Response to fever and utilization of standby emergency treatment (SBET) for malaria in travellers to Southeast Asia: a questionnaire-based cohort study

National recommendations for malaria prophylaxis for travellers to low- or intermediate-risk areas vary. Depending on seasonality, mode of travel, length of stay, travellers are advised to perform mosquito protection and chemoprophylaxis or carry standby emergency treatment (SBET). SBET is a concept according to which travellers carry anti-malarials (e.g., atovaquone/proguanil or artemether/lumefantrine), which have to be self-administered in case of fever and the inability to rule out malaria as the cause of fever within 24 h. The rationale behind the strategy of SBET is that the potential occurrence of side effects during continuous chemoprophylaxis might outweigh the relatively small risk of developing malaria in areas of low malaria transmission. The continuous decrease in malaria incidence in many low-transmission areas, e.g., in South- and Southeast Asia (SEA), as well as increasing drug resistance have also served as arguments in favour of SBET. The Societies for Tropical Medicine of Germany and Switzerland, for example, promote SBET for all areas of low and medium malaria transmission along with protection against mosquito bites instead of chemoprophylaxis [1]. The World Health Organization (WHO) recommends this approach to travellers “in some occupational groups who make frequent short stops in countries or areas with malaria risk over a prolonged period of time” and short-term travellers to “remote rural areas where there is very low risk of infection” [2]. The Centers for Disease Control and Prevention (CDC) in the USA, in contrast, recommend to carry SBET to ensure high-quality treatment in case of a diagnosis of malaria, accounting for the increasing numbers of fake anti-malarials in some countries of SEA [3].

While the concept of SBET appears straightforward in theory, it is unclear whether or not travellers are willing or able to apply SBET correctly while being abroad. In fact, there has been repeated criticism that travellers may be unable to make correct decisions in case of onset of fever during travel and tend to apply medication incorrectly [4, 5]. To date only two publications from 1995 are available concerning these issues. Both studies demonstrated that only a small fraction of travellers had to self-administer SBET. Additionally, when Plasmodium falciparum antibody levels were assessed in all travellers after return it turned out that even this low number of self-administrations proved to be a massive overuse of SBET, since most SBET users had no antibodies [4, 6].

Moreover, the SBET concept is based on the assumption that reliable medical care is generally not available at malaria-endemic tourist destinations. Yet, infrastructure for tourism, as well as medical emergency care has improved significantly in the past decades in many countries of SEA. At the same time, numbers of travellers to those regions have increased substantially due to a major surge in the availability of flight connections as well as a dramatic decrease in airline fares [7]. Concurrently to increased travel, malaria transmission in most parts of SEA has decreased, resulting in smaller numbers of imported malaria from the region [8, 9]. India also recorded a decline in malaria cases, but predominantly through control of falciparum malaria. In contrast, the relative proportion of Plasmodium vivax cases was increasing on the Indian sub-continent [10].

The aim of the present study was to assess utilization of SBET in the face of changing background conditions. Therefore, a cohort study in a population travelling to areas of low and medium malaria transmission in South Asia and SEA was performed.

A substantial proportion of 18% of travellers to regions of South Asia and SEA with medium and low risk for malaria transmission reported febrile illness during travel. Only very few travellers adhered to the pre-travel advice to seek medical support within 24 h in case of fever. Only 2 out of 714 travellers self-administered SBET during travel, but both of them applied an incorrect regimen and took a single tablet only, which would not have any therapeutic effect in case of true malaria. The study team is not aware of any case of malaria in the study population.

In assessing the concept of SBET, three main problems were identified in travellers with fever during travel: (i) a major proportion of travellers did not carry SBET although it was prescribed; (ii) non-adherence to pre-travel advice while being abroad; and, (iii) incorrect self-administration of SBET.

Travellers recruited for this study were young with a median age of 32 years, healthy, disproportionally well educated and the majority was proficient with travelling to (sub-) tropical countries. In this respect characteristics of this population are comparable to those from other studies and it seems justifiable to assume, that the current results can be generalized to other traveller populations attending pre-travel clinics [11, 12].

Despite the changed landscape of malaria since 1995 when the last data on SBET utilization was published, the findings are in line with the prior studies. In a Swiss study from 1995, only six (0.5%) out of 123 febrile travellers applied SBET and only four of them applied the correct regimen [4]. In a German multi-centre study, 1.4% (40/2867) of travellers reported SBET use. Malaria antibody levels were later demonstrated in four participants who applied SBET [6]. Increasing evidence therefore indicates that only a small proportion of travellers to low risk malaria areas adheres to pre-travel advice based on the SBET concept.

The low acceptance and carriage rate of SBET in this study population is however surprising. Only 16% of travellers carrying SBET took any correct measure and 20% of travellers not carrying SBET sought medical assistance after the onset of fever which is a strikingly low figure regarding the standardized pre-travel advice and the educational level of the study population. Explanations for this result may be various: available data suggest that the recall rate of information after medical consultations showed overall good results suggesting that key messages seem to be well captured [13‐15]. Since most consultations incorporate one or more vaccinations, injection anxiety, which has been shown quite common in some populations could be a potential distractor [16, 17]. However, the only available study in this context showed no association between recall of information and injection anxiety [18]. In any case, provision of simplified key messages after vaccination may facilitate better recognition of information. In general, studies assessing a traveller’s knowledge about travel-related health issues underlined a general increase of knowledge after pre-travel advice, so that other factors are likely to have contributed to non-adherence to emergency measures in case of fever in the current study [19‐21]. In particular, in areas where population density and accessibility to medical facilities is good, tourists might tend to delay the decision to consult a doctor in favour of waiting for spontaneous recovery. Carriage of SBET could further encourage travellers to defer a medical consultation thereby waiting for the fever to drop. Challenges in adherence are not limited to the concept of SBET but are also seen for continuous malaria chemoprophylaxis for travellers to high-risk countries [22‐26]. Several studies prove that the majority of returning travellers with malaria did not take malaria chemoprophylaxis or applied an incorrect regimen, the majority being travellers visiting friends or relatives (VFR) abroad [22, 27‐31].

