Patricia Schlagenhauf

GeoSentinel surveillance of illness in returned travelers, 2007-2011.

BACKGROUND International travel continues to increase, particularly to Asia and Africa. Clinicians are increasingly likely to be consulted for advice before travel or by ill returned travelers. OBJECTIVE To describe typical diseases in returned travelers according to region, travel reason, and patient demographic characteristics; describe the pattern of low-frequency travel-associated diseases; and refine key messages for care before and after travel. DESIGN Descriptive, using GeoSentinel records. SETTING 53 tropical or travel disease units in 24 countries. PATIENTS 42 173 ill returned travelers seen between 2007 and 2011. MEASUREMENTS Frequencies of demographic characteristics, regions visited, and illnesses reported. RESULTS Asia (32.6%) and sub-Saharan Africa (26.7%) were the most common regions where illnesses were acquired. Three quarters of travel-related illness was due to gastrointestinal (34.0%), febrile (23.3%), and dermatologic (19.5%) diseases. Only 40.5% of all ill travelers reported pretravel medical visits. The relative frequency of many diseases varied with both travel destination and reason for travel, with travelers visiting friends and relatives in their country of origin having both a disproportionately high burden of serious febrile illness and very low rates of advice before travel (18.3%). Life-threatening diseases, such as Plasmodium falciparum malaria, melioidosis, and African trypanosomiasis, were reported. LIMITATIONS Sentinel surveillance data collected by specialist clinics do not reflect healthy returning travelers or those with mild or self-limited illness. Data cannot be used to infer quantitative risk for illness. CONCLUSION Many illnesses may have been preventable with appropriate advice, chemoprophylaxis, or vaccination. Clinicians can use these 5-year GeoSentinel data to help tailor more efficient pretravel preparation strategies and evaluate possible differential diagnoses of ill returned travelers according to destination and reason for travel. PRIMARY FUNDING SOURCE Centers for Disease Control and Prevention.

Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study

Abstract Objective To compare the tolerability of malaria chemoprophylaxis regimens in non-immune travellers. Design Randomised, double blind, study with placebo run-in phase. Setting Travel clinics in Switzerland, Germany, and Israel. Main outcome measure Proportion of participants in each treatment arm with subjectively moderate or severe adverse events. Participants 623 non-immune travellers to sub-Saharan Africa: 153 each received either doxycycline, mefloquine, or the fixed combination chloroquine and proguanil, and 164 received the fixed combination atovaquone and proguanil. Results A high proportion of patients reported adverse events, even in the initial placebo group. No events were serious. The chloroquine and proguanil arm had the highest proportion of mild to moderate adverse events (69/153; 45%, 95% confidence interval 37% to 53%), followed by mefloquine (64/153; 42%, 34% to 50%), doxycycline (51/153; 33%, 26% to 41%), and atovaquone and proguanil (53/164; 32%, 25% to 40%) (P = 0.048 for all). The mefloquine and combined chloroquine and proguanil arms had the highest proportion of more severe events (n = 19; 12%, 7% to 18% and n = 16; 11%, 6% to 15%, respectively), whereas the combined atovaquone and proguanil and doxycycline arms had the lowest (n = 11; 7%, 2% to 11% and n = 9; 6%, 2% to 10%, respectively: P = 0.137 for all). The mefloquine arm had the highest proportion of moderate to severe neuropsychological adverse events, particularly in women (n = 56; 37%, 29% to 44% versus chloroquine and proguanil, n = 46; 30%, 23% to 37%; doxycycline, n = 36; 24%, 17% to 30%; and atovaquone and proguanil, n = 32; 20%, 13% to 26%: P = 0.003 for all). The highest proportion of moderate or severe skin problems were reported in the chloroquine and proguanil arm (n= 12; 8%, 4% to 13% versus doxycycline, n = 5; 3%, 1% to 6%; atovaquone and proguanil, n = 4; 2%, 0% to 5%; mefloquine, n = 2; 1%, 0% to 3%: P = 0.013). Conclusions Combined atovaquone and proguanil and doxycyline are well tolerated antimalarial drugs. Broader experience with both agents is needed to accumulate reports of rare adverse events.

