 2008. We compared the data with information available on numbers of travelers and antimalarial drug sales to determine whether these sources could be useful in improving the existing surveillance system and pretravel advice. 2010 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2010; Volume 17 (Issue 6): 400 404

Imported Malaria, Finland, 1995 to 2008 401 Methods Data Sources Surveillance Data Notifications of malaria cases from the NIDR included information on age, sex, nationality, date of diagnostic specimen, and country of infection. Additional data on country of birth and malaria-related deaths were obtained from the National Population Information System. Country of birth was used instead of nationality to avoid confusion caused by double nationalities or changes in nationalities. Traveling Data Numbers of travelers were obtained from Statistics Finland (SF) and the Association of Finnish Travel Agents (AFTA). SF data included annual numbers of overnight leisure trips abroad by destination country during 1997 to 2008 and monthly numbers of overnight leisure trips to malaria-endemic countries during 2000 to 2008. Data from SF were based on monthly telephone interview surveys, targeting 2,200 persons per month. 7 Countries were grouped into one of two categories limited risk or risk based on maps published by the World Health Organization. 8 AFTA data included annual number of organized trips during 1999 to 2007. Drug Data Quarterly numbers of antimalarial drug sales in defined daily dose (DDD) and volume were obtained from the Finnish Medicines Agency (FIMEA) during 1997 to 2007. Only drugs classified as antimalarials according to the Anatomical Therapeutic Chemical classification system 9 and prescribed in Finland for malaria chemoprophylaxis were included in the analysis. Definitions and Grouping Case Definition Persons with laboratory-confirmed Plasmodium infections notified to the NIDR during 1995 to 2008. Laboratory confirmation denotes parasites in microscopic examination of a blood smear. Cases were classified as Finnish- or foreign-born. Country of birth and country of infection were classified into one of the six World Health Organization (WHO) regions 10 : European (EUR), South-East Asian (SEAR), African (AFR), Western Pacific (WPR), Eastern Mediterranean (EMR), and Americas (AMR), which are based on the Global Burden of Disease regional classification system. An additional region (MIX) was created for cases where at least two countries belonging to different WHO regions had been visited. Statistical Analysis We used linear regression for trend analysis. Data were analyzed using Stata software, version 10.0 (Stata Corporation, College Station, TX, USA). Results From 1995 through 2008, a total of 484 cases of malaria (range 22 59 cases/y; average annual incidence 0.7/100,000 population) were identified; 283 cases were Finnish-born and 201 foreign-born. The median age of all cases was 32 (range 0 80) years, and 69% were males. Around 15% of all cases were children (<18 y); 72% foreign- and 28% Finnish-born. Three malariarelated deaths occurred during the study period: one in 1995 and two in 1998. Plasmodium falciparum was the most frequently identified species (61%), followed by Plasmodium vivax (22%), Plasmodium ovale (10%), Plasmodium malariae (2%), and six cases (1%) of unknown species (Figure 1). Plasmodium falciparum was mostly acquired in AFR (93%) and Pvivaxin SEAR (44%). Since 1997, the number of P falciparum infections had decreased (n = 31 in 1997 and n = 15 in 2007), but in 2008 there was a peak (n = 33) due to a cluster of cases (n = 12) among Finnish travelers returning from the Gambia. The total number of malaria cases followed the same trend as the number of P falciparum cases. The most common region of infection was AFR (76%), followed by SEAR (12%) and EMR, AMR, WPR, and MIX (3% each). The most common countries of infection were Nigeria, Ghana, and United Republic of Tanzania in AFR, and India and Indonesia in SEAR. Of foreign-born cases whose country of birth was available (n = 166), most were born in a country in AFR (n = 120, 72%) or SEAR (n = 19, 11%). The number of cases among Finnish- and foreign-born individuals decreased after 1997, but a peak was observed in 2008, reflecting a cluster of Finnish cases returning from the Gambia. In 80% of the cases (389 of 484), both the country of birth and the place of infection were available. Among foreign-born cases, 89% of infections (128 of 144) were acquired in the region of birth, mostly in AFR (n = 106) or SEAR (n = 13). The average annual number of organized trips from Finland abroad during 1999 to 2007 was around 940,000 (Figure 2). There was a sudden drop in the numbers Figure 1 Annual number of malaria cases by species, Finland 1995 to 2008.

