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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Usually, malaria is diagnosed both by physicians and laboratories. They report the cases on standard notification forms. Within 1 week, physicians have to complete a supplementary form with more detailed questions regarding the geographical origin of the infection, the use of chemoprophylaxis, and the progression of the disease (this form can be downloaded in French [http://www.bag-anw.admin.ch/infreporting/forms/d//malaria_d.pdf] and German [http://www.bag-anw.admin.ch/infreporting/forms/d//malaria_d.pdf]. All data are transferred to the Swiss Federal Office of Public Health (SFOPH) to be registered into a database, regularly analyzed, and published as government reports in updates and annual bulletins (http://www.bag.admin.ch/themen/medizin/00682/00684/01086/index.html?lang=de, German; http://www.bag.admin.ch/themen/medizin/00682/00684/01086/index.html?lang=fr, French). These data were the basis of this study. Independently, all deaths are reported through death certificates sent to the Swiss Federal Office of Statistics (SFOS). In some situations, only the SFOS was notified, and in these cases, little epidemiologic data were available.
In a second step, hospitals in which fatal cases happened were contacted. The case histories, clinical records, and interviews with some of the concerned physicians provided large and detailed data of many of the fatal cases.
The detailed data on the fatal cases were analyzed, interpreted, and compared with the results and conclusions from the analysis of the basic data from the SFOPH. Statistical analysis was performed using the Mann-Whitney U test, and significance was defined as P 
0.05 (two-tailed). In this study, all mixed infections notified to the SFOPH were considered as falciparum infections if one of the species was P. falciparum.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Two thousand eight hundred seventy-one (62.4%) of the infections were caused by P. falciparum, and this species was responsible for all of the 33 deaths; in two cases, there was co-infection with P. vivax and P. malariae, respectively.
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).
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). The increasing proportion of falciparum infections imported by African nationals from African countries is the reason for this trend among falciparum cases. In contrast, there was a decline in the number of cases imported by Swiss nationals.
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shows an overview of the fatal cases that were notified during the observation period. This collective consisted of 25 (75.8%) men and 8 (24.2%) women. The mean age was 51.6 years (range, 26–80 years; outlier: 4-year-old girl), which is 10–15 years above the annual means of ages for falciparum cases in 1988–2002. Only two deaths of non-Europeans were notified. Both of them, a 35-year-old man from Ghana and a 4-year-old girl from former Zaïre, were visiting relatives in their country of origin (so-called visiting friends and relatives [VFRs]). The other imported infections were acquired by Europeans, mostly traveling as tourists. Sub-Saharan Africa was the source of all the imported infections, and Kenya was by far the most visited country among them (15/25, 60%). Travel duration was known for 18 of the cases. The mean travel duration was 14 days, and all travel was in the range of a short-term stay in the endemic countries (range, 2–30 days). Chemoprophylaxis was either not taken at all (16/19, 84.2%) or on an irregular basis (2/19), which means that these travelers either took a drug that was not recommended in that situation or a recommended drug but did not take it properly or discontinued the prophylaxis. The 4-year-old girl traveling to former Zaïre used a chemoprophylaxis with chloroquine/proguanil in 1996, when mefloquine was considered to be more efficacious and was recommended also for children > 5 kg. However, if there was a contraindication against mefloquine (which is not known), chloroquine/proguanil was recommended as a second choice at that time. At least two travelers had been prescribed mefloquine by their general practitioners but did not take it. A 52-year-old woman traveled to Kenya without chemoprophylaxis after a fatal misunderstanding with her general practitioner, although she was aware of the risk of malaria.
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). The median duration of symptomatic infection (symptom onset – death) was 8 days (interquartile range, 10.0–5.5; 23 cases).
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Apart from the imported cases, two persons acquired infection in Switzerland, namely a 53-year-old man, who lived near the international airport of Geneva and probably was bitten by a mosquito brought by plane from an endemic area in July 1996, and a 70-year-old man, who was found to have acquired a falciparum infection after he received large amounts of blood products in the context of two operations in 1999.1,2 From 1988 to 2002, a total of 11 cases with unusual transmission were notified, that is, eight cases of odyssean, two cases of induced, and one case of congenital falciparum malaria. Because there were two deaths in this category, the calculated CFR was high (18.2%).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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When analyzing fatal cases caused by falciparum malaria, almost every case is a complex entity of factors leading to infection and death. This study clarified what these decisive factors were, the circumstances that contributed to the deaths, and how these fatalities could have been prevented. This global approach seems to be at the same time a strength and a weakness of this study.