In consequence of an expanding tourism industry, travel to SEA is steadily increasing. For 2014, international tourist arrivals in the region rose to 96.7 million, which is a nearly fivefold increase since 1990 [7]. Concurrently to increasing travel, malaria transmission in South Asia and SEA has decreased over the past years. Between 2000 and 2015 the estimated number of malaria cases and deaths for the whole WHO region Southeast Asia declined by 39 and 37%, respectively [32]. It has been argued before that the malaria risk for travellers is not correlated with infection rates in the local population and attack rates in visitors may likely be higher because of the absence of partial immunity in contrast to the local populations [33]. Recent studies confirmed the trend of decreasing cases of imported malaria cases from SEA [9, 34]. According to data from malaria surveillance reports from the USA and 12 European countries, malaria cases imported from countries of SEA declined by 47% between 2003 and 2008 [8]. Another assessment of 320 imported cases of malaria between 1994 and 2012 from Denmark showed an annual decline of 6.5% [35].

However, India and Indonesia, as it is the case with notification data in Table 5, constitute two of the main source countries for imported malaria. In a retrospective analysis of national notification data from Canada, 9.2% of imported malaria cases originated from India. India displayed the most common source country for vivax malaria cases [36]. Whilst this should be taken into account during pre-travel advice, the notification data to the RKI presented in this study show low and declining numbers of malaria cases imported from South and SEA to Germany. Indeed, these data underline the economical impact of over-prescription of SBET, if compared to the annual numbers of travellers to SEA. Using figures provided by the German Travel Association (DRV), 1,769,825 individuals travelled to countries considered in this study in 2015 [37]. Considering a price of 42 Euro per unit, this would translate to 71.4 million Euros spent for SBET in 2015 in Germany alone. Facing the low number of imported falciparum malaria (13 cases during the past 5 years), these expenses hardly pass any cost-benefit analysis. In the light of the decreased numbers of imported malaria and the fact that the majority of reported cases are P. vivax cases, strategies for travellers to these regions have to be reassessed, in particular, because relapse of P. vivax is not adequately prevented by regular chemoprophylaxis or treated by a standard regimen of standby emergency treatment.

Even though atovaquone/proguanil is generally considered safe, up to 82% of patients reported an adverse event [38, 39]. The benefit-risk ratio for continuous malaria chemoprophylaxis is consecutively very low for most regions in SEA, and does not pose a viable alternative [40]. However, data from the current study reinforce the assumption that SBET has to be critically assessed. Equipping travellers with an anti-malarial has the potential to lead to a false sense of security and an uncritical perception of the risk of malaria during travel, favouring short-sleeved clothes and avoidance of repellents. Unattended administration of SBET harbours the risk of missing other medical conditions. The vast majority of travellers sojourn on popular tourist routes and visit similar places at their destinations. During the past two decades healthcare systems in most countries of South Asia and SEA have improved, although they remain at a low standard. However, from the main tourist tracks medical facilities can usually be reached within 24 h, particularly in metropolitan areas. One of the male travellers in this study who used SBET started intake of medication in Kolkata, where it would easily have been possible to find a hospital to rule out malaria [21]. There are however arguments in favour of SBET. First, travellers have advanced to more remote areas worldwide and carriage of SBET can be life-saving in cases when travellers are unable to reach a health facility due to missing infrastructure or external factors, e.g., severe weather conditions. Secondly, carriage of high-quality medication ensures safe treatment in view of increasing numbers of fake anti-malarials, especially in Asia [41‐43]. Third, studies have shown that long-term travel can result in a higher cumulative risk for malaria [44, 45]. Those travellers may benefit from provision of SBET given the assumption that they tend to visit more rural regions. However, it is not possible to support this recommendation with the current study data, since only individuals travelling for no longer than 12 weeks were recruited.

This study has some limitations to be taken into account. As described above, a selective population of travellers visiting a health facility for pre-travel advice was studied. This population may not be comparable to the overall population travelling to South Asia and SEA. Earlier data demonstrated that travellers who attended a travel clinic have better knowledge about potential risks and protective measures [46]. Yet unpublished data from the Hamburg Airport Survey also suggest that travellers in the overall population have less frequently attended a travel clinic and are less frequently carrying SBET. Finally, it was not possible to completely rule out malaria in returned travellers, since no serology for Plasmodium spp. was performed. However, conduct of phone interviews 4–6 weeks after return makes unrecognized episodes of clinically relevant malaria unlikely.

Only a very small proportion of travellers to low-risk malaria areas experiencing fever while abroad adhered to pre-travel advice related to the concept of SBET. Travel advice concerning malaria in South Asia and SEA should focus on appropriate mosquito bite protection and clearly emphasize the need to see a doctor within 24 h after onset of fever. Travellers with need of SBET should be carefully selected. Recommendations related to SBET should be revisited and limited to selected situations only, e.g., long-term travel or travel to remote rural areas.