402 Guedes et al. Figure 2 Malaria cases and number of organized trips abroad (data from AFTA), Finland 1999 to 2007. during 2001 to 2003, down to 880,000 trips per year. A concomitant drop was seen in the number of malaria cases. During 1997 to 2008 the total number of overnight leisure trips abroad nearly doubled, from 1.7 million in 1998 to 3.3 million in 2008. The increasing trend observed with overnight leisure trips was also seen in travel to malaria-endemic countries, including high-risk areas (Figure 3). Antimalarial drug sales decreased nearly 50%, from 49,000 units in 1997 to 25,000 in 2005, but since 2005 a new increase was observed, and in 2007 the number of units sold was roughly 61,000. The same trend was observed for sales expressed in daily treatment doses (DDD) for different antimalarials (Figure 4). Antimalarial drug sales were highest during the first (35%) and last quarters (18%) of the years and followed the same seasonal pattern as traveling (Figure 5). Malaria cases occurred year-round with an increasing trend toward the end of the year (data not shown). Discussion This nationwide population-based study showed that even though traveling to malaria-endemic areas increased during the 14-year period, no corresponding increase in malaria cases occurred. Moreover, during Number of malaria cases 45 40 35 30 25 150 20 15 100 10 50 5 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 0 Year All trips to malaria Malaria cases endemic countries Figure 3 Malaria cases and number of trips to malariaendemic countries (data from SF), Finland 2000 to 2008. 300 250 200 Number of trips (thousands) Figure 4 Number of antimalarial drug sales, Finland 1997 to 2007. Figure 5 Seasonality of traveling to malaria-endemic countries and antimalarial drug sales, Finland 2000 to 2007. the same period, the overall antimalarial drug sales decreased, while a slight increase was observed with the last available data. The increase in travels to endemic areas with no concomitant increase in drug sales suggests that travel advice was not reaching all groups of travelers. It appears that this concerns especially immigrants visiting friends and relatives (VFR) in their former home country and travelers on self-organized trips, because a significant proportion of travelers with malaria in Finland were observed in these groups. During the study period, nearly 500 malaria cases (average annual incidence 0.7/100,000 population) were reported in Finland. All cases were imported; no autochthonous cases have been found in Finland since the 1950s. 11 Malaria is a notifiable disease in most of the European countries, but underreporting exists; in some European countries, underreporting of imported malaria cases is estimated to be as high as 60%, 12 whereas the estimate for Finland is around 20%. 13 We believe, however, that in reality, there is no significant underreporting in Finland. The reference laboratory collects additional information from clinicians, and these two databases have been compared annually; the same individual cases have been identified in both (H. Siikamäki, unpublished results). Data from annual surveys showed a linear increase in the total number of leisure trips abroad since 1997.

Imported Malaria, Finland, 1995 to 2008 403 However, data on organized trips show an almost constant number of passengers over the years, with a drop between 2001 and 2003 probably due to the media attention given to the September 11th attacks in 2001 and the Severe Acute Respiratory Syndrome epidemic in 2003. 13 Data from annual surveys do not, however, reflect these episodes. The numbers of travelers to malaria-endemic countries have increased since 2000 and were highest in the first and last quarter of the year, probably reflecting Christmas and winter holidays. The number of malaria cases did not follow any seasonality, likely because of the small number of cases per quarter. The lack of increase in the numbers of organized trips and the concomitant increase in traveling to malaria-endemic areas suggest that self-organized trips to malaria-endemic areas has increased. We used antimalarial drug sales as an indicator of the use of chemoprophylaxis. Drug sales have also been used as an indirect measure of disease activity. 