This is a strength because the examination of all data about the fatal cases of these years went beyond a case report and allowed the identification of the most important key events associated with these fatal outcomes. This is a weakness because, with such a broad approach, it is impossible to provide statistically significant evidence about many of the conclusions we drew that go deeper into the complex mechanisms of traveler’s malaria than just morbidity and mortality. This needs a much more specific approach and appropriate data collection from the beginning other than that used in this retrospective study.
There is no statistical evidence in our study that, for example, the patients who died of malaria had poorer pre-travel advice, longer patient’s delays, or more missed diagnosis than the others. The calculated CFR of 1.2% for falciparum infections is comparable with the average CFRs reported from other countries of Europe in these years.3,4 However, comparing the CFRs in different countries can be difficult, because different notification systems and profiles of patients can strongly affect these values. Furthermore, in addition to some under-reporting in Switzerland, many infections in Swiss nationals or residents are diagnosed and treated in foreign and endemic countries without being reported to the SFOPH and do not appear in our statistics.5
Non-immune Europeans traveling as tourists accounted for almost all of the deaths, and severe infection and fatalities among this group remain a regular event. Fortunately, this group has a slightly decreasing trend. The non-Europeans had a significantly lower CFR than the Europeans. This might be because, due to their acquired semi-immunity, the inflammatory response to the parasite is limited and the disease is less severe (clinical immunity), and they often have lower parasitemic levels than those recorded in non-immune travelers (anti-parasite immunity). However, many of them are not aware that this semi-immunity wanes quickly when they are not exposed to mosquito bites in Switzerland. An Italian study identified these patients, mostly traveling to their countries of origin to VFRs as a high-risk group for malaria infections because they tend to underestimate the risk of infection and rarely take any chemoprophylaxis.6 We observed that, in Switzerland from 1988 to 2002, the number of falciparum malaria cases in migrants steadily increased.
The mean age of the fatal cases exceeded the annual means by 10–15 years, which is in line with a recent study that identified age as a risk factor for fatal outcome of falciparum malaria.7
All imported infections were acquired in Sub-Saharan Africa, particularly in Kenya. This and generally the very few numbers of notified falciparum infections imported from outside the African continent show the lower risk in areas besides Africa—except some high risk regions—as well as the appropriateness of the current Swiss prevention strategies for all these areas, including the recommendation of emergency stand-by-emergency treatment (SBET) for low-risk areas.
Typical patterns and key events were found in the case histories that were associated with fatal outcome involved both travelers and physicians.
Even if in many cases the reasons for not taking or discontinuing chemoprophylaxis was not known, it is remarkable that none of the travelers in our study performed a correct and recommended prophylaxis (except the 4-year-old girl who used a second-choice drug). General practitioners should acquaint travelers with the disease and be in a position to provide travelers with clear and balanced information about anti-malarial drugs and mosquito bite protection. In 1997, a study regarding German and Swiss general practitioners concluded that many of them gave incorrect or unsatisfactory pre-travel advice deviating from the current recommendations, leading to misunderstandings and confusion, with the consequences that prescribed drugs are not taken or discontinued prematurely.8 Current information on the recommendations is readily available (www.bag.admin.ch/infekt/reise/f [French], www.bag.admin.ch/infekt/reise/d [German], or www.safetravel.ch) and is also comprehensible and recommended for the informed traveler. Travelers who do not seek medical advice rely mainly on recommendations of travel operators, friends, or experiences, and often drugs that are no longer up-to-date and less efficacious are taken. They are often unaware or have a false perception of the tolerability profiles of anti-malarial medications.9 General practitioners should be aware that they can greatly influence opinions about anti-malarial drugs in the population.10 It is also very important to advise the traveler how to react in case of illness after the return, because this will reduce the patient’s delay.
After infection, the first symptoms appeared on average 8 days (median, 6 days) after arrival in Switzerland. Physicians should question febrile patients about travel history. Early symptoms are very unspecific and not often not indicative of malaria or severe illness. This may also be a reason why patients often did not quickly seek medical help unless they had been instructed so earlier. In some cases, this led to extreme patient’s delays.
