Screening for malaria

Apart from maintaining the transmission of malaria in endemic areas [159, 164, 168], prolonged asymptomatic malaria infections may not be beneficial for individuals outside endemic areas despite lack of symptoms [174, 176]. Although this is an understudied subject, studies suggest association to anaemia [271], cognitive dysfunction [175], serious adverse events in pregnancy [157], and may be associated with bacterial infections [272], and all-cause mortality [174]. Asymptomatic disease may also progress into symptomatic disease, although under other conditions studies rather suggest a protective effect [100, 162, 273].

Currently, malaria is not targeted in health screening offered to migrants in Sweden, nor is it mentioned in the ECDC guidance on national screening [253], while in the US, CDC

recommends presumptive treatment with artemether/lumefantrine for migrants arriving from Sub-Saharan Africa [251]. Further studies on long term consequences of malaria infection

6 CONCLUSIONS

Episodes of severe malaria were caused by all species in patients diagnosed with malaria in Sweden.

Risk factors for severe P. falciparum was young and older age, patient origin in a non-endemic country, region of diagnosis, health care delay, as well as HIV, and pregnancy.

Risk factors for severe non-falciparum malaria was age >60years and health care delay, as well as endemic origin. Newly arrived migrants were identified as a risk group for severe non-falciparum malaria, most were newly arrived Eritrean migrants.

In P. falciparum episodes with parasitemia ≥2% without severe signs at presentation, oral treatment was strongly associated with progress to severe malaria. This supports initiation of intravenous treatment in P. falciparum cases with elevated parasitemia, even without other signs of severity.

Compared to P. vivax, the risk of relapse was lower in P. ovale, demonstrating different relapsing character of the two species. Due to the limited number of relapse episodes in P.

ovale the effect of primaquine in preventing relapses remain uncertain.

When evaluating the WHO criteria for severe malaria, we identified a set of three warning signs for unfavourable outcome, consisting of cerebral impairment (GCS ≤14 or multiple convulsions), ≥2% P. falciparum parasitemia, or respiratory distress (respiratory rate >30 or clinical signs of acidotic breathing). A presentation of any of these three signs indicate high risk of severity and parental antimalarial therapy should be considered.

In migrants arriving from Sub-Saharan Africa, malaria parasites were particularly prevalent in migrants resettling in Sweden from DRC and Uganda, and the prevalence was highest in children with this origin, reaching over 30%. Belonging to a family with a member testing positive, was strongly associated with PCR positivity. Screening for malaria should be considered in migrants, especially in children, arriving from high endemic countries as well as around confirmed cases.

Within the first year of arrival, there was no significant difference in malaria prevalence in migrants from DRC and Uganda by duration of stay, and the longest duration of residency in Sweden was 386 days in a participant carrying P. falciparum indicating a long duration of infection.

7 POINTS OF PERSPECTIVE

Malaria in travellers and migrants includes a wide spectrum of clinical presentation, from severe manifestations with multiple organ impairment to asymptomatic parasite prevalence, seen in migrants from high-endemic countries. An ideal approach in the clinic, therefore, needs to deal with all these aspects of malaria infection. That is, optimal management without delay and early identification of patients at risk for severe disease, as well as limiting the health gap in migrants by assessing malaria and other infectious diseases in migrants.

Migration health and integration are subjects of concern and importance. Studies report unmet health care needs and, along with psychological disorders, and often a high burden of infectious diseases in comparison to the population in the receiving country. Screening is a useful tool for early detection and improved prognosis of other infections, such as HIV, but studies are lacking in malaria. Studies on the burden and consequences of chronic parasitic infection, caused by malaria as well as other parasites such as Schistosoma and Strongyloides may be needed to elucidate a public health issue and guide measures for reducing these potential health inequalities. Expanding Study IV to also analyse for other parasitic diseases is a natural elongation, and in fact, this has recently been started.

The diagnostic tool for these other parasitic diseases includes serology. In malaria, an

optimised serologic panel reflecting high risk of ongoing malaria parasitemia could be useful to select patient for further testing with a high specific molecular method, such as LAMP or PCR, or to select patients for presumptive antimalarial treatment.

