Who are you and what is your research focus?

Thank you for this opportunity to have an interview. My name is Patricia Schlagenhauf and I am a Professor (Travel Medicine and Malaria) at the EBPI and Head of the WHO Collaborating Centre for Travellers’ Health and Director of EuroTravNet, a network of clinics throughout Europe that focus on the surveillance of travel-related infection. My research focus is quite broad and seems to be ever increasing. At the moment, I have a lot of studies going on that look at the epidemiology of infection in travellers, including a very innovative SNF-founded project called ITIT (Illness Tracking In Travellers) which uses an app to track symptoms and illness in travellers during and after their travel. This is an important “citizen science” study with the potential to revolutionize traveller health surveillance. Our project partner here is the World Health Organization. Another very important project is the "Mosquito on Board"-Project which looks at the potential for stowaway invasive mosquitos on aircraft coming to Europe- an important topic in the light of climate change and mosquito-borne infections in Europe including dengue and malaria. A further research focus of course is work with the GeoSentinel and EuroTravNet, international networks that focus on the surveillance of illness in travellers on a global level. Also my work with the World Health Organization in guideline development on the use of border screening to check the distribution and spread of diseases with pandemic potential is fascinating. More recently, we are also looking at tick-borne, co-infections in Switzerland. I also have a strong research collaboration with the Swiss Armed Forces and here we evaluate post COVID sequelae in young men. My first love in research is however travellers’ malaria and here my research looks at the epidemiology of malaria in travellers, malaria medications including novel formulations and recently malaria medication concentrations in hair.

At which places is there a risk of malaria?

The largest and greatest risk is in sub-Saharan Africa but basically malaria is present in many tropical areas and subtropical areas throughout the world. Now, there are several different types of malaria. The most important, in terms of risk, for travellers is probably Plasmodium falciparum which has a high case fatality if untreated. This is the predominant species in sub-Saharan Africa. Asia has a high burden of P. vivax malaria. In terms of places at risk of malaria: another research focus of mine is the impact of climate change on the possibility of the renewed transmission of malaria in Europe, for example. So, the list of places where a malaria risk exists is fluid. There are a lot of changing boundaries .Last month some locally acquired malaria cases were reported from Florida, USA!

What are causes, as well as symptoms and effects of malaria on the human organism?

The cause of malaria in humans is an infection by a parasite called Plasmodium. This parasite is transmitted by the Anopheles mosquito and the Anopheles mosquito bites the human and injects malaria “sporozoites” which is the form of infection in the mosquito that can be transmitted to humans after a mosquito bite. When the sporozoites are injected into the bloodstream of a bitten human, within about a half an hour these parasites disappear into the liver where they have a cycle, and they multiply and then they emerge in the bloodstream of the human and pose the typical early symptoms of malaria such as fever or chills. When this is not treated or when the person has no semi-immunity these symptoms can progress, and the parasite can invade several organs and cause multiple organ damage. A very severe form of malaria is cerebral malaria, where the brain is affected. So, malaria, untreated, in non-immune humans would have quite a high case fatality rate .But usually in industrial countries, malaria infections are treated and associated with a much lower mortality.

This leads me to our next question: When is it indicated to take malaria medication?

Again, you should take antimalaria medication if you're travelling to an area of considerable or high risk. As part of my work with the Swiss working group for travellers malaria we look at assessing risk at various geographic destinations and based on a certain level of risk in the local population as well as cases in returning travellers we have delineated the malaria risk areas into high risk, meaning a chemoprophylaxis is indicated, seasonal risk where the chemoprophylaxis is only indicated for certain times of the year and then low risk or minimal risk, where just mosquito bite protection is indicated.

How effective is the protection from chemoprophylaxis? What does the effectiveness depend on?

The malaria medication for chemoprophylaxis is very, very effective. All of the studies show over 95% effectiveness. We're talking about the three priority antimalarials which are atovaquone-proguanil or Malarone, mefloquine and doxycycline. But the effectiveness does vary, it really depends on the intake of the medication. So, adherence or compliance with the medication is absolutely key for travellers. There is no point in having an expensive chemoprophylaxis in your bag if you don't take it. It won't protect you against malaria. So, intake is very important, adherence is very important and then there are some personal factors that also influence the protection. For example, studies have found that a higher dose may perhaps be needed for very obese people and they may not be protected adequately with the regular dosage of antimalarials. Other studies have shown that the absorption and the pharmacokinetics of malaria drugs very much depend on the individual and also on how you take the medication. If you take atovaquone-proguanil on an empty stomach the absorption is very poor and it is advised to take this medication with fat containing foods. But the most important thing is the adherence meaning that the traveler adheres to the schedule. Recently we published a very nice study called "HAIR" which shows the concentration of antimalarials in the hair of returned travellers and with this technique we could show that the people were taking their anti-malaria medication and we could also show the timing of the malaria medication intake, because the hair saves the concentration of the drug at the timepoint it's taken. So, we found this very innovative and we're continuing now with this to see if we can use it for further studies.

