- Email: [email protected]
Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations
Travel Medicine and Infectious Disease xxx (2017) 1e7
Contents lists available at ScienceDirect
Travel Medicine and Infectious Disease journal homepage: www.elsevierhealth.com/journals/tmid
Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations Mithula Shellvarajah a, Christoph Hatz b, Patricia Schlagenhauf a, * a
University of Zürich Centre for Travel Medicine, WHO Collaborating Centre for Travellers' Health, Institute for Epidemiology, Biostatistics and Prevention, Hirschengraben 84, 8001 Zurich, Switzerland Swiss Tropical & Public Health Institute, University of Basel, Switzerland
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 November 2016 Received in revised form 5 September 2017 Accepted 7 September 2017 Available online xxx
Introduction: Malaria prevention can be complex due to the individual characteristics of the traveller, travel destination, duration of stay and type of travel. Our aim in this study was to document malaria chemoprophylaxis recommendations provided by travel-medicine experts in Europe for specific risk groups of travellers visiting malaria-endemic areas of sub-Saharan Africa. Methods: Travel medicine experts in Europe were asked to complete an online questionnaire, a 28-item Survey Monkey survey, on 11 malaria prevention scenarios. We also reviewed the recommendations of the UK, U.S. CDC, Germany, Switzerland, WHO and the electronic Medicines Compendium (eMC) for malaria prevention in risk groups. Results: The questionnaire was sent to 110 travel medicine experts in 19 countries. The response rate was 44.55%. The experts would recommend, as first choice, malaria chemoprophylaxis atovaquone/proguanil for an adult traveller with no co-morbidities travelling for 2 weeks (91.67% of experts) and for 2 months (51.06%), for a healthy tourist child travelling for two weeks (68.09%) and for an adult traveller with liver cirrhosis (57.78%). Mefloquine was the first choice for a healthy tourist child travelling for 2 months (59.57%), for a tourist infant (8 kg) travelling for 2 weeks (59.57%) and for 2 months (68.09%), for a pregnant VFR (74.47%), for a breast-feeding mother with her 5 kg infant (72.34%) and for a VFR family with limited budget (63.83%). For an adult traveller with renal impairment the experts recommended mefloquine (42.22%) or doxycycline (37.78%). All experts (100%) recommended mosquito repellents. Mosquito nets were recommended routinely by 95.35% of the experts, air-conditioning by 83.72% and impregnated clothing by 81.40%. Conclusion: The European experts differ in pre-travel anti-malarial recommendations for risk groups visiting malaria endemic areas of sub-Saharan Africa. Contraindications are not always observed and there are no uniform recommendations for high-risk groups. 9 experts would recommend atovaquone/ proguanil to a traveller with severe renal impairment although most reviewed national recommendations consider this a contraindication. Discordance in recommendations, a lack of key data and few chemoprophylaxis options limit choices for pre-travel health advisors. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Malaria Chemoprophylaxis Atovaquone/proguanil Doxycycline Mefloquine Risk groups Expert opinion Recommendations
1. Background In 2014, the world tourism organization (WTO) reported 1138 millions arrivals worldwide and the forecast for 2030 is 1.8 billion international tourists. Travel to Africa grew by 2% in 2014 and to
* Corresponding author. E-mail address: [email protected] (P. Schlagenhauf).
sub-Saharan Africa by 3% [1]. An earlier study noted a statistically significant increase in travel-related diseases acquired in sub-Saharan Africa by ill travellers presenting in Europe. Malaria was one of the top diagnoses, mainly acquired in sub-Saharan Africa by men (68%) and by those whose purpose of travel was “visiting friends and relatives” (VFR) (52%) [2]. The findings of the study showed that, for all traveller groups (including the risk groups and VFRs), pre-travel consultation
http://dx.doi.org/10.1016/j.tmaid.2017.09.002 1477-8939/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
2
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
significantly lowers the proportionate morbidity ratios for Plasmodium falciparum malaria [2]. These results demonstrate the importance and effectiveness of pre-travel prevention strategies [2]. Travellers to high risk malaria-endemic areas should receive anti-malarial advice: a combination of mosquito avoidance measures and chemoprophylaxis [3]. Since 1980, the spread of chloroquine resistant Plasmodium falciparum malaria has extended through sub-Saharan Africa [4,5]. Currently recognized priority chemoprophylaxis recommendations for travellers to sub-Saharan Africa are atovaquone/proguanil, doxycycline and, as second choice in some countries, mefloquine [6e8]. Malaria prevention can be complex due to the individual characteristics of the traveller, travel destination, duration of the stay and type of travel [9]. The complexity of providing advice is increased in groups such as immunosuppressed travellers, young children, pregnant women and long-term travellers [9,10]. The risk is also higher in previously semi-immune people who have moved to countries without highly endemic malaria as the immunity wanes. Those visiting friends and relatives in their home countries (VFR) are less likely to receive pre-travel advice [11]. Because drug safety studies and efficiency strategies are lacking for all risk groups, recommendations can be complex [11]. European experts generally follow the national and/or international recommendations for malaria chemoprophylaxis. A previously published Delphi method study regarding malaria chemoprophylaxis recommendations showed that the experts varied widely among the preferred chemoprophylaxis recommendations. The choices were affected by „a high degree of subjectivity and national policy differences“ [12,13]. 2. Objective Our aim in this study was to document malaria chemoprophylaxis recommendations provided by travel-medicine experts in Europe for specific risk groups of travellers visiting malariaendemic areas of sub-Saharan Africa and to document whether routine protective measures are recommended. We also aimed to review national and international recommendations with regard to malaria prevention recommendations for certain risk groups.
Saharan Africa. The experts were asked whether they would prescribe malaria chemoprophylaxis to each risk group or not. If so, they could order by choice (1st preference, alternative choice) one out of three malaria chemoprophylaxis: atovaquone/proguanil, doxycycline or mefloquine. The goal was to have two answers regarding each risk group of traveller: i.e. expert opinion on the first and the second choice of chemoprophylaxis. Concerning the questions about mosquito bite measures the experts had to answer “yes” if they recommend the measure routinely for travellers visiting malaria-endemic areas of subSaharan Africa, or “no” if not. The questionnaire responses were collected and analysed by Survey monkey. We compared the national recommendations of United Kingdom (UK), Germany (DE), Switzerland (CH) and from the Centers for Disease Control and Prevention from the Unites States of America (U.S. CDC), and the international recommendations of the World Health Organization (WHO) for the special risk groups. The medication specifications and recommendations on contraindications and precautions of the European electronic Medicines Compendium (eMC) were considered for the background to the discussion and recommendations. The electronic Medicines Compendium (eMC) lists information about all medicines, which are approved either by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and/or European Medicines Agency (EMA). It is provided from the medicine regulatory agencies. It serves as an important source of product information. 4. Results The questionnaire was sent to 110 pre-travel medicine experts. A total of 49 experts participated on this study; the response rate was 44.55%. 87.75% of them (n ¼ 43) completed the whole questionnaire. The experts participated from 19 different countries (see Table 1). 61.22% of the participants were older than 50 years (n ¼ 30) and 63.27% were male (n ¼ 31). In 48.98% of the experts' clinics, more than 200 pre-travel consultations are done per month.
