Malaria in travellers and migrants : disease severity and long term effects

Malaria is a potentially fatal infection, where prompt and correct management is crucial for the outcome. Despite international efforts to reduce transmission, there are over 200 million new malaria cases with approximately 400 000 deaths per year, the majority occurring in Sub-Saharan Africa. Globalization, in terms of travel and migration, brings malaria also to non-endemic countries. Approximately 100-300 cases of malaria are diagnosed in Sweden per year, with significant variations during the last years due to changes in travel and migration patterns. Despite a well-established national surveillance, the clinical presentation, outcome and risk factors for severe malaria have not previously been described. Individuals growing up in endemic areas, gradually develop immunity, first to the most severe forms of malaria and eventually also to mild disease. However, how long protection against severe disease is maintained in individuals that are no longer exposed is not clear. Moreover, non-communicable diseases and obesity increase globally, including in travellers and populations living in malaria endemic areas, but the impact of comorbidities on the severity of malaria has not been systematically assessed. In addition to the well-described acute complications, malaria may cause long-term consequences that have been much less investigated. The association between malaria and Burkitt lymphoma in African children is since long recognized, but it is unknown if malaria is related to other cancer forms.

In this thesis, we have investigated risk factors for severe disease in travellers and migrants diagnosed with malaria in Sweden 1995-2015. Moreover, by using the Swedish surveillance system and national health and demographic registers, we studied long-term consequences of malaria in terms of lymphoma and other cancer. In Study I, we assessed the risk of severe P. falciparum in immigrants from Sub-Saharan Africa and non-immune travellers. We showed that duration of residency in a malaria-free country was associated with the most severe manifestations of malaria. Immigrants who had lived for ≥15 years in Sweden had a similar risk of severe disease as travellers with origin in non-endemic countries, suggesting that immunity to severe malaria is lost after many years without re-exposure. In Study II, we observed higher prevalence of chronic diseases among patients with severe malaria, and demonstrated that diabetes, obesity and combinations of metabolic risk factors strongly associated with severe malaria, both in non-immune travellers and migrants from endemic areas. In Study III, we identified age ≤5 and ≥40 years, pregnancy, HIV, non-endemic origin and health care delay as risk factors for severe disease in P. falciparum malaria. In non-falciparum episodes, age >60 years, health care delay and endemic origin were identified as risk factors for severe disease. Newly arrived migrants were found to be a risk group for both severe P. falciparum and non-falciparum malaria. Moreover, the current WHO criteria for severe malaria did not reflect severity of disease in this non-endemic setting. In Study IV, we demonstrated that malaria was associated with an increased risk of lymphoid neoplasm, especially B-cell lymphoma, in individuals born in malaria endemic areas diagnosed with malaria in Sweden. There was no increased risk of cancer overall, nor did single malaria episodes in travellers confer an increased risk. The results suggest that repeated exposure to malaria during childhood may lead to development of lymphoid neoplasms later in life.

In conclusion, this thesis has identified new risk factors for severe malaria and potential long-term consequences in travellers and migrants, with implications for improved strategies in the management, follow up and prevention of malaria, both in imported cases and in populations at repeated risk of infection.

List of scientific papers

I. Färnert A, Wyss K, Dashti S, Naucler P. Duration of residency in a non-endemic area and risk of severe malaria in African immigrants. Clinical Microbiology and Infection. 2015;21(5):494-501.
https://doi.org/10.1016/j.cmi.2014.12.011

II. Wyss K, Wångdahl A, Vesterlund M, Hammar U, Dashti S, Naucler P, Färnert A. Obesity and diabetes as risk factors for severe Plasmodium falciparum malaria: Results from a Swedish nationwide study. Clinical Infectious Diseases. 2017;65(6):949-58.
https://doi.org/10.1093/cid/cix437

III. Wångdahl A, Wyss K, Saduddin D, Bottai M, Ydring E, Vikerfors T, Färnert A. Severity of Plasmodium falciparum and non-falciparum malaria in travelers and migrants: A nationwide observational study over 2 decades in Sweden. Journal of Infectious Diseases. 2019;220(8): 1335-45.
https://doi.org/10.1093/infdis/jiz292

IV. Wyss K, Granath F, Wångdahl A, Djärv T, Fored M, Naucler P, Färnert A. Malaria and risk of lymphoid neoplasms and other cancer: A nationwide population based cohort study. [Accepted]
https://doi.org/10.1186/s12916-020-01759-8