Is malaria medication alone sufficient or does it need to be combined with other protective measures? If so, which ones?

Malaria medication is of course very important for those high-risk areas and mosquito bite protection must always be used. There is also the issue of risk perception on the part of the traveller. So even though they have been told that the malaria risk at this particular destination is high, they may also meet other travelers who say "oh, I've been here many times and I've never had malaria and I never take anything.". That also impacts the perception of the traveller. The medication of course is most useful if you use it in connection with anti-mosquito bite measures. And that is the Achilles heel of travel medicine because it is very difficult to ensure adherence with those anti-mosquito measures. So, for example we recommend that travellers apply DEET or an effective repellent on the skin. And then we recommend that they use impregnated clothing. Regarding, the repellent on the skin, we also looked at that in a study and found that less than 2% of travelers use an adequate concentration of repellent on their skin. I think everyone does slap on a little repellent but actually, if you look at the instructions, you're supposed to have a wetting of the skin on all areas that are exposed. So, you can imagine that's not done very well. And then the impregnated clothing, that's done to some extent but it's also difficult because it does have a certain scent and people on holidays don't really want to use that all the time. Also, when you wash the clothing, you lose this impregnation. So, it requires a lot of discipline to protect yourself against malaria whether it's taking the drugs, and or using the mosquito bite measures.

What are the differences between the various antimalarial medication?

The three priority antimalarials that we have for chemoprophylaxis here in Switzerland are mefloquine, atovaquone-proguanil and doxycycline. Mefloquine is taken just once a week and for that reason it was very popular. Some studies showed that it had an excess of neuropsychiatric adverse events compared to other antimalarials, so it has fallen a little bit into the second row of choices. Atovaquone-proguanil is first choice at the moment in Switzerland. It has the advantage that you just need to take it for one week post-travel but it's a daily regimen, so people have to take it every day and it can also be quite expensive. Then you have doxycycline which can be recommended as a third line drug for high-risk areas. It has the disadvantage that it can cause photosensitivity which, as you can imagine, in tropical/subtropical areas is a distinct disadvantage. It can also cause proliferation of vaginal candida in women which is also something that isn't so great for travellers. But it is a very good drug in some circumstances, It does offer additional protection against certain forms of diarrhea and certain forms of tick-borne illnesses. Another big disadvantage of doxycycline is daily dosing and the four weeks post travel intake. So, just to get back to the adherence thing, if I quote a very old saying: "The more complex the medication/prescription, the poorer the adherence." So that's a crux with antimalarials.

What criteria do you use to decide on a medication? Are there factors, such as gender or age, that are important in the choice?

Very much so! So, the choice with malaria medication is actually quite complex! It needs really an in-depth knowledge of all those medications, their interactions, their adverse events, their price, their indications, contraindications. So, for example, some of the malaria medications are not allowed for small children, and small children are a high-risk group, so one has to be sure that you have an option that you can offer. Pregnant women, especially first trimester pregnant women, can't take all anti-malarials. You have some people who are taking co-medication that doesn't mix well with one or other of the antimalarials. And of course, you also have certain contraindications in terms of preexisting illness. And then, price is a big issue. For some VFR-families (VFR stands for "visiting friends and relatives" in the country of origin), they constitute a very high-risk group for malaria and if you are recommending chemoprophylaxis for an entire family, with a drug that is extraordinarily expensive!- that prescription simply won't be filled. So, sometimes one has to juggle price and use. With regards to gender, in my studies I have found that women tend to be more adherent with medication and also with anti-mosquito bite measures. But they also tend to report more adverse events. So perhaps there is a need to do some research on dose tailoring for women.

What are the most common side effects?

Each antimalarial has its spectrum of known adverse events, so with atovaquone-proguanil it definitely is gastrointestinal, you have gastrointestinal problems and often it's difficult to decide if it's due to GIT-disturbance during the trip or due to the medication. Mefloquine is related to causing changes in mood, feeling a little bit down, feeling a little depressed. It's contraindicated for people with a history of depression. Mefloquine has also been associated with having very vivid dreams, which you may or may not enjoy - it's something to be aware of. And doxycycline of course then on account of its photosensitivity potential, has been associated with reddening of the skin and with candida superinfections, such as vaginitis.

Are serious interactions possible with other medications or substances, such as alcohol and harder drugs?

That's a very good one. The interactions between antimalarials and alcohol are very important because I think a lot of people consume alcohol when they're travelling. To the best of my knowledge this interaction has only been checked with mefloquine. In a study of driving under the effect of mefloquine or alcohol and the combined effect of mefloquine and alcohol mefloquine didn't really impact on driving ability. But there are case reports of persons who have for example consumed a half bottle of whiskey on the day of their mefloquine intake and who experienced psychiatric events. Now, whether that's due to the personality and the drinking or the personality and the drinking and the mefloquine - that is hard to decipher. I don't know any studies that look at the combined use of antimalarials, marijuana or cocaine or other drugs of abuse. This would certainly be an interesting avenue to study. There are interactions between certain antimalarials and other drugs or food - for example doxycycline is a tetracycline antibiotic, it can interact with milk, for example, if you take it at the same time or if you take it at the same time as some antacids. So, there are a lot of potential interactions between the antimalarials and other medications. Mefloquine can also interact with certain drugs that are used for neuropsychiatric conditions, but because a neuropsychiatric condition per se is a contraindication for mefloquine there shouldn't be dual use.