3. Methods
4.1. Malaria chemoprophylaxis recommendations
This study was done between October and December 2014. Leading travel medicine experts in Europe were asked to complete an online questionnaire on malaria prevention. These European experts were identified using the International Society of Travel Medicine (ISTM-) Clinic directory and also by asking colleagues from EuroTravNet (http://www.istm.org/eurotravnet) and TropNet (http://www.tropnet.net) to participate. A 28-item questionnaire in English by Survey Monkey with 27 multiple-choice questions and one open question was specifically created for this study. The first 4 questions characterised the experts: practising country, sex, age and number of monthly pretravel-consultations undertaken. The country list included all European Union (EU-) and European Free Trade Association (EFTA) countries. The next 23 questions were about malaria prophylaxis recommendations. In the questions regarding malaria chemoprophylaxis we built risk groups of travellers. There were 11 travel scenarios. Our defined risk groups were: short term traveller (2 weeks), long term traveller (2 months), pregnant women in first trimester, breast-feeding mother, 6-years old tourist child, tourist infant (8 kg), VFR family with limited budget, traveller with liver cirrhosis due to hepatitis C virus (HCV) and traveller with renal impairment (glomerular filtration rate (GFR) < 30 ml/min). All travel scenarios were to sub-
The results of the questionnaire are reported in Table 2 and Table 3. All scenarios involved malaria-endemic areas of sub-
Table 1 Participated countries on the malaria survey. Countries
%, (Number)
Austria Belgium Croatia Denmark Finland France Germany Ireland Italy Lithuania Netherlands Norway Portugal Romania Slovak Republic Spain Switzerland Turkey United Kingdom
6.12% (3) 8.16% (4) 4.08% (2) 6.12% (3) 8.16% (4) 12.24% (6) 4.08% (2) 2.04% (1) 6.12% (3) 2.04% (1) 4.08% (2) 2.04% (1) 8.16% (4) 2.04% (1) 2.04% (1) 2.04% (1) 12.24% (6) 2.04% (1) 6.12% (3)
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
3
Table 2 Expert opinion on malaria chemoprophylaxis in special risk groups e survey results. Question on the use of chemoprophylaxis in a particular risk group
n ¼ 100% Atovaquone/ Doxycycline Mefloquine None/No good proguanil alternatives
Q5. Which chemoprophylaxis would you recommend as a first choice for an adult traveller visiting malaria-endemic areas of sub-Saharan Africa for two weeks with no co-morbidities? Q6. Is there an effective alternative chemoprophylaxis for this traveller?
48
91.67%
4.17%
4.17%
e
48
6.25%
41.67%
50.00%
2.08%
68.09%
2.13%
29.79%
e
27.66%
e
63.83%
8.51%
38.30%
e
59.57%
2.13%
Q7: What would you recommend for a healthy 6-year old tourist child visiting malaria- endemic areas 47 of sub-Saharan Africa for two weeks? Q8: Is there an effective alternative chemoprophylaxis for this child? 47 Q9: What would you recommend as chemoprophylaxis for an infant (8 kg) visiting malaria-endemic 47 areas of sub-Saharan Africa for two weeks? Q10: Is there an effective alternative chemoprophylaxis for this infant? 47
25.53%
e
21.28%
53.19%
47
51.06%
6.38%
42.55%
e
47
40.43%
40.43%
19.15%
e
Q13: If this business traveller deployed for 2 months in malaria-endemic areas of sub-Saharan Africa, is 47 accompanied by a 6- year old child? Which chemoprophylaxis would you recommend for the child? Q14: Is there an effective alternative chemoprophylaxis for this child? 47
40.43%
e
59.57%
e
55.32%
e
31.91%
12.77%
29.79%
e
68.09%
2.13%
Q11: Which chemoprophylaxis would you recommend for an adult business traveller with no comorbidities deployed for 2 months in malaria-endemic areas of sub-Saharan Africa? Q12: Is there an effective alternative chemoprophylaxis for this traveller?
Q15: If this business traveller deployed for 2 months in malaria endemic areas of sub-Saharan Africa, is 47 accompanied by an infant (8 kg)? What would you recommend for the infant? Q16: Is there an effective alternative chemoprophylaxis for this infant? 47
31.91%
e
14.89%
53.19%
6.38%
27.66%
63.83%
2.13%
6.38%
53.19%
27.66%
12.77%
14.89%
2.13%
74.47%
8.51%
23.40%
6.38%
10.64%
59.57%
47
25.53%
e
72.34%
2.13%
47
38.30%
2.13%
12.77%
46.81%
45
57.78%
20.00%
15.56%
6.67%
45
11.11%
22.22%
20.00%
46.67%
Q25: What would you recommend for an adult traveller with renal impairment (glomerular filtration 45 rate (GFR) < 30 ml/min) visiting malaria-endemic areas of sub-Saharan Africa? Q26: Is there an effective alternative chemoprophylaxis for this traveller? 45
20.00%
37.78%
42.22%
e
e
37.78%
37.78%
24.44%
Q17: Which chemoprophylaxis would you recommend for a VFR family returning to their country of 47 origin in West Africa for a 2-month trip. All family members are healthy and the budget is limited. Q18: Is there an effective alternative chemoprophylaxis for this group of travellers? 47 Q19: Which chemoprophylaxis would you recommend for a pregnant VFR (1st trimester) visiting her 47 family in rural Nigeria? Q20: Is there an effective alternative chemoprophylaxis for this pregnant traveller? 47 Q21: Which chemoprophylaxis would you recommend for a breast-feeding mother visiting rural Nigeria? The breastfed infant weighs 5 kg. Q22: Is there an effective alternative chemoprophylaxis for this mother? Q23: What would you recommend for an adult traveller with liver cirrhosis due to HCV visiting malaria-endemic areas of sub-Saharan Africa? Q24: Is there an effective alternative chemoprophylaxis for this traveller?
Table 3 Expert opinion on recommendations for personal protection measures against mosquito bites e survey results. Q27: Apart from chemoprophylaxis, do you recommend mosquito bite prevention for travellers to malaria endemic areas of sub-Saharan Africa? If yes, Yes please mark all measures that you routinely recommend? (n ¼ 43 ¼ 100%)
No
DEET/Icaridin/EBAAP containing mosquito repellents Citriodora (paramenthane-3,8-diol) PMD repellents Natural oil repellents Insecticide impregnated clothing Burning coils Knock-down sprays Air-conditioning Mosquito nets Ultrasound devices
e 79.07% 93.02% 18.60% 72.09% 62.79% 16.28% 4.65% 95.35%
Saharan Africa. The experts would recommend, as first choice, malaria chemoprophylaxis atovaquone/proguanil for an adult traveller with no co-morbidities travelling for 2 weeks (91.67% of experts) and for 2 months (51.06%), for a healthy tourist child travelling for two weeks (68.09%) and for an adult traveller with liver cirrhosis (57.78%). Mefloquine was the first choice for a healthy tourist child travelling for 2 months (59.57%), for a tourist infant (8 kg) travelling for 2 weeks (59.57%) and for 2 months (68.09%), for a pregnant VFR (74.47%), for a breast-feeding mother with her 5 kg infant (72.34%) and for a VFR family with limited budget (63.83%). For an adult traveller with renal impairment the experts recommended mefloquine (42.22%) or doxycycline (37.78%). All experts (100%)
100% 20.93% 6.98% 81.40% 27.91% 37.21% 83.72% 95.35% 4.65%
recommended mosquito repellents. Mosquito nets were recommended routinely by 95.35% of the experts, air-conditioning by 83.72% and impregnated clothing by 81.40%. 4.2. National and international recommendations review We searched national and international recommendations for information regarding malaria chemoprophylaxis recommendations for special risk groups. The risk groups were: pregnant woman, breastfeeding mother, young child, infant, severe renal impairment and severe hepatic impairment. We found information in international recommendations of the World Health Organization (WHO) and national recommendations
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
4
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
of Germany (DE), Switzerland (CH) and United Kingdom (UK) and from the Centers for Disease Control and Prevention from the United States of America (U.S. CDC). We also checked the information about the malaria chemoprophylaxis drugs in the electronic Medicines Compendium (eMC). The results (Table 4) show a wide range of recommendations and some contradictory advice in the international recommendations [14e19]. 5. Discussion The European experts differ in pre-travel anti-malarial recommendations for risk groups visiting malaria endemic areas of subSaharan Africa and contraindications are not always observed. The European countries follow the national and/or international recommendations for malaria recommendations. Many countries have a list of malaria chemoprophylaxis recommendations listed by regions. But for risk groups there are no clear uniform recommendation lists. The reviewed recommendations agree in some points but in many areas, there is considerable discord [8]. For example the national recommendations of Germany do not recommend atovaquone/proguanil for children weighing less than 11 kg whereas the UK national recommendations do not recommend atovaquone/ proguanil for infant weighing less than 5 kg. There are also some answers from the experts that are in disccordance with the reviewed national recommendations and that could potentially lead to bad health outcomes. For example: 9 experts would recommend atovaquone/proguanil to a traveller with severe renal impairment although almost in all reviewed national recommendations this use would be contraindicated. In Europe, in 2014, the European Medicines Agency (EMA) issued recommendations on strengthened warnings, prescribing checklists and updates to the product information of mefloquine. A commentary has discussed the implications of these changes and
the possible outcome that mefloquine will be displaced as a firstline anti-malaria medication with the result that vulnerable groups such as VFR and long-term travellers, pregnant travellers and young children may be deprived of an anti-malarial that has been used for these niche groups and for whom no alternative is currently available [7]. Many of the discrepancies occur because drug safety studies are limited for these risk groups. When evidence-based data are unavailable, then health professional's opinion and careful risk assessment enter the recommendations. This discordance in recommendations and lack of chemoprophylaxis options pose challenges for recommendation interpretation in the pre-travel setting. 5.1. Pregnant or breastfeeding women Providing malaria chemoprophylaxis for pregnant women is challenging because drug safety studies are limited due to ethical, legal and safety problems [9,10,20]. In the experts' response, mefloquine is the first choice recommendation for a pregnant women and for a breastfeeding mother (Fig. 1). In the electronic Medicines Compendium recommendations mefloquine is not recommended in first trimester „unless the expected benefit justifies the potential risk to the foetus“. For more information they refer to national and international recommendations [19]. U.S. CDC and Switzerland allow mefloquine for all 3 trimesters, and also the UK permits mefloquine for all 3 trimesters, but advises caution in the first trimester [15,16,18]. Atovaquone/proguanil is not recommended during pregnancy because evidence-based data are limited [21]. Doxycycline is contraindicated in pregnancy [9]. However, the recommendations from the UK allow doxycycline „under special circumstances, if requires before 15 week's gestation, it should not be withheld if other options are unsuitable“ [16]. A retrospective study of pooled data on 542 cases of imported malaria in pregnant women reported in Europe, the US and Japan showed that imported malaria cases in pregnancy are mainly
Table 4 Results of the literature search on national and international recommendations regarding malaria prevention in special risk groups.
