Stand-by emergency treatment (SBET) of malaria in Spanish travellers: a cohort study

Malaria prophylaxis differs substantially from traveller to traveller and from region to region, even within a single country. This variability is a function of national recommendations, intensity of transmission, predominance of Plasmodium species and characteristics of the travel, such as destination, itinerary, duration, season and type of travel [1, 2]. Stand-by emergency treatment (SBET) is an approach based on traveller self-treatment to be used when a possible malarial infection could occur while overseas and a prompt medical evaluation is not possible because the traveller is staying in a remote area [3]. SBET should be presumptively self-administered when access to medical care is not available in less than 24 h and the traveller develops a febrile illness consistent with malaria. The traveller should be advised that SBET is a temporary measure for suspected malaria. It is not counterfeit, and it will not interact adversely with the traveller’s other medicines, but a prompt medical evaluation remains imperative [3, 4].

The SBET prescription associated with mosquito avoidance measures is due to a risk-benefits analysis, since the incidence of adverse effects of chemoprophylaxis could outweigh the attack rate of malaria in areas at low risk of transmission [5, 6]. Moreover, the development of further anti-malarial drug resistances, associated with medication intake, and the presence of counterfeit medication in remote areas also foster SBET use [7].

The World Health Organization (WHO) provides general guidelines that travellers carrying SBET should observe, such as to consult a physician immediately if fever occurs 1 week or more after entering an endemic area, to start the SBET when medical care is not available within 24 h of the onset of fever and then to seek medical care as soon as possible for a complete evaluation and to exclude other illnesses and to use antipyretics to lower fever and reduce vomiting due to anti-malarial drugs [5].

Despite these guidelines, the medical community is currently debating the concept of SBET [8–10], and the available literature is partial insufficient to draw firm conclusions. Moreover, regarding the topic of travellers’ adherence to SBET, very little has been published [11–14]; hence, the aim of this study was to determine travellers’ compliance with prescribed SBET.

From January to December 2017, 5436 travellers presented to the HUB Travel Medicine Clinic, and 1025 intended to travel to malaria-endemic areas, being prescribed SBET in 14.1% of cases (n = 145) as a reliable malaria self-treatment when the traveller planned to stay in remote areas with low risk for disease transmission. All of them agreed to participate in the study by completing the pre-travel questionnaire. A flow-chart of participants can be seen in Fig. 1.

Among travellers who had used atovaquone/proguanil as anti-malarial chemo-prophylaxis (n = 16) in previous travels, 12.5% of them (n = 2) were women of 50 years old (yo) and 26 yo who reported experiencing nausea and vomiting as AEs.

Of the recruited participants, 98 also completed the online survey for a total response rate of 67.6%; of those, only 37 (37.8%) actually carried anti-malarial drugs while travelling abroad, while 61 travellers to which SBET was prescribed did not buy the drugs before travelling. No participants’ baseline or travel characteristic was shown as significantly associated (p value > 0.05) with this behaviour.

The consultation of regional Electronic Medical Records HC3 System [15] of all participants confirmed no malaria cases, nor other travel-related health problems in the rest of the study population. No visits to general practitioners (GPs) or emergency departments were observed in the study and follow-up periods.

This cohort study offers a first insight into travellers’ use of the SBET in Spain.

Because of travel characteristics, foremost the median length of stay of 29 days, staying in remote areas with low intensity of malaria transmission and a scarce number of imported cases from these areas, the study group was selected as a candidate of SBET strategy instead of anti-malarial chemoprophylaxis.

The most noticeable data yielded through the online post-travel survey is about the consistent number of travellers who did not even carry atovaquone/proguanil while travelling abroad, with two-thirds of them (62.2%) not following medical prescriptions. This behaviour may be explained by the idea that going to areas with low risk for malaria infection falsely reassures travellers [16], leading them to believe it is unnecessary to buy drugs themselves. In this behavioural domain, there were no differences associated with travellers’ demographic profiles or travel characteristics, presenting it as a widespread perception [11]. This aspect represents an unpredictable widespread behaviour among travellers that should be taken into account during pre-travel medical care. These findings foster the idea that more studies are needed to investigate this domain, as well as the implementation of instructive programmes designed to improve the level of compliance to SBET recommendations among travellers.