Studying malaria in a non-endemic environment, where there is no risk of reinfection, may be beneficial for example in studies with longitudinal data collection. The natural duration of malaria is an understudied subject, that have clear implications in malaria elimination and eradication strategies. A longitudinal study with multiple testing occasions after arrival in a non-endemic country could help answering some of the questions around the true duration of Plasmodium infection in humans.

Moreover, the effects on health from asymptomatic malaria infection needs to be

investigated, however, as these effects may be discrete, such studies are challenging due to the need of long-term high-quality data. A prospective approach with linking to registers, for example the diagnosis register, could be a useful approach. Such studies could help in forming strategies for improving health in migrants, for example with screening strategies.

Timely measures with diagnostics and initiation of treatment are important factors for a successful management of malaria. In non-endemic countries, where malaria is rare, delay to diagnosis is a key risk factor for severe malaria. Measures to improve management of fever in the returned traveller and newly arrived migrant could include improved triage, for example routinely asking patients with fever about recent stays abroad. Also in the management of diagnosed malaria in non-endemic countries, further improved and adapted treatment guidelines and scoring systems could help improve outcome.

8 POPULÄRVETENSKAPLIG SAMMANFATTNING

Malaria är en potentiellt dödlig sjukdom som orsakade cirka 241 miljoner fall och 627 000 dödsfall 2020, de flesta hos barn i Afrika söder om Sahara. Malaria orsakas av parasiten Plasmodium, som sprids av myggor. Det finns fem arter av Plasmodium som normalt orsakar infektion hos människor: P. falciparum, P. vivax, P. ovale, P. malariae och P. knowlesi.

Symtomen på malaria kan vara lindriga, men utan korrekt behandling kan de utvecklas till en livshotande sjukdom med svåra symtom såsom medvetslöshet, andningssvårigheter, nedsatt njurfunktion och annan funktionssvikt i de vitala organen, vilket medför hög dödlighet. Det är därför viktigt att tidigt identifiera patienter med hög risk för allvarlig malaria. Allvarlig malaria definieras av Världshälsoorganisationen (WHO) och intravenös behandling

rekommenderas för patienter som uppfyller något av kriterierna för allvarlig sjukdom. Det är dock inte klargjort om dessa kriterier och rekommendationer är optimala i icke-endemiska länder såsom Sverige.

I områden där malaria sprids drabbas främst barn av allvarlig malaria och befolkningen blir alltmer immun med tiden, vilket ger ett skydd mot allvarlig malaria. Migranter som kommer från länder med hög spridning av malaria kan i stället vara bärare av malariaparasiter utan att uppleva särskilda besvär, risken för spridning är närmast obefintlig, men infektionen kan innebära negativa effekter på hälsan för bäraren.

Denna avhandling består av fyra delartiklar om malaria bland resenärer och migranter i Sverige.

I den första studien beskriver och sammanfattar vi 2653 fall av malaria hos resenärer och migranter diagnostiserade i Sverige. Vi studerade riskfaktorer för svår malaria och fann att patienter med både låg och äldre ålder, patienter med ursprung i Sverige eller annat land utan spridning av malaria samt försenad malariadiagnos, hade en ökad risk för allvarlig sjukdom.

Vi fann även att patienter med över 2 % av de röda blodkropparna infekterade av P.

falciparum parasiter löpte hög risk för försämring om tablettbehandling gavs istället för intravenös behandling. Dessutom noterades att svår malaria också orsakades av de Plasmodium-arter som ofta beskrivs som godartade, nämligen P. vivax, P. ovale och P.

malariae, och många av de svårt sjuka av dessa malariaarter var nyanlända migranter.

I den andra studien utvärderade vi hur läkemedlet primakin påverkade risken för återfall efter en infektion orsakad av P. vivax och P. ovale malaria. Det är välkänt att primakin minskar risken för återfall vid P. vivax, men effekten är mera osäker vid P. ovale. Som väntat minskade primakin signifikant risken för återfall i P. vivax. P. ovale däremot orsakade få återfall och därför var effekten av primakin mer svårvärderad.