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
5
Fig. 2. Recommendation for a baby (8 kg) visiting malaria-endemic areas of SubSaharan Africa for two weeks. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
Fig. 1. Recommendation for a pregnant VFR (1st trimester) visiting her family in rural Nigeria. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
P. falciparum acquired in sub- Saharan Africa and that approximately 18% of cases are complicated and severe [22]. This study also showed that over 85% of pregnant women who imported malaria did not use chemoprophylaxis. Concerning breastfeeding women, mefloquine is compatible while breastfeeding [22]. Atovaquone/ proguanil is generally not recommended for low weight babies and doxycycline is contraindicated while breastfeeding. The weight of the breastfed infant should be considered for the recommendation. 5.2. Young children and infants It is difficult to make evidence-based recommendations about malaria chemoprophylaxis for children and infants because drug safety data for this group are lacking. In expert's opinion atovaquone/proguanil is the first choice recommendation for a short trip of a young child and mefloquine for a longer trip of a young child and for infants. The electronic Medicines Compendium mentions, “Atovaquone/proguanil has not been established for prophylaxis of malaria in patients who weight less than 40 kg“. Because drug safety studies are lacking, atovaquone/proguanil is not recommended for children weighing less than 11 kg (in the United States for children weighing less than 5 kg) [9,15]. In the United States “prophylactic dosing for children weighing less than 11 kg constitutes off-label use“ [15]. The electronic Medicines Compendium mentions that for infants less than 3 months old or weighing less than 5 kg there are limited data for the use of mefloquine. Mefloquine is well tolerated by infants > 5 kg and children with good adherence (Fig. 2) [8,23]. Doxycycline is contraindicated in small children and infant because it may cause discoloured teeth and bone malformation [9]. There is a discrepancy in the national recommendations about the age when doxycycline can be used safely. For example in UK the use of doxycycline is contraindicated under 12 years and in the U.S. under 8 years.
The recommendations are also inconsistent for traveller with hepatic impairment. In Germany and Switzerland all three chemoprophylaxis are contraindicated [17,18]. Electronic Medicines Compendium and UK mention using atovaquone/proguanil can be used for these patients even though data are missing [16,19]. In the UK doxycycline is not recommended [16]. The electronic Medicines Compendium, UK and Germany agree about the contraindication of mefloquine for patients with hepatic impairment [16,17,19]. For the experts in our survey, atovaquone/proguanil is the first choice recommendation for a traveller with hepatic impairment. Even though mefloquine is contraindicated in the national recommendations, almost 14% of the experts would recommend it for traveller with hepatic impairment (Fig. 4). The electronic Medicines Compendium recommends caution in prescribing mefloquine to patients with severe renal impairment because data are limited [19]. All recommendations agree with the contraindication of atovaquone/proguanil for those patients (except UK where it is not recommended). The electronic Medicines Compendium and the UK guidelines state that doxycycline is suitable for these patients [16,19]. In our experts' survey, mefloquine is the first choice recommendation for travellers with severe renal impairment, 21% would recommend atovaquone/proguanil although it is contraindicated in the reviewed recommendations (Fig. 5). 5.4. Short-term traveller All three anti-malarials are indicated as short-term malaria chemoprophylaxis. In Germany, doxycycline use is „off-label“, but since 2003 the DGT recommend it [17]. Atovaquone/proguanil is well tolerated and was mainly prescribed for short-term travel of less than one month [6,8]. Atovaquone/proguanil is registered in some European countries for limited duration only and the cost of the regimen is high. Also drug safety studies and effectiveness for long-term travels are scarce [6,14]. 5.5. Long-term traveller
5.3. Severe hepatic and renal impairment Proguanil is excreted through the kidney suggesting that dosage adjustment is necessary for travellers with renal impairment [17]. Mefloquine and doxycycline are mostly excreted by liver [17]. Malaria chemoprophylaxis regimens have not been tested in travellers with severe hepatic and renal impairment.
Most recommendations define „long term traveller“ as an individual travelling for more than 6 months. All three chemoprophylaxis regimens are allowed. In Germany the use of doxycycline as malaria chemoprophylaxis is „off-label“. Some European countries allow atovaquone/proguanil as chemoprophylaxis with a time restriction of 12 months. Mefloquine is the best-documented drug
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
6
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
for long-term use and it is well tolerated [9,24]. Studies showed that atovaquone/proguanil has also been well tolerated by longterm travellers [25,26].
5.6. VFR family The survey's experts opinion shows that mefloquine and doxycycline are good options for a VFR family with limited budget (Fig. 3). Mefloquine is the cheapest effective chemoprophylaxis and can be prescribed for children and adults. It can also be used for a longer period of travel and for highly endemic malaria risk areas [8,14,27]. Depending on the age of the family members (eg young child, infant), doxycycline is contraindicated. Doxycycline is similar in cost as mefloquine [8]. Atovaquone/proguanil is rarely recommended because of the high cost [6].
Fig. 4. Recommendation for an adult traveller with liver cirrhosis due to HCV visiting malaria-endemic areas of Sub-Saharan Africa. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
5.7. Mosquito bite measures All the European experts agree to routinely recommend personal protection measures against mosquito bites to traveller visiting malaria-endemic areas of sub-Saharan Africa. Most of them would recommend, repellents, mosquito nets, air-conditioning and impregnated clothing. The experts would not recommend ultrasound devices, natural oil repellents, PMD repellents, burning coils and knock-down sprays. Only European experts were asked to take part in this study. A strength of our study is the participation of recognized travel medicine centers and experts. The experts who participated in the survey cumulatively see more than 180000 patients monthly in their clinics or more than 2 million travellers per year. A potential limitation of this study was that the European experts could only choose one out of three malaria chemoprophylaxis whereas, theoretically, other options would have been possible. Another limitation was that the information about the travel scenarios was brief and that is why some scenarios were not clear for all participants. All specific risk groups were travellers visiting malaria-endemic areas of sub-Saharan Africa and we suggest, as an area of further study, that other malaria-endemic areas should be used for a similar survey. We also recommend that national and international recommendations should be adjusted and provide clear and concise advice for malaria chemoprophylaxis for these risk groups.