Travel and migration associated infectious diseases morbidity in Europe, 2008

BackgroundEuropeans represent the majority of international travellers and clinicians encountering returned patients have an essential role in recognizing, and communicating travel-associated public health risks.MethodsTo investigate the morbidity of travel associated infectious diseases in European travellers, we analysed diagnoses with demographic, clinical and travel-related predictors of disease, in 6957 ill returned travellers who presented in 2008 to EuroTravNet centres with a presumed travel associated condition.ResultsGastro-intestinal (GI) diseases accounted for 33% of illnesses, followed by febrile systemic illnesses (20%), dermatological conditions (12%) and respiratory illnesses (8%). There were 3 deaths recorded; a sepsis caused by Escherichia coli pyelonephritis, a dengue shock syndrome and a Plasmodium falciparum malaria.GI conditions included bacterial acute diarrhea (6.9%), as well as giardiasis and amebasis (2.3%). Among febrile systemic illnesses with identified pathogens, malaria (5.4%) accounted for most cases followed by dengue (1.9%) and others including chikungunya, rickettsial diseases, leptospirosis, brucellosis, Epstein Barr virus infections, tick-borne encephalitis (TBE) and viral hepatitis. Dermatological conditions were dominated by bacterial infections, arthropod bites, cutaneous larva migrans and animal bites requiring rabies post-exposure prophylaxis and also leishmaniasis, myasis, tungiasis and one case of leprosy. Respiratory illness included 112 cases of tuberculosis including cases of multi-drug resistant or extensively drug resistant tuberculosis, 104 cases of influenza like illness, and 5 cases of Legionnaires disease. Sexually transmitted infections (STI) accounted for 0.6% of total diagnoses and included HIV infection and syphilis. A total of 165 cases of potentially vaccine preventable diseases were reported. Purpose of travel and destination specific risk factors was identified for several diagnoses such as Chagas disease in immigrant travellers from South America and P. falciparum malaria in immigrants from sub-Saharan Africa. Travel within Europe was also associated with health risks with distinctive profiles for Eastern and Western Europe.ConclusionsIn 2008, a broad spectrum of travel associated diseases were diagnosed at EuroTravNet core sites. Diagnoses varied according to regions visited by ill travellers. The spectrum of travel associated morbidity also shows that there is a need to dispel the misconception that travel, close to home, in Europe, is without significant health risk.

Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag

To compare the impact of various dosage forms of melatonin and placebo on jet lag symptoms, 320 volunteers who had flights over 6 to 8 time zones were recruited for a double-blind, randomized, placebo-controlled study. The volunteers received either melatonin 0.5-mg fast-release (FR) formulation, melatonin 5-mg FR formulation, melatonin 2-mg controlled-release (CR) formulation, or placebo. The study medication was taken once daily at bedtime during 4 days after an eastward flight. The volunteers completed the Profile of Mood States (POMS), sleep log, and symptoms questionnaires once daily and the Karolinska Sleepiness Scale (KSS) three times daily prior to departure and during the 4 days of medication intake postflight. A total of 234 (73.1%) participants were compliant and completed the study. The FR melatonin formulations were more effective than the slow-release formulation. The 5-mg FR formulation significantly improved the self-rated sleep quality (p < .05), shortened sleep latency (p < .05), and reduced fatigue and daytime sleepiness (p < .05) after intercontinental flight. The lower physiological dose of 0.5 mg was almost as effective as the pharmacological dose of 5.0 mg. Only the hypnotic properties of melatonin, sleep quality and sleep latency, were significantly greater with the 5.0-mg dose.

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.

BACKGROUND Travel is important in the acquisition and dissemination of infection. We aimed to assess European surveillance data for travel-related illness to profile imported infections, track trends, identify risk groups, and assess the usefulness of pre-travel advice. METHODS We analysed travel-associated morbidity in ill travellers presenting at EuroTravNet sites during the 5-year period of 2008-12. We calculated proportionate morbidity per 1000 ill travellers and made comparisons over time and between subgroups. We did 5-year trend analyses (2008-12) by testing differences in proportions between subgroups using Pearsons χ(2) test. We assessed the effect of the pre-travel consultation on infection acquisition and outcome by use of proportionate morbidity ratios. FINDINGS The top diagnoses in 32 136 patients, ranked by proportionate morbidity, were malaria and acute diarrhoea, both with high proportionate morbidity (>60). Dengue, giardiasis, and insect bites had high proportionate morbidity (>30) as well. 5-year analyses showed increases in vector borne infections with significant peaks in 2010; examples were increased Plasmodium falciparum malaria (χ(2)=37·57, p<0·001); increased dengue fever (χ(2)=135·9, p<0·001); and a widening geographic range of acquisition of chikungunya fever. The proportionate morbidity of dengue increased from 22 in 2008 to 36 in 2012. Five dengue cases acquired in Europe contributed to this increase. Dermatological diagnoses increased from 851 in 2008 to 1102 in 2012, especially insect bites and animal-related injuries. Respiratory infection trends were dominated by the influenza H1N1 pandemic in 2009. Illness acquired in Europe accounted for 1794 (6%) of all 32 136 cases-mainly, gastrointestinal (634) and respiratory (357) infections. Migration within Europe was associated with more serious infection such as hepatitis C, tuberculosis, hepatitis B, and HIV/AIDS. Pre-travel consultation was associated with significantly lower proportionate morbidity ratios for P falciparum malaria and also for acute hepatitis and HIV/AIDS. INTERPRETATION The pattern of travel-related infections presenting in Europe is complex. Trend analyses can inform on emerging infection threats. Pre-travel consultation is associated with reduced malaria proportionate morbidity ratios and less severe illness. These findings support the importance and effectiveness of pre-travel advice on malaria prevention, but cast doubt on the effectiveness of current strategies to prevent travel-related diarrhoea. FUNDING European Centre for Disease Prevention and Control, University Hospital Institute Méditerranée Infection, US Centers for Disease Control and Prevention, and the International Society of Travel Medicine.