I den tredje studien beskriver vi hur väl WHO:s kriterier för svår malaria motsvarar allvarlig sjukdom hos resenärer och migranter med malaria i Sverige. Vi utvärderade också flera modeller från tidigare studier som har föreslagits för att utvärdera eller förutspå

svårighetsgraden av en malariainfektion. Här upptäckte vi att patienter med nedsatt

medvetandenivå, andningsproblem eller som har över 2 % av de röda blodkropparna infekterade med malariaparasiter hade en högre risk för ogynnsamt utfall (död eller behov vård på intensivvårdsavdelning i 2 dagar eller mer).

I den fjärde studien var målet att undersöka hur stor andel av migranter som kommer till Sverige från Afrika söder om Sahara som bär på malariaparasiter. Vi fann att 8% av alla studiedeltagare bar på malariaparasiter i blodet, och en majoritet av dem hade varit bosatta i Uganda innan de kom till Sverige. En särskilt hög andel malariabärare hittades hos barn som anlände från Uganda och över 30 % var malariapositiva i vårt test. Bland deltagare som testade positivt för malaria var den längsta vistelsetiden i Sverige 386 dagar.

Sammanfattningsvis identifierades flera riskfaktorer för allvarlig malaria hos resenärer och migranter. Risken för återfall av P. ovale är låg, och behovet av primakinbehandling är fortfarande osäkert. Vid utvärderingen av kriterierna för allvarlig malaria identifierades tre tydliga varningstecken. Vi rapporterar också en hög förekomst av malariaparasiter hos migranter som flyttar till Sverige från DRC och Uganda, särskilt bland barn. Resultatet kan vägleda handläggning och behandling av malaria och om införande av screening för malaria hos migranter bör övervägas.

9 ACKNOWLEDGEMENTS

First of all, I want to express my humble and sincere gratitude towards all study participants. I would also like to thank everybody who supported and contributed to this work or made the time spent on this thesis worthwhile, interesting, and fun.

With a warm and special thanks to:

Anna Färnert, my supervisor. Thank you for the never-ending stream of good advice, your genuine enthusiasm, and your kind and constant support. I am so grateful that you took me onboard on this, included me in your skilled and diverse research group and supervised me with such incredible patience and ambition.

Tomas Vikerfors, my co-supervisor. You have opened many doors for me and given me inspiration and the idea that nothing is beyond do-able with hard work (provided you have a space, like you said: a children’s play-house in the garden, for self-isolation and undisturbed research time). You have never failed to send your encouragement throughout these years, that meant a lot. Thank you.

Christina Carlander, my co-supervisor and former mentor. Thank you for allowing of your time for my rants of insecurity and self-doubt. In retrospect, I can see how subtle yet forceful your hints of advice were. Thank you for being such a committed and caring co-supervisor.

Peter Kragsbjerg, my mentor. When it comes to the spoken word, less is more. Good talk.

Thanks.

Katja Wyss, my research colleague and friend. With your enthusiasm and knowledge, you are such a rising star. Thank you for all insightful comments on manuscripts and for being such an amusing, kind and dedicated colleague.

The past and present members of the Färnert Research Group – Christopher Sundling, Julius Lautenbach, David Plaza, Aurelie Miglar, Asghar Muhammad, Akua Botwe, Peter Jahnmatz, Doreen Mutemi, Caroline Rönnberg, Klara Sondén and Victor Yman.

The level of expertise and commitment in this group is so impressive, I learned so much from you. A special thanks to Fariba Foroogh for all the kindness, help and unconditional support during these years, Rebecca Tafesse Bogale for the way you excelled in every task in the malaria migrant project, Carolann Mwita for your skilfully work in the malaria migrant project, Ioanna Broumou for sharing your PCR expertise, Suzanne Desirée van der Werff for being genuine, kind and helpful and Ana Requena Mendez for your enthusiasm and valuable input in expanding the project to include also the ”other parasites”.

Urban Hellgren at Karolinska Huddinge, thank you for the warm welcome in the field of tropical medicine. Your knowledge and curiosity are really inspiring. Thank you for all the good advice in the primaquine study, and for the excellent course in tropical medicine held

together with Hilmir Asgeirsson and Sara Roth de Albaquerque - Thank you for arranging the amazing field trip to Tanzania despite the minimal notice.

Matteo Bottai, Linnea Widman, David Grannas at the Unit for Biostatistics at the

Department of Environmental Medicine, Karolinska Institutet as well as Philippe Wagner at Centrum för Klinisk Forskning in Region Västmanland for the statistical support.