Fig. 3. Recommendation for a VFR family with limited budget returning to their country of origin in West Africa for a 2-month trip. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
Fig. 5. Recommendation for an adult traveller with renal impairment (GFR < 30 ml/ min) visiting malaria-endemic areas of Sub-Saharan Africa. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
6. Conclusions In summary the European experts would recommend atovaquone/proguanil for an adult traveller with no co-morbidities travelling for 2 weeks or for 2 months, for a healthy tourist child travelling for two weeks and for an adult traveller with liver impairment. Mefloquine would be first choice for a healthy tourist child travelling for 2 months, for a tourist infant (8 kg) travelling for 2 weeks and for 2 months, for a pregnant VFR, for a breast-feeding mother with her 5 kg infant and for a VFR family with limited budget. For an adult traveller with renal impairment the experts recommend mefloquine or doxycycline. The survey shows discrepancies in expert advice for risk groups and highlights the complexity of malaria prophylaxis decisions. We identify areas where more data are needed to facilitate malaria chemoprophylaxis decision making. These are: retrospective database analyses of exposure to anti-malarials by pregnant women in the first trimester. This has been done for mefloquine but could also be done for other anti-malarials. Furthermore, pooled data analyses from large clinics could provide data on the use, pharmacokinetics and tolerability of anti-malarials in individuals with severe renal and hepatic impairment. Pharmacokinetic studies on the use of malaria chemoprophylaxis in young children should be a focus for research. Both experts and general practice travel medicine advisories would
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
be well served by clear, evidence-based, easily accessible, national and international recommendations. Conflict of interest The costs of doing the online survey were covered by a general, student, dissertation fund supported by F. Hoffmann-La Roche. CH was a member the advisory boards of GSK (educational Programme), Janssen and Sigma Tau over the last 2 years. PS has received research funds and consultancy fees from F. Hoffmann-La Roche, research funding and travel expenses from GlaxoSmithKline and is a member of the Sigma Tau and Sixty Degrees advisory boards. References [1] UNWTO Tourism Highlights, 2014. [20.04.2015]. 16]. Available from: http:// media.unwto.org/press-release/2015-01-27/over-11-billion-touriststravelled-abroad-2014. [2] Schlagenhauf P, Weld L, Goorhuis A, Gautret P, Weber R, von Sonnenburg F, et al. Travel-associated infection presenting in Europe (2008-12): an analysis of EuroTravNet longitudinal, surveillance data, and evaluation of the effect of the pre-travel consultation. Lancet Infect Dis 2015;15(1):55e64. [3] Centers for Disease Control and Prevention (CDC): Malaria. Health Information for International Travel Atlanta: Public Health Service; [20.04.2015]. Available from: http://www.cdc.gov/malaria/travelers/drugs.html. [4] Kouyate B, Sie A, Ye M, De Allegri M, Muller O. The great failure of malaria control in Africa: a district perspective from Burkina Faso. PLoS Med 2007;4(6):e127. [5] Moran JS, Bernard KW. The spread of chloroquine-resistant malaria in Africa. Implications for travelers. JAMA 1989;262(2):245e8. [6] Bloechliger M, Schlagenhauf P, Toovey S, Schnetzler G, Tatt I, Tomianovic D, et al. Malaria chemoprophylaxis regimens: a descriptive drug utilization study. Travel Med Infect Dis 2014;12(6 Pt B):718e25. [7] Schlagenhauf P, Hatz C, Behrens R, Visser L, Funk M, Holzer B, et al. Mefloquine at the crossroads? Implications for malaria chemoprophylaxis in Europe. Travel Med Infect Dis 2015;13(2):192e6. [8] Schlagenhauf P, Adamcova M, Regep L, Schaerer MT, Rhein HG. The position of mefloquine as a 21st century malaria chemoprophylaxis. Malar J 2010;9:357. [9] Schlagenhauf P, Petersen E. Malaria chemoprophylaxis: strategies for risk groups. Clin Microbiol Rev 2008;21(3):466e72. [10] Schlagenhauf P, Blumentals W, Suter P, Regep L, Vital-Durand G, Schaerer M, et al. Pregnancy and fetal outcomes after exposure to mefloquine in the preand periconception period and during pregnancy. Clin Infect Dis 2012;54(11): e124e31. [11] Chen LH, Keystone JS. New strategies for the prevention of malaria in travelers. Infect Dis Clin North Am 2005;19(1):185e210.
7
[12] Calleri G, Behrens RH, Schmid ML, Gobbi F, Grobusch MP, Castelli F, et al. Malaria chemoprophylaxis recommendations for immigrants to Europe, visiting relatives and friendsea Delphi method study. Malar J 2011;10:137. [13] Calleri G, Behrens RH, Bisoffi Z, Bjorkman A, Castelli F, Gascon J, et al. Variability in malaria prophylaxis prescribing across Europe: a Delphi method analysis. J Travel Med 2008;15(5):294e301. [14] International travel and health, 2015 updates, malaria: World Health Organization; [cited 2015 30.08.2017]. Available from: http://www.who.int/ith/en. [15] Paul M, Arguin KRT. Chapter 3- Infectious Diseases Related To Travel. Malaria. Centers for Disease Control and Prevention [updated June 12, 201730.18.2017]. Available from: http://wwwnc.cdc.gov/travel/yellowbook/ 2018/infectious-diseases-related-to-travel/malaria. [16] Guidelines for malaria prevention in travellers from the UK 2016, published 29 July 2014 Public Health England: [updated December 201630.08.2017]. Available from: https://www.gov.uk/government/publications/malariaprevention-guidelines-for-travellers-from-the-uk. [17] Empfehlungen zur Malariavorbeugung: Deutsche Gesellschaft für Tropenmedizin und Internationale Gesundheit (DTG); [updated Mai 201730.08.2017]. Available from: https://www.dtg.org/images/ Empfehlungen/DTG_Malaria_2017.pdf. [18] Malariaschutz für Kurzzeitaufenthalter (Reisen bis zu 3 Monaten). Richtlinien und Empfehlungen. Bundesamt für Gesundheit (BAG), Schweizerische Arbeitsgruppe für Reisemedizin (SAR). : Bundesamt für Gesundheit (BAG), Schweizerische Arbeitsgruppe für Reisemedizin (SAR). ; [updated Januar 2016 (ersetzt die Version vom M€ arz 2006)30.08.2017]. Available from: http://www. osir.ch/PDF/malaria_nfm_2016BAG.pdf. [19] electronic Medicines Compendium [30.08.2017]. Available from: http://www. medicines.org.uk/emc/about-the-emc. [20] Gonzalez R, Hellgren U, Greenwood B, Menendez C. Mefloquine safety and tolerability in pregnancy: a systematic literature review. Malar J 2014;13:75. [21] Irvine MH, Einarson A, Bozzo P. Prophylactic use of antimalarials during pregnancy. Can Fam Physician 2011;57(11):1279e81. nez B, et al. Imported [22] Kaeser A, Arguin P, Chiodini P, Smith V, Delmont J, Jime malaria in pregnant women: a retrospective pooled analysis. Travel Med Infect Dis 2015;13:300e10. [23] Luxemburger C, Price RN, Nosten F, Ter Kuile FO, Chongsuphajaisiddhi T, White NJ. Mefloquine in infants and young children. Ann Trop Paediatr 1996;16(4):281e6. [24] Pennie RA, Koren G, Crevoisier C. Steady state pharmacokinetics of mefloquine in long-term travellers. Trans R Soc Trop Med Hyg 1993;87(4):459e62. [25] Overbosch D. Post-marketing surveillance: adverse events during long-term use of atovaquone/proguanil for travelers to malaria-endemic countries. J Travel Med 2003;10(Suppl 1):S16e20. discussion S1e3. [26] van Genderen PJ, Koene HR, Spong K, Overbosch D. The safety and tolerance of atovaquone/proguanil for the long-term prophylaxis of plasmodium falciparum malaria in non-immune travelers and expatriates [corrected]. J Travel Med 2007;14(2):92e5. [27] Widmer LL, Blank PR, Van Herck K, Hatz C, Schlagenhauf P. Cost-effectiveness analysis of malaria chemoprophylaxis for travellers to West-Africa. BMC Infect Dis 2010;10:279.