14 Antimalarial drug sales were highest in the first and last quarter of the years, following the same trend as traveling to malariaendemic countries. Drug sales decreased since 1997, but started to increase slowly from 2005 onward. This increase coincided with the marketing authorization of atovaquone/proguanil combination in Finland in 2006. The drug got its first marketing approval in 1996, but was registered only 10 years later. Sales of proguanil decreased until 2006 when it stopped being used as a single agent. During the 1990s chloroquine was used also to treat rheumatic disorders but, in the last 10 years, its use for this purpose was very unlikely (Professor Marjatta Leirisalo-Repo, personal communication, January 25, 2010). This change probably contributes to the decrease in the use of chloroquine. Caution should be used when interpreting the trends on DDD sales. Differences in drug accessibility and approval schemes should be taken into account when drug usage is compared between countries. Although doxycycline is included in the Finnish guidelines for malaria chemoprophylaxis, it was not included in our study. Doxycycline is mainly used for other indications, and there was no way of discriminating between the proportions of sales used for different purposes. Taking this into account, it remains fully possible that the use of doxycycline as an antimalarial could have increased significantly and this increase could, at least partly, account for the decrease observed with the other drugs sales. Our results show that antimalarial drug sales cannot be used alone to assess the use of chemoprophylaxis. The decrease in drug sales may be explained by several factors such as travelers fearing adverse drug reactions, 15 choosing to buy drugs at destination, 16 or underestimating the risk of malaria. During recent years internet discussion sites have become an important source of information for travelers and may sometimes even be trusted more than official sites. In addition, the level of compliance to antimalarials is known to be low, 5,6,17 and no data exist as to whether people buying the drugs actually take them accurately. Travelers may also take other prophylactic measures such as repellents, long-sleeved clothing, and sleeping under a bed net. Our data showed no increasing trend in malaria cases, except for a peak in the number of cases in the last quarter of 2008 due to a cluster of Finnish travelers to the Gambia. 18 None of the travelers had used adequate prophylaxis. Additional information on malaria surveillance in Finland showed that in 79% of the 271 malaria cases diagnosed during 2000 to 2008, travelers had used no malaria prophylaxis or had taken it irregularly (H. Siikamäki, unpublished results). Interestingly, the increased travel to malaria-endemic countries was not followed by an increase in the numbers of imported malaria cases. These data may be at least partly explained by the fact that the increase in the number of trips was mostly to areas with limited risk. On the other hand, it may also reflect a change in epidemiology and a decreasing malaria risk in endemic areas, consistent with the reports of Behrens and colleagues 19 from West Africa and Latin America 20 and of Schmid and colleagues 21 from India. Approximately 40% of the malaria cases occurred among foreign-born individuals, most frequently among persons born in AFR or SEAR, which were also the two most common regions of infection. This is in line with a recent report showing that in Europe immigrants accounted for 50% of the total number of malaria cases, 22 and, as in other studies, 2,23,24 persons VFR accounted for almost 90% of the cases among foreignborn individuals. In our study, children constituted more than one quarter of the total number of cases among foreign-born individuals. VFR and second-generation VFR are known to be at increased risk for malaria. 23,25,26 Probable reasons are poor knowledge of malaria transmission and prevention 27 and misconceptions of lifelong immunity. 28 We considered that acquiring the infection in the region of birth was an indicator of being a VFR, but we did not have information on individual countries, and, therefore, misclassification bias might exist. Additional information for the 112 malaria cases diagnosed during 2001 to 2009 shows that 25% of all cases were VFR, 17% recently arrived immigrants, and 6% foreign visitors (H. Siikamäki, unpublished results). The surveillance system in Finland could be improved. Important information, such as country of birth and residence, destination and reason for travel, time of travel, and use of chemoprophylaxis, has been collected in the additional register, but is missing in the main register and should be linked to it. To be able to use travel data for surveillance, data storage and collection from partner institutions should be (re)organized and information on individual countries made available. International airport surveys collecting data on countries of destination 19 and places from which trips are bought (travel agency, web resources) could give accurate information for planning and targeting pre-travel advice. This would allow us to have denominators suitable for performing a risk analysis instead of a merely descriptive evaluation.