Most patients presented first to a general practitioner, and the diagnosis was initially very often missed. Frequently, the symptoms were ascribed to flu-like viral syndromes. Sudden deterioration is not a rare event in falciparum malaria and dismissing febrile patients with a travel history that includes a sojourn in malaria-endemic areas without thinking of and ruling out this potentially lethal infection can be fatal. Once the suspicion of a possible falciparum malaria is raised, the general practitioner should clarify the exact (species) diagnosis and the clinical assessment of the state of health of the patient.
The microscopic diagnosis is made by analyzing thick (detection of parasitemia) and thin (species identification) blood films. The detection of parasites can be very time-consuming, especially in cases with low parasitemia, and identifying the plasmodia species can be a very difficult task. Delayed recognition of P. falciparum led, at least in one of the fatal cases, to an important delay of appropriate treatment. Therefore, the microscopical diagnosis should be done or at least confirmed by an expert laboratory as fast as possible, at least within 12 hours. One single negative result does not rule out falciparum malaria, and blood analyses should be repeated after 12–24 hours. For an immediate laboratory assessment, physicians can use falciparum rapid tests as a helpful tool, using a positive test result as a positive predictor for infection. A recent meta-analysis has shown that rapid malaria tests are useful in the assessment of febrile travelers returning from Sub-Saharan Africa11 with the probability of P. falciparum malaria estimated at 97% (CI, 92–99%) after a positive test result. However, here also, blood should be brought or sent to an expert laboratory, and one negative rapid test result does not rule out falciparum malaria. A study in 2002 showed that, if the clinical suspicion is high but microscopy is still delayed or negative, there are clinical and laboratory predictors that fully justify presumptive anti-malarial treatment.12 The strongest predictors for malaria infection in that study were enlarged spleen (clinically assessed) and thrombocytopenia.
Regarding the state of health of the patient, every physician should bear in mind that severe falciparum malaria can be a sudden, life-threatening event. If falciparum malaria is suspected and the patient is in a bad state of health, he must be hospitalized, and a specialist in travel or tropical medicine should be immediately consulted.
The median delay of 5 days between the onset of symptoms and the establishment of the correct diagnosis is in line with other observations with P. falciparum.13,14 Ideally, these delays could be reduced to 1 or 2 days, if the patients would seek immediately help in case of illness after travel and if physicians were more aware of the disease and did not miss the diagnosis. The median of 8 days that remained for the patients to live after the symptom onset (and so only a median of 3 days from the correct diagnosis until death) suggest that the patients were already in an advanced disease stage when correctly diagnosed and treated. Once severe malaria had developed, various vital organs were often affected, and even optimal intensive care did not prevent fatal outcome. The difficulties in treating severe complications and multi-organ failures underline the importance of prevention, ideally pre-travel.
Typical patterns and key events identified in this study examined not only the travel period itself and the anti-malarial interventions used (mosquito bite protection, chemoprophylaxis) but primarily the period before and after travel, including the pre-travel communication between health care providers and travelers, the patient’s post-travel handling of illness, the correct establishing or ruling out of the diagnosis, and the prompt treatment initiation. Interestingly, a recent American study examining malaria-related deaths among US travelers made equal or very similar observations as to how these deaths could have been prevented.15 The study concluded that health care providers must educate travelers about malaria and keep in mind the importance of taking a travel history, obtaining a blood film for suspected malaria, and seeking expert advice. Furthermore, according to that study, hospitals in the United States should have intravenous quinidine gluconate on formulary because it is the only drug available to treat severe malaria in the United States. In our study, we did not observe any delay in treatment because of unavailability of therapeutic agents.
| How a GP helps to prevent fatalities due to P. falciparum |
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| Stage | What to do |
| All three months |
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| Pre-travel |
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| Post-travel |
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The two Swiss nationals who were infected in Switzerland died of airport malaria and transfusion-transmitted malaria, respectively. Those very rare cases usually have much higher CFRs, because the diagnosis is often excessively delayed because of the absence of a history of exposure to potentially malaria-infected mosquito bites.16 Airport malaria occurs mainly in hot summers favoring the survival of the mosquitoes. Physicians should keep these possibilities in the back of their minds when treating patients with unclear fever or thrombocytopenia.