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
Contents lists available at ScienceDirect
Travel Medicine and Infectious Disease journal homepage: www.elsevierhealth.com/journals/tmid
Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations Mithula Shellvarajah a, Christoph Hatz b, Patricia Schlagenhauf a, * a
University of Zürich Centre for Travel Medicine, WHO Collaborating Centre for Travellers' Health, Institute for Epidemiology, Biostatistics and Prevention, Hirschengraben 84, 8001 Zurich, Switzerland Swiss Tropical & Public Health Institute, University of Basel, Switzerland
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 November 2016 Received in revised form 5 September 2017 Accepted 7 September 2017 Available online xxx
Introduction: Malaria prevention can be complex due to the individual characteristics of the traveller, travel destination, duration of stay and type of travel. Our aim in this study was to document malaria chemoprophylaxis recommendations provided by travel-medicine experts in Europe for specific risk groups of travellers visiting malaria-endemic areas of sub-Saharan Africa. Methods: Travel medicine experts in Europe were asked to complete an online questionnaire, a 28-item Survey Monkey survey, on 11 malaria prevention scenarios. We also reviewed the recommendations of the UK, U.S. CDC, Germany, Switzerland, WHO and the electronic Medicines Compendium (eMC) for malaria prevention in risk groups. Results: The questionnaire was sent to 110 travel medicine experts in 19 countries. The response rate was 44.55%. The experts would recommend, as first choice, malaria chemoprophylaxis atovaquone/proguanil for an adult traveller with no co-morbidities travelling for 2 weeks (91.67% of experts) and for 2 months (51.06%), for a healthy tourist child travelling for two weeks (68.09%) and for an adult traveller with liver cirrhosis (57.78%). Mefloquine was the first choice for a healthy tourist child travelling for 2 months (59.57%), for a tourist infant (8 kg) travelling for 2 weeks (59.57%) and for 2 months (68.09%), for a pregnant VFR (74.47%), for a breast-feeding mother with her 5 kg infant (72.34%) and for a VFR family with limited budget (63.83%). For an adult traveller with renal impairment the experts recommended mefloquine (42.22%) or doxycycline (37.78%). All experts (100%) recommended mosquito repellents. Mosquito nets were recommended routinely by 95.35% of the experts, air-conditioning by 83.72% and impregnated clothing by 81.40%. Conclusion: The European experts differ in pre-travel anti-malarial recommendations for risk groups visiting malaria endemic areas of sub-Saharan Africa. Contraindications are not always observed and there are no uniform recommendations for high-risk groups. 9 experts would recommend atovaquone/ proguanil to a traveller with severe renal impairment although most reviewed national recommendations consider this a contraindication. Discordance in recommendations, a lack of key data and few chemoprophylaxis options limit choices for pre-travel health advisors. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Malaria Chemoprophylaxis Atovaquone/proguanil Doxycycline Mefloquine Risk groups Expert opinion Recommendations
1. Background In 2014, the world tourism organization (WTO) reported 1138 millions arrivals worldwide and the forecast for 2030 is 1.8 billion international tourists. Travel to Africa grew by 2% in 2014 and to
* Corresponding author. E-mail address: [email protected] (P. Schlagenhauf).
sub-Saharan Africa by 3% [1]. An earlier study noted a statistically significant increase in travel-related diseases acquired in sub-Saharan Africa by ill travellers presenting in Europe. Malaria was one of the top diagnoses, mainly acquired in sub-Saharan Africa by men (68%) and by those whose purpose of travel was “visiting friends and relatives” (VFR) (52%) [2]. The findings of the study showed that, for all traveller groups (including the risk groups and VFRs), pre-travel consultation
http://dx.doi.org/10.1016/j.tmaid.2017.09.002 1477-8939/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
2
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
significantly lowers the proportionate morbidity ratios for Plasmodium falciparum malaria [2]. These results demonstrate the importance and effectiveness of pre-travel prevention strategies [2]. Travellers to high risk malaria-endemic areas should receive anti-malarial advice: a combination of mosquito avoidance measures and chemoprophylaxis [3]. Since 1980, the spread of chloroquine resistant Plasmodium falciparum malaria has extended through sub-Saharan Africa [4,5]. Currently recognized priority chemoprophylaxis recommendations for travellers to sub-Saharan Africa are atovaquone/proguanil, doxycycline and, as second choice in some countries, mefloquine [6e8]. Malaria prevention can be complex due to the individual characteristics of the traveller, travel destination, duration of the stay and type of travel [9]. The complexity of providing advice is increased in groups such as immunosuppressed travellers, young children, pregnant women and long-term travellers [9,10]. The risk is also higher in previously semi-immune people who have moved to countries without highly endemic malaria as the immunity wanes. Those visiting friends and relatives in their home countries (VFR) are less likely to receive pre-travel advice [11]. Because drug safety studies and efficiency strategies are lacking for all risk groups, recommendations can be complex [11]. European experts generally follow the national and/or international recommendations for malaria chemoprophylaxis. A previously published Delphi method study regarding malaria chemoprophylaxis recommendations showed that the experts varied widely among the preferred chemoprophylaxis recommendations. The choices were affected by „a high degree of subjectivity and national policy differences“ [12,13]. 2. Objective Our aim in this study was to document malaria chemoprophylaxis recommendations provided by travel-medicine experts in Europe for specific risk groups of travellers visiting malariaendemic areas of sub-Saharan Africa and to document whether routine protective measures are recommended. We also aimed to review national and international recommendations with regard to malaria prevention recommendations for certain risk groups.
Saharan Africa. The experts were asked whether they would prescribe malaria chemoprophylaxis to each risk group or not. If so, they could order by choice (1st preference, alternative choice) one out of three malaria chemoprophylaxis: atovaquone/proguanil, doxycycline or mefloquine. The goal was to have two answers regarding each risk group of traveller: i.e. expert opinion on the first and the second choice of chemoprophylaxis. Concerning the questions about mosquito bite measures the experts had to answer “yes” if they recommend the measure routinely for travellers visiting malaria-endemic areas of subSaharan Africa, or “no” if not. The questionnaire responses were collected and analysed by Survey monkey. We compared the national recommendations of United Kingdom (UK), Germany (DE), Switzerland (CH) and from the Centers for Disease Control and Prevention from the Unites States of America (U.S. CDC), and the international recommendations of the World Health Organization (WHO) for the special risk groups. The medication specifications and recommendations on contraindications and precautions of the European electronic Medicines Compendium (eMC) were considered for the background to the discussion and recommendations. The electronic Medicines Compendium (eMC) lists information about all medicines, which are approved either by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and/or European Medicines Agency (EMA). It is provided from the medicine regulatory agencies. It serves as an important source of product information. 4. Results The questionnaire was sent to 110 pre-travel medicine experts. A total of 49 experts participated on this study; the response rate was 44.55%. 87.75% of them (n ¼ 43) completed the whole questionnaire. The experts participated from 19 different countries (see Table 1). 61.22% of the participants were older than 50 years (n ¼ 30) and 63.27% were male (n ¼ 31). In 48.98% of the experts' clinics, more than 200 pre-travel consultations are done per month.