While it is well known that a large number of people travel without a pre-travel medical consultation [17, 18], a major interest of such a cohort is the relevant number of travellers that still travel without any protection against malaria, although they attended a specific travel clinic where they were informed about risks and received a medical prescription of SBET that could be collected from a pharmacy for less than € 5.

The vast majority of the respondents (95.9%) declared that they did not experience any possible malarial symptoms during travel. Only 4 responders took drugs because of the onset of fever without other symptoms for 3 women, and of fever and diarrhoea in a fourth user. Two SBET users also reported to have complied with the dosage of 4 tablets taken on a daily basis, during 3 days. Not all users sought medical attention nor interrupted their travel. None of these was confirmed as a malaria case from the consultation of regional medical records during the follow-up period.

Even if only represented by 4 travellers, the portion of SBET users (4.1%) in this study is in concordance with results reported by other published studies [11–14]. However, a general scarce level in the application of medical advice was shown in this cohort, since these interviewees detailed an incorrect administration of the SBET regimen. This highlights two relevant issues, regarding the information provided to travellers during pre-travel care, as well as the risk of exposure to drug AEs due to their erroneous use. The use of a strong dose of atovaquone/proguanil in a short period of time increases the likelihood of AEs and toxicity, to which travellers might be needlessly exposed, such as the 22-yo user that also reported general malaise and nausea as atovaquone/proguanil AEs. Also alarming is travellers’ perception of the emergency treatment as an alternative for medical care, although guidelines strongly recommend immediate medical consulting.

Prescription of this prevention strategy is currently increasing, with a natural change from chemoprophylaxis to SBET [19], due to travellers’ preferences for SBET itself more than traditional prophylaxis [20]. Indeed, several arguments support the concept of SBET in those areas with a low risk transmission: (1) the use of SBET, instead of chemoprophylaxis, reduces the likelihood of the development of AEs of the medication; (2) the developing of drug resistances and the presence of counterfeit anti-malarial drugs in these areas also lead healthcare professionals to indicate emergency treatment; (3) some travellers’ characteristics represent situations in which this option can be considered, such as travellers without a definite itinerary, short-stay travellers (such as those who travel for professional purposes) and those who move to remote areas or areas devoid of medical facilities.

While the smooth utility of SBET is ensured if instructions for use are followed, as this research showed, SBET is not a reliable choice for most travellers due to misuse.

Due to this lack of strong scientific evidence regarding the effectiveness of prophylaxis regimens other than traditional chemoprophylaxis, the current UK guidelines for malaria prevention in travellers place emphasis only on the implementation of interventions to avoid exposure, such as precautions against mosquito bites (frequent repellent use, appropriate clothing, insecticide residual spraying, sleeping under a bed net) or seeking medical advice as soon as symptoms develop, without the use of a specific anti-malarial [21].

The main limitations of the study are as follows. First, the number of travellers who visited the clinic to whom SBET was prescribed was limited as a real-world study; for this reason, and due to the likely multi-factoral nature, it was not possible to assess the barriers to their mis-implementation of pre-travel recommendations. Second, there is potential bias due to the use of a traceable and not anonymous online survey, where respondents could be influenced by researchers’ expectations or hide the actual incorrect behaviours. Consultation of regional medical records likely softened this limitation, even though participants may not have sought medical care for minor health problems, leading to underestimation of the actual incidence of travel-related health problems.

Despite these limitations, since the participants in this study represented the standard travel population, it is possible to state that the selected cohort is representative of the target population. Moreover, the enrolment of a consecutive cohort reduces problems of selection and participant bias.

In conclusion, the findings addressed travellers’ adherence and behaviours toward SBET, expressing an incorrect use of the emergency treatment in cases of presumptive malaria symptoms. Substantial concerns about SBET itself as well as on the need to design and implement proven prevention measures for malaria arise from this information, and they should be taken into account during pre-travel consultation, since the success of this strategy for malaria prevention depends on travellers’ strong adherence to it.