We conclude that imported falciparum malaria is still a frequent event in Switzerland and a challenge to travel health practitioners and general practitioners. The main group at high risk of death are non-immune Swiss and European nationals traveling as tourists to Africa. On the other hand, the numbers of falciparum cases is increased in travelers, mainly of African origin, who have settled in Switzerland and whose previously acquired semi-immunity has waned. Most infections with P. falciparum occur in Sub-Saharan Africa and can be attributed to an incorrect use or non-use of prophylactic measures. Despite increasing resistance, the three recommended drug regimens (mefloquine, atovaquone/proguanil, and doxycycline) are still highly effective in P. falciparum–endemic areas. Travelers taking regular and recommended chemoprophylaxis do not appear in the group of fatal infections. Many travelers do not use chemoprophylaxis, possibly because of perceived adverse events or because they think that malaria is readily curable. Prevention strategies must try to reach these travelers. Travel operators and airlines can facilitate this process. The attention of both travelers and physicians should be raised even more to create a broad awareness of the disease. General practitioners play a decisive role before and after their patients travel to falciparum-endemic areas. They should be aware of their importance in preventing fatalities caused by malaria and update regularly with the current and standardized information about drug recommendations to avoid confusion and folklore-based opinions among the travelers. Most important is providing individually tailored protection with concise advice on how to handle an eventual infection. General practitioners who see departing or returned travelers should not hesitate to draw on specialist advice if they are not familiar with malaria. Most important, post-travel is the advice to "think" malaria. Otherwise, a malarial infection can easily be missed or misdiagnosed, particularly in the influenza season. These patients may be unable to attend a follow-up visit if their condition has worsened. Once the suspicion is raised, microscopic diagnosis by an expert laboratory is required as soon as possible. One negative blood slide does not rule out falciparum malaria and has to be repeated within the next 12–24 hours. When expert laboratory analysis is negative or still delayed, physicians must begin antimalarial treatment if the clinical suspicion is high (summary of positive indicators like clinical presentation, travel history, positive rapid dip-stick test). If the condition of the patient is indicative of severe infection, hospital admission with specialist advice is imperative. The most important findings of our study regarding the role of the general practitioners have been put in the info box.
Further research on the knowledge, attitudes, and practices of travelers and general practitioners regarding malaria prevention and treatment is needed. What proportion of travelers to malaria endemic areas seek pre-travel advice and do not use the recommended chemoprophylaxis? What are the exact reasons for non-adherence? The role and protective effect of acquired semi-immunity needs clarification.. Kenya was the main destination for the travelers with fatal outcomes. Does this pinpoint Kenya as a main tourist destination of the Swiss residents or could it suggest a higher prevalence of mosquitoes/plasmodia or overly careless travel operators giving false advice in that region. The future role and applications for rapid diagnostic tests need further evaluation in the travel clinic setting. Currently, they serve as a useful tool but do not replace expert microscopy.
Reducing infections and fatalities among travelers is an achievable goal, and the attitudes and practices of both travelers and physicians need to be addressed.
Received June 16, 2005. Accepted for publication July 19, 2006.
Acknowledgments: The authors thank the physicians and hospitals who provided detailed clinical data for this study, Prof. Christoph Hatz for productive cross-reading, and Dr. Lehky-Hagen for contributions to this work. We are indebted to Simone Graf, from the SFOPH, for contributions that were central to this manuscript.
* Address correspondence to Patricia Schlagenhauf, WHO CC for Travellers’ Health, Division of Epidemiology and Communicable Diseases, Institute for Social and Preventive Medicine, University of Zurich, Hirschengraben 84, CH-8001 Zurich, Switzerland. E-mail: pat{at}ifspm.unizh.ch 
Authors’ addresses: Daniel Christen, WHO CC for Travellers’ Health, Division of Epidemiology and Communicable Diseases, Institute for Social and Preventive Medicine, University of Zurich, Hirschengraben 84, CH-8001 Zurich, Switzerland, Telephone: 41-44-6344630, E-mail: christendaniel{at}gmx.net. Robert Steffen, WHO CC for Travellers’ Health, Division of Epidemiology and Communicable Diseases, Institute for Social and Preventive Medicine, University of Zurich, Hirschengraben 84, CH-8001 Zurich, Switzerland, Telephone: 41-44-6344620, Fax: 41-44-6344984, E-mail: roste{at}ofspm.unizh.ch. Patricia Schlagenhauf, WHO CC for Travellers’ Health, Division of Epidemiology and Communicable Diseases, Institute for Social and Preventive Medicine, University of Zurich, Hirschengraben 84, CH-8001 Zurich, Switzerland, Telephone: 41-44-6344630, E-mail: pat{at}ifspm.unizh.ch.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  Severe and Lethal Falciparum Malaria in Europe Journal Watch Infectious Diseases, January 3, 2007; 2007(103): 4 - 4. [Full Text]
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