3. Methods
4.1. Malaria chemoprophylaxis recommendations
This study was done between October and December 2014. Leading travel medicine experts in Europe were asked to complete an online questionnaire on malaria prevention. These European experts were identified using the International Society of Travel Medicine (ISTM-) Clinic directory and also by asking colleagues from EuroTravNet (http://www.istm.org/eurotravnet) and TropNet (http://www.tropnet.net) to participate. A 28-item questionnaire in English by Survey Monkey with 27 multiple-choice questions and one open question was specifically created for this study. The first 4 questions characterised the experts: practising country, sex, age and number of monthly pretravel-consultations undertaken. The country list included all European Union (EU-) and European Free Trade Association (EFTA) countries. The next 23 questions were about malaria prophylaxis recommendations. In the questions regarding malaria chemoprophylaxis we built risk groups of travellers. There were 11 travel scenarios. Our defined risk groups were: short term traveller (2 weeks), long term traveller (2 months), pregnant women in first trimester, breast-feeding mother, 6-years old tourist child, tourist infant (8 kg), VFR family with limited budget, traveller with liver cirrhosis due to hepatitis C virus (HCV) and traveller with renal impairment (glomerular filtration rate (GFR) < 30 ml/min). All travel scenarios were to sub-
The results of the questionnaire are reported in Table 2 and Table 3. All scenarios involved malaria-endemic areas of sub-
Table 1 Participated countries on the malaria survey. Countries
%, (Number)
Austria Belgium Croatia Denmark Finland France Germany Ireland Italy Lithuania Netherlands Norway Portugal Romania Slovak Republic Spain Switzerland Turkey United Kingdom
6.12% (3) 8.16% (4) 4.08% (2) 6.12% (3) 8.16% (4) 12.24% (6) 4.08% (2) 2.04% (1) 6.12% (3) 2.04% (1) 4.08% (2) 2.04% (1) 8.16% (4) 2.04% (1) 2.04% (1) 2.04% (1) 12.24% (6) 2.04% (1) 6.12% (3)
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
3
Table 2 Expert opinion on malaria chemoprophylaxis in special risk groups e survey results. Question on the use of chemoprophylaxis in a particular risk group
n ¼ 100% Atovaquone/ Doxycycline Mefloquine None/No good proguanil alternatives
Q5. Which chemoprophylaxis would you recommend as a first choice for an adult traveller visiting malaria-endemic areas of sub-Saharan Africa for two weeks with no co-morbidities? Q6. Is there an effective alternative chemoprophylaxis for this traveller?
48
91.67%
4.17%
4.17%
e
48
6.25%
41.67%
50.00%
2.08%
68.09%
2.13%
29.79%
e
27.66%
e
63.83%
8.51%
38.30%
e
59.57%
2.13%
Q7: What would you recommend for a healthy 6-year old tourist child visiting malaria- endemic areas 47 of sub-Saharan Africa for two weeks? Q8: Is there an effective alternative chemoprophylaxis for this child? 47 Q9: What would you recommend as chemoprophylaxis for an infant (8 kg) visiting malaria-endemic 47 areas of sub-Saharan Africa for two weeks? Q10: Is there an effective alternative chemoprophylaxis for this infant? 47
25.53%
e
21.28%
53.19%
47
51.06%
6.38%
42.55%
e
47
40.43%
40.43%
19.15%
e
Q13: If this business traveller deployed for 2 months in malaria-endemic areas of sub-Saharan Africa, is 47 accompanied by a 6- year old child? Which chemoprophylaxis would you recommend for the child? Q14: Is there an effective alternative chemoprophylaxis for this child? 47
40.43%
e
59.57%
e
55.32%
e
31.91%
12.77%
29.79%
e
68.09%
2.13%
Q11: Which chemoprophylaxis would you recommend for an adult business traveller with no comorbidities deployed for 2 months in malaria-endemic areas of sub-Saharan Africa? Q12: Is there an effective alternative chemoprophylaxis for this traveller?
Q15: If this business traveller deployed for 2 months in malaria endemic areas of sub-Saharan Africa, is 47 accompanied by an infant (8 kg)? What would you recommend for the infant? Q16: Is there an effective alternative chemoprophylaxis for this infant? 47
31.91%
e
14.89%
53.19%
6.38%
27.66%
63.83%
2.13%
6.38%
53.19%
27.66%
12.77%
14.89%
2.13%
74.47%
8.51%
23.40%
6.38%
10.64%
59.57%
47
25.53%
e
72.34%
2.13%
47
38.30%
2.13%
12.77%
46.81%
45
57.78%
20.00%
15.56%
6.67%
45
11.11%
22.22%
20.00%
46.67%
Q25: What would you recommend for an adult traveller with renal impairment (glomerular filtration 45 rate (GFR) < 30 ml/min) visiting malaria-endemic areas of sub-Saharan Africa? Q26: Is there an effective alternative chemoprophylaxis for this traveller? 45
20.00%
37.78%
42.22%
e
e
37.78%
37.78%
24.44%
Q17: Which chemoprophylaxis would you recommend for a VFR family returning to their country of 47 origin in West Africa for a 2-month trip. All family members are healthy and the budget is limited. Q18: Is there an effective alternative chemoprophylaxis for this group of travellers? 47 Q19: Which chemoprophylaxis would you recommend for a pregnant VFR (1st trimester) visiting her 47 family in rural Nigeria? Q20: Is there an effective alternative chemoprophylaxis for this pregnant traveller? 47 Q21: Which chemoprophylaxis would you recommend for a breast-feeding mother visiting rural Nigeria? The breastfed infant weighs 5 kg. Q22: Is there an effective alternative chemoprophylaxis for this mother? Q23: What would you recommend for an adult traveller with liver cirrhosis due to HCV visiting malaria-endemic areas of sub-Saharan Africa? Q24: Is there an effective alternative chemoprophylaxis for this traveller?
Table 3 Expert opinion on recommendations for personal protection measures against mosquito bites e survey results. Q27: Apart from chemoprophylaxis, do you recommend mosquito bite prevention for travellers to malaria endemic areas of sub-Saharan Africa? If yes, Yes please mark all measures that you routinely recommend? (n ¼ 43 ¼ 100%)
No
DEET/Icaridin/EBAAP containing mosquito repellents Citriodora (paramenthane-3,8-diol) PMD repellents Natural oil repellents Insecticide impregnated clothing Burning coils Knock-down sprays Air-conditioning Mosquito nets Ultrasound devices
e 79.07% 93.02% 18.60% 72.09% 62.79% 16.28% 4.65% 95.35%
Saharan Africa. The experts would recommend, as first choice, malaria chemoprophylaxis atovaquone/proguanil for an adult traveller with no co-morbidities travelling for 2 weeks (91.67% of experts) and for 2 months (51.06%), for a healthy tourist child travelling for two weeks (68.09%) and for an adult traveller with liver cirrhosis (57.78%). Mefloquine was the first choice for a healthy tourist child travelling for 2 months (59.57%), for a tourist infant (8 kg) travelling for 2 weeks (59.57%) and for 2 months (68.09%), for a pregnant VFR (74.47%), for a breast-feeding mother with her 5 kg infant (72.34%) and for a VFR family with limited budget (63.83%). For an adult traveller with renal impairment the experts recommended mefloquine (42.22%) or doxycycline (37.78%). All experts (100%)
100% 20.93% 6.98% 81.40% 27.91% 37.21% 83.72% 95.35% 4.65%
recommended mosquito repellents. Mosquito nets were recommended routinely by 95.35% of the experts, air-conditioning by 83.72% and impregnated clothing by 81.40%. 4.2. National and international recommendations review We searched national and international recommendations for information regarding malaria chemoprophylaxis recommendations for special risk groups. The risk groups were: pregnant woman, breastfeeding mother, young child, infant, severe renal impairment and severe hepatic impairment. We found information in international recommendations of the World Health Organization (WHO) and national recommendations
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
4
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
of Germany (DE), Switzerland (CH) and United Kingdom (UK) and from the Centers for Disease Control and Prevention from the United States of America (U.S. CDC). We also checked the information about the malaria chemoprophylaxis drugs in the electronic Medicines Compendium (eMC). The results (Table 4) show a wide range of recommendations and some contradictory advice in the international recommendations [14e19]. 5. Discussion The European experts differ in pre-travel anti-malarial recommendations for risk groups visiting malaria endemic areas of subSaharan Africa and contraindications are not always observed. The European countries follow the national and/or international recommendations for malaria recommendations. Many countries have a list of malaria chemoprophylaxis recommendations listed by regions. But for risk groups there are no clear uniform recommendation lists. The reviewed recommendations agree in some points but in many areas, there is considerable discord [8]. For example the national recommendations of Germany do not recommend atovaquone/proguanil for children weighing less than 11 kg whereas the UK national recommendations do not recommend atovaquone/ proguanil for infant weighing less than 5 kg. There are also some answers from the experts that are in disccordance with the reviewed national recommendations and that could potentially lead to bad health outcomes. For example: 9 experts would recommend atovaquone/proguanil to a traveller with severe renal impairment although almost in all reviewed national recommendations this use would be contraindicated. In Europe, in 2014, the European Medicines Agency (EMA) issued recommendations on strengthened warnings, prescribing checklists and updates to the product information of mefloquine. A commentary has discussed the implications of these changes and
the possible outcome that mefloquine will be displaced as a firstline anti-malaria medication with the result that vulnerable groups such as VFR and long-term travellers, pregnant travellers and young children may be deprived of an anti-malarial that has been used for these niche groups and for whom no alternative is currently available [7]. Many of the discrepancies occur because drug safety studies are limited for these risk groups. When evidence-based data are unavailable, then health professional's opinion and careful risk assessment enter the recommendations. This discordance in recommendations and lack of chemoprophylaxis options pose challenges for recommendation interpretation in the pre-travel setting. 5.1. Pregnant or breastfeeding women Providing malaria chemoprophylaxis for pregnant women is challenging because drug safety studies are limited due to ethical, legal and safety problems [9,10,20]. In the experts' response, mefloquine is the first choice recommendation for a pregnant women and for a breastfeeding mother (Fig. 1). In the electronic Medicines Compendium recommendations mefloquine is not recommended in first trimester „unless the expected benefit justifies the potential risk to the foetus“. For more information they refer to national and international recommendations [19]. U.S. CDC and Switzerland allow mefloquine for all 3 trimesters, and also the UK permits mefloquine for all 3 trimesters, but advises caution in the first trimester [15,16,18]. Atovaquone/proguanil is not recommended during pregnancy because evidence-based data are limited [21]. Doxycycline is contraindicated in pregnancy [9]. However, the recommendations from the UK allow doxycycline „under special circumstances, if requires before 15 week's gestation, it should not be withheld if other options are unsuitable“ [16]. A retrospective study of pooled data on 542 cases of imported malaria in pregnant women reported in Europe, the US and Japan showed that imported malaria cases in pregnancy are mainly
Table 4 Results of the literature search on national and international recommendations regarding malaria prevention in special risk groups.
