Ausgabe 1/2007

Malaria self-testing by travellers

Malaria self-testing by travellers: opportunities and limitations

Accurate and timely treatment of imported malaria requires fast and reliable diagnosis. Microscopic examination of stained blood films still remains the mainstay of diagnostic methods. However, correct interpretation of blood films requires considerable expertise that is not necessarily available at peripheral medical centres in non-endemic countries. The availability of a rapid and reliable diagnostic test could improve the quality of malaria diagnosis in febrile travellers after their return to non-endemic countries. Fast and simple immuno-chromatographic tests are marketed since several years. These kits are based on the detection of circulating parasite-specific antigen in full blood by use of specific antibodies which are bound to a membrane. The extremely simple test methodology is intriguing: full blood (be it venous or from finger prick) is dotted on the test strip and lysed by a buffer. The resulting solution moves on the filter up to the test filed where specific antibodies are bound. A few minutes after washing with a second buffer, the result is visible as a colorimetric band. Due to the simple handling of the test, travellers to malarious areas are sometimes advised to carry the test kit as emergency tool in their luggage and to use it themselves in case they develop fever in a situation where they cannot reach adequate professional help within a safe time limit. The utilization of this method by travellers has been subject of intensive discussion among travel medicine specialists.

Sensitivity and specificity of dipstick tests in various populations
Until the end of 2006, Pubmed lists 78 published studies evaluating different commercial malaria dipstick tests in different populations. The majority of these studies was performed in endemic regions in populations who had developed semi-immunity to malaria. The sensitivity for detecting symptomatic P. falciparum infection ranged between 60.4% and 100%. In some instances, a positive dipstick result was obtained even before parasite detection by microscopical examination. Some studies showed a worrisome tendency of dipstick tests to remain negative in selected patients, even with high parasite loads but this problem appears to have disappeared in recent test batches. Recent publications show a very high detection rate for malaria at 97% and more.

Self-testing by travellers
Following marketing of the first dipstick tests for use in medical settings, travellers were detected as a new target group. Due to the extremely simple handling of the kits that can be used without further laboratory equipment, tests were recommended for self-use by febrile travellers. When carrying a test kit to endemic areas, travellers would have the possibility to perform fast and accurate diagnosis by themselves without having to rely on locally available infrastructure. Depending on the outcome of the test, the traveller would than be able to treat himself for falciparum malaria with an emergency medication (“stand-by therapy”). A negative test result would then prevent a traveller from taking unnecessary or even potentially harmful medication. The utilization of this scenario by travellers was subject of intensive debate among travel medicine specialists. Several studies tried to validate if laymen inexperienced with diagnostic tools were capable to handle the test kits in a situation of extreme stress and to decide correctly for or against treatment upon the result.
In a Swiss study, 160 healthy Swiss travelers were asked prior to travel to perform the ParaSightF test following written instructions. Only 75% of the individuals could perform the test correctly. Following a more thorough written and oral instruction, the performance rate increased to 90%. However, even then the interpretation of results was unsatisfactory (70.6% correct interpretation with 14.1% false-negative results). A second study was done within this setting among 98 healthy Swiss volunteers, this time comparing ParasightF and ICT P.f. tests. This investigation demonstrated again high level of interpretation and technical problems in both tests without any difference in the performance of either. In a study done in London, 153 symptomatic returnees from endemic areas were asked to perform the ICT P.f. themselves and to interpret the results. Patients received detailed instructions on test procedures by the study coordinators and were handed a modified and improved manual. These measures improved success rates: 91% of study participants were able to perform the test correctly. All patients with falciparum malaria (n=22) were able to diagnose themselves. The most realistic setting was achieved in a study done in Kenya: febrile travellers who presented at one of the outpatient departments at the coast south of Mombasa were recruited for this study. These patients were asked to perform the test (ICT P.f. ) themselves according to the manual provided by the manufacturer, without prior instruction. The performance of the study participants was note by independent observers on a standardized questionnaire, results were checked against microscopy. Only 68% of the patients were able to perform and to interpret the test correctly. Reasons for problems with test performance are listed in table 4. The most important result was that 10 out of 11 patients with confirmed falciparum malaria were not able to achieve the diagnosis by using the dipstick test. When tested by the attending physician all patients were clearly positive in the test device.

Conclusions
Accurate and timely diagnosis and treatment of falciparum malaria in non-endemic areas is frequently complicated by lack of experience on the side of involved laboratory personal. Diagnostic tools based on the dipstick principle for the detection of plasmodial histidine-rich protein 2 (HRP-2) and parasite-specific lactate-dehydrogenase (pLDH), respectively, have become available for the qualitative detection of falciparum malaria. All dipstick tests have the potential of enhancing speed and accuracy of the diagnosis of falciparum malaria, especially when non-specialized laboratories are involved. The majority of studies evaluating malaria dipstick tests showed a high sensitivity and specificity for the detection of P. falciparum. In single cases, malaria diagnosis was achieved 1-2 days faster by dipstick test than by microscopy. This shows the potential use of the method: the infection might have been overlooked at a later stage without the dipstick test result. However, several studies demonstrated that patients with high parasitaemia remained negative in the rapid diagnostic tests. Even though reasons for this are not entirely clear, these reports give a clear message: microscopy must not be neglected in favour of performing dipstick tests alone.
Non-falciparum malaria is not reliably detected by the available dipstick tests, in particular not in patients with low parasitaemia. Major modifications and improvements have to be done before dipstick tests might find their place in the diagnosis of tertian or quartan malaria.
Studies investigating the quality of malaria self-testing in travellers to endemic areas are difficult to construct. Different scenarios have been used: asymptomatic travellers pre travel, symptomatic travellers post travel, and symptomatic travellers during travel. When original instructions of the manufacturers were used, performance was invariably disappointing. Results suggest that persons without previous experience in performing laboratory tests will have problems in stressful situation to proceed correctly with a test kit for self-testing. Especially the high failure rate in patients with falciparum malaria in the realistic setting of a outpatient clinic in Africa points towards the problem that patients with falciparum malaria may simply be too sick to perform self-testing, interpret results and decide on malaria treatment. Self-use of dipstick tests for malaria diagnosis by travelers should not be recommended routinely as there is enough evidence that performance and interpretation of results by the traveler is uncertain. Dipstick tests can only be recommended to travelers for specific situations (i.e. long term stay, far away from medical assistance, expedition-type travel) after appropriate instruction and training, including a successful performance of the test procedure.

With all limitations listed in this article, dipstick tests for malaria diagnosis are still a potentially very useful, additional tool. Trained laboratory personal has in general no problems in doing the tests. Still, exclusion of malaria should never be based on a negative dipstick test alone. The absolute need of thin and thick blood film microscopy in every single patient with suspected malaria has not yet been put aside by the introduction of dipstick tests.

By Tomas Jelinek
Berlin Center for Travel & Tropical Medicine, Germany
www.bctropen.de