Multicenter EuroTravNet/GeoSentinel Study of Travel-related Infectious Diseases in Europe

We analyzed prospective data on 17,228 European patients who sought treatment at GeoSentinel sites from 1997 to 2007. Gastrointestinal illness (particularly in tourists), fever (those visiting friends and relatives [VFRs]), and skin disorders (in tourists) were the most common reasons for seeking medical care. Diagnoses varied by country of origin, region visited, or categories of travelers. VFRs who returned from sub-Saharan Africa and Indian Ocean islands were more likely to experience falciparum malaria than any other group. Multiple correspondence analysis identified Italian, French, and Swiss VFRs and expatriate travelers to sub-Saharan Africa and Indian Ocean Islands as most likely to exhibit febrile illnesses. German tourists to Southeast and south-central Asia were most likely to seek treatment for acute diarrhea. Non-European travelers (12,663 patients from other industrialized countries) were less likely to acquire certain travel-associated infectious diseases. These results should be considered in the practice of travel medicine and development of health recommendations for European travelers.

Chikungunya and dengue autochthonous cases in Europe, 2007–2012

A large number of autochthonous cases of dengue fever (2237) and chikungunya fever (231) occurred in Europe (Italy, France, Croatia, Madeira) during the period covered by our analysis (2007-2012). In all dengue outbreaks, the circulating strain, identified by means of molecular analysis, was the DENV-1 strain. Dengue and chikungunya are infectious diseases that often result in hospitalizations and are associated with high public health costs. The dengue epidemic on the island of Madeira resulted in 122 hospitalizations. Only one death (from chikungunya) occurred but long-term sequelae were described after the chikungunya outbreak in Emilia-Romagna, Italy. Vector control is key to reducing the impact of these diseases. During the chikungunya outbreak in Italy and the dengue outbreak in Madeira, appropriate measures for the control of mosquitoes (Aedes aegypti and Aedes albopictus) were effectively implemented. The effectiveness of these measures (reducing the number of breeding sites, application of pesticides and insecticides, public health education) was shown in the context of these real-life outbreaks. All the pre-requisites for autochthonous transmission of both dengue virus and chikungunya virus (vectors, viremic returned travellers, climatic conditions) are present in Europe. Constant surveillance is imperative.

The position of mefloquine as a 21st century malaria chemoprophylaxis.

BackgroundMalaria chemoprophylaxis prevents the occurrence of the symptoms of malaria. Travellers to high-risk Plasmodium falciparum endemic areas need an effective chemoprophylaxis.MethodsA literature search to update the status of mefloquine as a malaria chemoprophylaxis.ResultsExcept for clearly defined regions with multi-drug resistance, mefloquine is effective against the blood stages of all human malaria species, including the recently recognized fifth species, Plasmodium knowlesi. New data were found in the literature on the tolerability of mefloquine and the use of this medication by groups at high risk of malaria.DiscussionUse of mefloquine for pregnant women in the second and third trimester is sanctioned by the WHO and some authorities (CDC) allow the use of mefloquine even in the first trimester. Inadvertent pregnancy while using mefloquine is not considered grounds for pregnancy termination. Mefloquine chemoprophylaxis is allowed during breast-feeding. Studies show that mefloquine is a good option for other high-risk groups, such as long-term travellers, VFR travellers and families with small children. Despite a negative media perception, large pharmaco-epidemiological studies have shown that serious adverse events are rare. A recent US evaluation of serious events (hospitalization data) found no association between mefloquine prescriptions and serious adverse events across a wide range of outcomes including mental disorders and diseases of the nervous system. As part of an in-depth analysis of mefloquine tolerability, a potential trend for increased propensity for neuropsychiatric adverse events in women was identified in a number of published clinical studies. This trend is corroborated by several cohort studies that identified female sex and low body weight as risk factors.ConclusionThe choice of anti-malarial drug should be an evidence-based decision that considers the profile of the individual traveller and the risk of malaria. Mefloquine is an important, first-line anti-malarial drug but it is crucial for prescribers to screen medical histories and inform mefloquine users of potential adverse events. Careful prescribing and observance of contraindications are essential. For some indications, there is currently no replacement for mefloquine available or in the pipeline.