404 Guedes et al. The study yielded information useful in the planning and targeting of interventions. An important focus should be on reaching risk groups such as immigrants VFR and other travelers on self-organized trips. Declaration of Interests The authors state they have no conflicts of interest to declare. References 1. WHO. World Malaria Report 2008. 2008. Available at: http://www.who.int/malaria/wmr2008/. (Accessed 2009 Jan 23) 2. Smith AD, Bradley DJ, Smith V, et al. Imported malaria and high risk groups: observational study using UK surveillance data 1987 2006. BMJ 2008; 337:a120. 3. MacPherson DW, Gushulak BD, Baine WB, et al. Population mobility, globalization, and antimicrobial drug resistance. Emerg Infect Dis 2009; 15:1727 1732. 4. Moore DA, Grant AD, Armstrong M, et al. Risk factors for malaria in UK travellers. Trans R Soc Trop Med Hyg 2004; 98:55 63. 5. Chen LH, Wilson ME, Schlagenhauf P. Controversies and misconceptions in malaria chemoprophylaxis for travelers. JAMA 2007; 297:2251 2263. 6. Toovey S, Jamieson A. Rolling back malaria: how well is Europe doing? Travel Med Infect Dis 2003; 1:167 175. 7. Finnish Travel. 2009. Available at: http://www.stat.fi/meta/ til/smat en.html. (Accessed 2009 Jan 5) 8. WHO. Disease distribution maps. 2010. Available at: http://www.who.int/ith/en/. (Accessed 2010 Jun 1) 9. WHO Collaborating Centre for Drug Statistics Methodology. 2009. Available at: http://www.whocc.no/atcddd/. (Accessed 2009 Jan 20) 10. WHO. The World Health Report 2002 reducing risks, promoting healthy life. 2002. Available at: http://www. who.int/whr/2002/en/. (Accessed 2008 Nov 10) 11. Hulden L, Hulden L. The decline of malaria in Finland the impact of the vector and social variables. Malar J 2009; 8:94. 12. Legros F, Danis M. Surveillance of malaria in European Union countries. Euro Surveill 1998; 3:45 47. 13. Ahmad A, Krumkamp R, Reintjes R. Controlling SARS: a review on China s response compared with other SARS-affected countries. Trop Med Int Health 2009; 14(Suppl 1):36 45. 14. CDC. Pneumocystis pneumonia Los Angeles. MMWR Morb Mortal Wkly Rep 1981; 30:250 252. 15. Piyaphanee W, Wattanagoon Y, Silachamroon U, et al. Knowledge, attitudes, and practices among foreign backpackers toward malaria risk in southeast Asia. J Travel Med 2009; 16:101 106. 16. Schlagenhauf P, Petersen E. Malaria chemoprophylaxis: strategies for risk groups. Clin Microbiol Rev 2008; 21:466 472. 17. Millet JP, Garcia de Olalla P, Carrillo-Santisteve P, et al. Imported malaria in a cosmopolitan European city: a mirror imageoftheworld epidemiological situation. Malar J 2008; 7:56. 18. Valve K, Ruotsalainen E, Karki T, et al. Cluster of imported malaria from Gambia in Finland travellers do not listen to given advice. Euro Surveill 2008; 13(51):pii=19068. 19. Behrens RH, Carroll B, Smith V, Alexander N. Declining incidence of malaria imported into the UK from West Africa. Malar J 2008; 7:235. 20. Behrens RH, Carroll B, Beran J, et al. The low and declining risk of malaria in travellers to Latin America: is there still an indication for chemoprophylaxis? Malar J 2007; 6:114. 21. Schmid S, Chiodini P, Legros F, et al. The risk of malaria in travelers to India. J Travel Med 2009; 16:194 199. 22. Monge-Maillo B, Jimenez BC, Perez-Molina JA, et al. Imported infectious diseases in mobile populations, Spain. Emerg Infect Dis 2009; 15:1745 1752. 23. Baas MC, Wetsteyn JC, van Gool T. Patterns of imported malaria at the academic medical center, Amsterdam, the Netherlands. J Travel Med 2006; 13:2 7. 24. Mascarello M, Allegranzi B, Angheben A, et al. Imported malaria in adults and children: epidemiological and clinical characteristics of 380 consecutive cases observed in Verona, Italy. J Travel Med 2008; 15: 229 236. 25. Stager K, Legros F, Krause G, et al. Imported malaria in children in industrialized countries, 1992 2002. Emerg Infect Dis 2009; 15:185 191. 26. Leder K, Black J, O Brien D, et al. Malaria in travelers: a review of the GeoSentinel surveillance network. Clin Infect Dis 2004; 39:1104 1112. 27. Pistone T, Guibert P, Gay F, et al. Malaria risk perception, knowledge and prophylaxis practices among travellers of African ethnicity living in Paris and visiting their country of origin in sub-saharan Africa. Trans R Soc Trop Med Hyg 2007; 101:990 995. 28. Freedman DO. Clinical practice. Malaria prevention in short-term travelers. N Engl J Med 2008; 359: 603 612.