What about taking it during pregnancy?

At the moment, there are different regulations and guidelines throughout Europe which makes it very difficult. There is one study done in travellers examining the risk of stillbirth in conjunction with the use of mefloquine. We looked at a retrospective database of women who became pregnant while taking mefloquine and we didn't find any negative impact on the fetus on the possibility of stillbirth or on further development in those who took mefloquine during the first trimester. So right now, most countries of the world would say yes, mefloquine in the first trimester is important to take if there is a high risk and it's possible. There are fewer data on atovaquone-proguanil in the first trimester. There are quite good data on the second and third trimester for almost all of those drugs. Doxycycline is not permitted in the later trimesters because it interferes with bone and teeth formation in the fetus So here in Switzerland, if it's the first trimester high risk women who absolutely have to travel - we would recommend all pregnant women not to travel to high-risk malaria areas - the first trimester we would recommend mefloquine and then the other trimesters we would have more options.

 Want to learn more about traveling while pregnant?

Are there certain diseases or other factors where antimalarial drugs are not recommended?

I think the risk of malaria in a high-risk area really outweighs a lot of those contraindications. Mefloquine is absolutely contraindicated in persons with current or previous psychiatric disorders. Renal and liver conditions may contraindicate some anti-malarials. Immunosuppressed people definitely should take antimalarials because if they contract malaria they are at high risk. There should be a careful risk/benefit balance calculation for malaria drugs.

What are the most exciting results of your research?

I suppose the most exciting results date back some time now. We did the first study ever worldwide, concurrently using all antimalarials where we had a four-arm, double-blind, placebo controlled study at multiple centers throughout Europe and in Israel. I think that really was a groundbreaking study because it was free of bias, everybody was blinded to the medication they were taking. We found that the drug with the best profile with regard to safety was atovaquone-proguanil, but only narrowly ahead. And then came mefloquine and then came doxycycline. And the drug regimen with the poorest profile was chloroquine-proguanil. Other studies have looked at malaria deaths in travellers and the risk factors involved. I'm doing a very nice study at the moment - it's not quite finished but it's using EuroTravNet data - and there I'm looking at the mosaic of malaria as it presents in Europe, looking at the impact of migration waves on imported malaria. And also, which I think is very exciting, looking at the colonial legacy of imported malaria. So, we can see, when we look at imported malaria in Belgium, imported malaria in the Netherlands, in the UK, there is a very distinct colonial pattern to this. So, I think these findings can also be used to formulate guidelines because you know then your risk communities. The HAIR study I also liked there we brought together a new method to evaluate concentrations of antimalarials in hair, which can be used I think in the future to look at adherence in studies - it's always a difficult one. I'm also very interested of course in everything that has to do with the malaria vaccine and I'm planning a study on injectable antimalarials that will have a vaccine-like effect. Another exciting prospect on the horizon is a possible study evaluating tafenoquine which is a new antimalarial that works at all stages of the parasite life cycle and I’m hoping to do something there in collaboration with other colleagues.

How do you think the field of 'malaria prevention' will change in the future?

I’m hoping there will be a vaccine for travellers. There is a vaccine at the moment for endemic area populations, but it has a very low efficacy and doesn't reach the 90+ percent efficacy that you would wish for in travellers. So, I think we will be stuck with the drugs for a long time, the chemoprophylactic drug tafenoquine will be coming soon to Europe and that will have a major impact because this is one drug that acts on all different types of malaria and on all stages of malaria. So, it's like a panacea for travellers’ malaria in general. I think that will be really important. Other areas of malaria prevention that I think need a lot more research include mosquito bite prevention, not just in terms of malaria protection but also with the threat of mosquito-borne infections worldwide. So, I think new drugs, particularly tafenoquine, gender issues in chemoprophylaxis, the possibility of a vaccine for travellers’ malaria and focus on anti-mosquito bite prevention, they will be the main focus areas of research for travellers’ malaria in the future.

Do you see malaria becoming an issue here in Europe too in the future?

I do think there is a possibility. We have recently published a paper on this theme and we looked at the areas in Europe that are most likely to be increasingly receptive to malaria and those are situated on the Mediterranean basin, southern Europe but we also saw that Central Europe will have conditions that are conducive to malaria transmission, particularly in a six month period between April and October. Right now, I think Europe is well placed with public health measures to prevent this from happening but don't forget, Europe was endemic for malaria back in the 19th century so we have to be careful it doesn't reappear.

Thank you so much for your time today and your work here at EBPI!