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
5
Fig. 2. Recommendation for a baby (8 kg) visiting malaria-endemic areas of SubSaharan Africa for two weeks. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
Fig. 1. Recommendation for a pregnant VFR (1st trimester) visiting her family in rural Nigeria. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
P. falciparum acquired in sub- Saharan Africa and that approximately 18% of cases are complicated and severe [22]. This study also showed that over 85% of pregnant women who imported malaria did not use chemoprophylaxis. Concerning breastfeeding women, mefloquine is compatible while breastfeeding [22]. Atovaquone/ proguanil is generally not recommended for low weight babies and doxycycline is contraindicated while breastfeeding. The weight of the breastfed infant should be considered for the recommendation. 5.2. Young children and infants It is difficult to make evidence-based recommendations about malaria chemoprophylaxis for children and infants because drug safety data for this group are lacking. In expert's opinion atovaquone/proguanil is the first choice recommendation for a short trip of a young child and mefloquine for a longer trip of a young child and for infants. The electronic Medicines Compendium mentions, “Atovaquone/proguanil has not been established for prophylaxis of malaria in patients who weight less than 40 kg“. Because drug safety studies are lacking, atovaquone/proguanil is not recommended for children weighing less than 11 kg (in the United States for children weighing less than 5 kg) [9,15]. In the United States “prophylactic dosing for children weighing less than 11 kg constitutes off-label use“ [15]. The electronic Medicines Compendium mentions that for infants less than 3 months old or weighing less than 5 kg there are limited data for the use of mefloquine. Mefloquine is well tolerated by infants > 5 kg and children with good adherence (Fig. 2) [8,23]. Doxycycline is contraindicated in small children and infant because it may cause discoloured teeth and bone malformation [9]. There is a discrepancy in the national recommendations about the age when doxycycline can be used safely. For example in UK the use of doxycycline is contraindicated under 12 years and in the U.S. under 8 years.
The recommendations are also inconsistent for traveller with hepatic impairment. In Germany and Switzerland all three chemoprophylaxis are contraindicated [17,18]. Electronic Medicines Compendium and UK mention using atovaquone/proguanil can be used for these patients even though data are missing [16,19]. In the UK doxycycline is not recommended [16]. The electronic Medicines Compendium, UK and Germany agree about the contraindication of mefloquine for patients with hepatic impairment [16,17,19]. For the experts in our survey, atovaquone/proguanil is the first choice recommendation for a traveller with hepatic impairment. Even though mefloquine is contraindicated in the national recommendations, almost 14% of the experts would recommend it for traveller with hepatic impairment (Fig. 4). The electronic Medicines Compendium recommends caution in prescribing mefloquine to patients with severe renal impairment because data are limited [19]. All recommendations agree with the contraindication of atovaquone/proguanil for those patients (except UK where it is not recommended). The electronic Medicines Compendium and the UK guidelines state that doxycycline is suitable for these patients [16,19]. In our experts' survey, mefloquine is the first choice recommendation for travellers with severe renal impairment, 21% would recommend atovaquone/proguanil although it is contraindicated in the reviewed recommendations (Fig. 5). 5.4. Short-term traveller All three anti-malarials are indicated as short-term malaria chemoprophylaxis. In Germany, doxycycline use is „off-label“, but since 2003 the DGT recommend it [17]. Atovaquone/proguanil is well tolerated and was mainly prescribed for short-term travel of less than one month [6,8]. Atovaquone/proguanil is registered in some European countries for limited duration only and the cost of the regimen is high. Also drug safety studies and effectiveness for long-term travels are scarce [6,14]. 5.5. Long-term traveller
5.3. Severe hepatic and renal impairment Proguanil is excreted through the kidney suggesting that dosage adjustment is necessary for travellers with renal impairment [17]. Mefloquine and doxycycline are mostly excreted by liver [17]. Malaria chemoprophylaxis regimens have not been tested in travellers with severe hepatic and renal impairment.
Most recommendations define „long term traveller“ as an individual travelling for more than 6 months. All three chemoprophylaxis regimens are allowed. In Germany the use of doxycycline as malaria chemoprophylaxis is „off-label“. Some European countries allow atovaquone/proguanil as chemoprophylaxis with a time restriction of 12 months. Mefloquine is the best-documented drug
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
6
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
for long-term use and it is well tolerated [9,24]. Studies showed that atovaquone/proguanil has also been well tolerated by longterm travellers [25,26].
5.6. VFR family The survey's experts opinion shows that mefloquine and doxycycline are good options for a VFR family with limited budget (Fig. 3). Mefloquine is the cheapest effective chemoprophylaxis and can be prescribed for children and adults. It can also be used for a longer period of travel and for highly endemic malaria risk areas [8,14,27]. Depending on the age of the family members (eg young child, infant), doxycycline is contraindicated. Doxycycline is similar in cost as mefloquine [8]. Atovaquone/proguanil is rarely recommended because of the high cost [6].
Fig. 4. Recommendation for an adult traveller with liver cirrhosis due to HCV visiting malaria-endemic areas of Sub-Saharan Africa. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
5.7. Mosquito bite measures All the European experts agree to routinely recommend personal protection measures against mosquito bites to traveller visiting malaria-endemic areas of sub-Saharan Africa. Most of them would recommend, repellents, mosquito nets, air-conditioning and impregnated clothing. The experts would not recommend ultrasound devices, natural oil repellents, PMD repellents, burning coils and knock-down sprays. Only European experts were asked to take part in this study. A strength of our study is the participation of recognized travel medicine centers and experts. The experts who participated in the survey cumulatively see more than 180000 patients monthly in their clinics or more than 2 million travellers per year. A potential limitation of this study was that the European experts could only choose one out of three malaria chemoprophylaxis whereas, theoretically, other options would have been possible. Another limitation was that the information about the travel scenarios was brief and that is why some scenarios were not clear for all participants. All specific risk groups were travellers visiting malaria-endemic areas of sub-Saharan Africa and we suggest, as an area of further study, that other malaria-endemic areas should be used for a similar survey. We also recommend that national and international recommendations should be adjusted and provide clear and concise advice for malaria chemoprophylaxis for these risk groups.
Fig. 3. Recommendation for a VFR family with limited budget returning to their country of origin in West Africa for a 2-month trip. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
Fig. 5. Recommendation for an adult traveller with renal impairment (GFR < 30 ml/ min) visiting malaria-endemic areas of Sub-Saharan Africa. P ¼ Atovaquone/proguanil; D ¼ Doxycycline; M ¼ Mefloquine; None.