Christine Stenström at the Department of Microbiology at Karolinska for your kindness and willingness to facilitate our research and for the enthusiasm for teaching malaria diagnostics.

The medical students, David Björklund, Emil Hallberg, Adina Hildell, Isabelle

Johansson, Suzanne Franson, Isabelle Eliasson, Ganna Vashchuk, Linda Peterson and Filip Lind, thanks for your effort! Co-supervising you was a thrill. I learned a lot, well aware that it should have been the other way around.

Angelica Gervin, Shelan Kaitoly, Berhane Tekleab, Sandra-Lee Wasserman and all the dedicated staff at Migranthälsan in Rissne as well as in Skärholmen and Fittja and Anders Eklund and Monica Malmtorp at Råby Vårdcentral och Asylhälsa in Västerås, thank you for believing in the project we involved you in and for all the important work you did. It was such a pleasure to work with you.

Infektionsmottagningen Solna – Irene Nordling, Monica Modin, Anna Dahlberg and Debbie Ribjer. Thank you for all your efforts in the Malaria Migrant study, and for always being so welcoming and supportive.

Olof Hertting, at Astrid Lindgren Children’s Hospital. Thank you for your all your input, interest and effort in the study on malaria in migrants.

Helena Hervius Askling for the collaboration resulting in the primaquine study.

Anna Löwhagen Welander and Mika Liljeback, the study nurses, thanks you for helping us out and for being so flexible and easy-going.

Elsie Ydring, Linda Trönnberg and Marika Hjertquist at the Public Health Agency, thank you for providing data from the Public Health Agency database

Anna Bergström at the Migration Agency for providing data from the Migration register.

Lillemor Melander, Anne Rasikari and Sahra Bunner for the invaluable assistance with all the practical things.

Anders Björkman, Pedro Gil and Isabel Veiga who first introduced me to malaria research and encouraged me despite my lack of talent in the lab.

Cherin Kamil, my boss at the Department of Infectious Diseases in Västerås. Thank you for your support during these years, for allowing me time off from the clinic, and for being such

All my dear colleagues at Infektionskliniken Västerås, the best colleagues there is. It is so very nice and unique how our individual qualities join to cover our shortcomings. I think you are all brilliant. Thanks; Torbjörn Larsson my roomie. I hope we’ll share space for years to come. I’m just guessing, but there might still be infinite ways to put our desks, and yet we’ve tried only 15-20 of them. Thanks for everything, and for brining coffee! Göran Åkerblom for your generosity, all the fun and for always giving us updates on the very latest from the social and cultural world. Anders Krifors for keeping up the tempo in the gym as well as in research, and in anything else in fact, Ann-Sofi Saidi for your personal involvement in things at work and for so successfully manoeuvring the impossible task of scheduling the doctors, Ingrid Selmeryd for supervising me so smoothly and organised during my ST, Emeli Månsson for radiating your clinical and scientific excellence, Karin Nordfors for sharing your vast knowledge on which days to drink white and which days to drink red, Erica Tibbelin for biting the head of people when they are idiots, Gabriel Heyman for promoting the intellectual view on things, Felix Schagatay for being such a nice companion, Stina Malmström for your insane pranks, and Mulki Rashid-Abdi for being an undercover rebel.

Eva-Lena Axelsson, Lotta Malmqvist, Lena Nilsen, Nathalie Peterson, Ann Ågren and Acki Frandsen at Infektionsmottagningen Västerås, thanks for always pointing me in the right direction, and Susanne Monié, Catta Olofsson, Maria Gothilander and Ylva Boman for the humour and open office doors, and for making my notes in the medical records appear stringent and complete. Sorry Ylva, the plant that I borrowed from you is dead, I couldn’t tell you face to face.

Otto Strauss, presently at Auckland DHB & Auckland University. Thank you for your inside knowledge on how to cope during the different phases of PhD training. I loved our drunken chats and how our ideas grew for every pint of IPA.

Linda, my wife, my love. Thank you for keeping my heart warm and for everything you have done for me and our sweet family. As you know, too much work makes me serious and dull, forgetful and distant, but it is you who set colour to this world.

Matilda and Viktor my dear kids, for all the joy, love and perspective that you bring.

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