6. Conclusions In summary the European experts would recommend atovaquone/proguanil for an adult traveller with no co-morbidities travelling for 2 weeks or for 2 months, for a healthy tourist child travelling for two weeks and for an adult traveller with liver impairment. Mefloquine would be first choice for a healthy tourist child travelling for 2 months, for a tourist infant (8 kg) travelling for 2 weeks and for 2 months, for a pregnant VFR, for a breast-feeding mother with her 5 kg infant and for a VFR family with limited budget. For an adult traveller with renal impairment the experts recommend mefloquine or doxycycline. The survey shows discrepancies in expert advice for risk groups and highlights the complexity of malaria prophylaxis decisions. We identify areas where more data are needed to facilitate malaria chemoprophylaxis decision making. These are: retrospective database analyses of exposure to anti-malarials by pregnant women in the first trimester. This has been done for mefloquine but could also be done for other anti-malarials. Furthermore, pooled data analyses from large clinics could provide data on the use, pharmacokinetics and tolerability of anti-malarials in individuals with severe renal and hepatic impairment. Pharmacokinetic studies on the use of malaria chemoprophylaxis in young children should be a focus for research. Both experts and general practice travel medicine advisories would
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002
M. Shellvarajah et al. / Travel Medicine and Infectious Disease xxx (2017) 1e7
be well served by clear, evidence-based, easily accessible, national and international recommendations. Conflict of interest The costs of doing the online survey were covered by a general, student, dissertation fund supported by F. Hoffmann-La Roche. CH was a member the advisory boards of GSK (educational Programme), Janssen and Sigma Tau over the last 2 years. PS has received research funds and consultancy fees from F. Hoffmann-La Roche, research funding and travel expenses from GlaxoSmithKline and is a member of the Sigma Tau and Sixty Degrees advisory boards. References [1] UNWTO Tourism Highlights, 2014. [20.04.2015]. 16]. Available from: http:// media.unwto.org/press-release/2015-01-27/over-11-billion-touriststravelled-abroad-2014. [2] Schlagenhauf P, Weld L, Goorhuis A, Gautret P, Weber R, von Sonnenburg F, et al. Travel-associated infection presenting in Europe (2008-12): an analysis of EuroTravNet longitudinal, surveillance data, and evaluation of the effect of the pre-travel consultation. Lancet Infect Dis 2015;15(1):55e64. [3] Centers for Disease Control and Prevention (CDC): Malaria. Health Information for International Travel Atlanta: Public Health Service; [20.04.2015]. Available from: http://www.cdc.gov/malaria/travelers/drugs.html. [4] Kouyate B, Sie A, Ye M, De Allegri M, Muller O. The great failure of malaria control in Africa: a district perspective from Burkina Faso. PLoS Med 2007;4(6):e127. [5] Moran JS, Bernard KW. The spread of chloroquine-resistant malaria in Africa. Implications for travelers. JAMA 1989;262(2):245e8. [6] Bloechliger M, Schlagenhauf P, Toovey S, Schnetzler G, Tatt I, Tomianovic D, et al. Malaria chemoprophylaxis regimens: a descriptive drug utilization study. Travel Med Infect Dis 2014;12(6 Pt B):718e25. [7] Schlagenhauf P, Hatz C, Behrens R, Visser L, Funk M, Holzer B, et al. Mefloquine at the crossroads? Implications for malaria chemoprophylaxis in Europe. Travel Med Infect Dis 2015;13(2):192e6. [8] Schlagenhauf P, Adamcova M, Regep L, Schaerer MT, Rhein HG. The position of mefloquine as a 21st century malaria chemoprophylaxis. Malar J 2010;9:357. [9] Schlagenhauf P, Petersen E. Malaria chemoprophylaxis: strategies for risk groups. Clin Microbiol Rev 2008;21(3):466e72. [10] Schlagenhauf P, Blumentals W, Suter P, Regep L, Vital-Durand G, Schaerer M, et al. Pregnancy and fetal outcomes after exposure to mefloquine in the preand periconception period and during pregnancy. Clin Infect Dis 2012;54(11): e124e31. [11] Chen LH, Keystone JS. New strategies for the prevention of malaria in travelers. Infect Dis Clin North Am 2005;19(1):185e210.
7
[12] Calleri G, Behrens RH, Schmid ML, Gobbi F, Grobusch MP, Castelli F, et al. Malaria chemoprophylaxis recommendations for immigrants to Europe, visiting relatives and friendsea Delphi method study. Malar J 2011;10:137. [13] Calleri G, Behrens RH, Bisoffi Z, Bjorkman A, Castelli F, Gascon J, et al. Variability in malaria prophylaxis prescribing across Europe: a Delphi method analysis. J Travel Med 2008;15(5):294e301. [14] International travel and health, 2015 updates, malaria: World Health Organization; [cited 2015 30.08.2017]. Available from: http://www.who.int/ith/en. [15] Paul M, Arguin KRT. Chapter 3- Infectious Diseases Related To Travel. Malaria. Centers for Disease Control and Prevention [updated June 12, 201730.18.2017]. Available from: http://wwwnc.cdc.gov/travel/yellowbook/ 2018/infectious-diseases-related-to-travel/malaria. [16] Guidelines for malaria prevention in travellers from the UK 2016, published 29 July 2014 Public Health England: [updated December 201630.08.2017]. Available from: https://www.gov.uk/government/publications/malariaprevention-guidelines-for-travellers-from-the-uk. [17] Empfehlungen zur Malariavorbeugung: Deutsche Gesellschaft für Tropenmedizin und Internationale Gesundheit (DTG); [updated Mai 201730.08.2017]. Available from: https://www.dtg.org/images/ Empfehlungen/DTG_Malaria_2017.pdf. [18] Malariaschutz für Kurzzeitaufenthalter (Reisen bis zu 3 Monaten). Richtlinien und Empfehlungen. Bundesamt für Gesundheit (BAG), Schweizerische Arbeitsgruppe für Reisemedizin (SAR). : Bundesamt für Gesundheit (BAG), Schweizerische Arbeitsgruppe für Reisemedizin (SAR). ; [updated Januar 2016 (ersetzt die Version vom M€ arz 2006)30.08.2017]. Available from: http://www. osir.ch/PDF/malaria_nfm_2016BAG.pdf. [19] electronic Medicines Compendium [30.08.2017]. Available from: http://www. medicines.org.uk/emc/about-the-emc. [20] Gonzalez R, Hellgren U, Greenwood B, Menendez C. Mefloquine safety and tolerability in pregnancy: a systematic literature review. Malar J 2014;13:75. [21] Irvine MH, Einarson A, Bozzo P. Prophylactic use of antimalarials during pregnancy. Can Fam Physician 2011;57(11):1279e81. nez B, et al. Imported [22] Kaeser A, Arguin P, Chiodini P, Smith V, Delmont J, Jime malaria in pregnant women: a retrospective pooled analysis. Travel Med Infect Dis 2015;13:300e10. [23] Luxemburger C, Price RN, Nosten F, Ter Kuile FO, Chongsuphajaisiddhi T, White NJ. Mefloquine in infants and young children. Ann Trop Paediatr 1996;16(4):281e6. [24] Pennie RA, Koren G, Crevoisier C. Steady state pharmacokinetics of mefloquine in long-term travellers. Trans R Soc Trop Med Hyg 1993;87(4):459e62. [25] Overbosch D. Post-marketing surveillance: adverse events during long-term use of atovaquone/proguanil for travelers to malaria-endemic countries. J Travel Med 2003;10(Suppl 1):S16e20. discussion S1e3. [26] van Genderen PJ, Koene HR, Spong K, Overbosch D. The safety and tolerance of atovaquone/proguanil for the long-term prophylaxis of plasmodium falciparum malaria in non-immune travelers and expatriates [corrected]. J Travel Med 2007;14(2):92e5. [27] Widmer LL, Blank PR, Van Herck K, Hatz C, Schlagenhauf P. Cost-effectiveness analysis of malaria chemoprophylaxis for travellers to West-Africa. BMC Infect Dis 2010;10:279.
Please cite this article in press as: Shellvarajah M, et al., Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: A survey of European expert opinion and international recommendations, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/ 10.1016/j.tmaid.2017.09.002