Migrants as a Major Risk Group for Imported Malaria in European Countries

Methods and Results Systematic searches of MEDLINE and available national malaria statistics were scanned to identify studies and reports showing the proportions of malaria cases occurring in nonnationals in European countries.Nonnationals were defined as being foreign born residents, which embraces various categories of migrants, including immigrants, refugees, asylum seekers, foreign workers, illegal migrants, or aliens. Only reports describing more than 250 malaria cases were included in the analysis. The period of the search was January 1991 to September 2001. A total of five MEDLINE reports2–6 were found that satisfied the inclusion criteria, and personal communication with surveillance groups provided additional information. Proportion of Nonnationals Depending on the country of origin of the report, the proportion of cases varied from 33% in the United Kingdom to 86% in a region of France, reflecting the profile of immigration in various areas at different time points. On pooling the reports, 43% of malaria cases registered in important European centers occur in nonnationals, frequently settled immigrants VFR. In Italy, where 44% of cases were related to foreigners, VFRs accounted for 72% of the cases reported in this group.2 Increasing Proportion of Nonnationals All reports describe an increasing proportion of malaria cases occurring in nonnationals. In the report describing imported malaria cases in northern Italy,4 the proportion of immigrants increased from 34% in 1991 to 59.9% in 1995 (p = .002). In the Netherlands, for the period 1979 to 1988, only 15% of cases were in persons originating in a malaria-endemic area, whereas for the period 1991 to 1994, 40% of cases were in persons from malaria-endemic areas, and 8% of cases were in children born to settled immigrants resident in the Netherlands.5 Comment Data from the aforementioned studies show that residents of foreign origin represent a growing proportion of imported cases, reflecting to some extent the increasing number of migrants in western Europe. In Britain, an older study has shown that migrants VFRs have a malaria incidence rate almost three times higher that that of tourists to Africa,7 suggesting a higher risk of exposure and/or insufficient protection measures. Although no prospective studies exist that confirm the hypothesis, migrants VFRs may be more exposed as they visit their families in rural areas with higher transmission rates and simple nonair-conditioned living conditions.Many return home during summer holidays, a period corresponding to the rainy season in West Africa or to the monsoon season in India when malaria transmission is at its peak.Many migrants VFRs mistakenly believe that they retain lifetime immunity and although immunity does wane when constant reexposure stops, some immunologic memory remains that partly explains the lower case fatality in Migrants .

Management of imported malaria in Europe

In this position paper, the European Society for Clinical Microbiology and Infectious Diseases, Study Group on Clinical Parasitology, summarizes main issues regarding the management of imported malaria cases. Malaria is a rare diagnosis in Europe, but it is a medical emergency. A travel history is the key to suspecting malaria and is mandatory in patients with fever. There are no specific clinical signs or symptoms of malaria although fever is seen in almost all non-immune patients. Migrants from malaria endemic areas may have few symptoms.Malaria diagnostics should be performed immediately on suspicion of malaria and the gold- standard is microscopy of Giemsa-stained thick and thin blood films. A Rapid Diagnostic Test (RDT) may be used as an initial screening tool, but does not replace urgent microscopy which should be done in parallel. Delays in microscopy, however, should not lead to delayed initiation of appropriate treatment. Patients diagnosed with malaria should usually be hospitalized. If outpatient management is preferred, as is the practice in some European centres, patients must usually be followed closely (at least daily) until clinical and parasitological cure. Treatment of uncomplicated Plasmodium falciparum malaria is either with oral artemisinin combination therapy (ACT) or with the combination atovaquone/proguanil. Two forms of ACT are available in Europe: artemether/lumefantrine and dihydroartemisinin/piperaquine. ACT is also effective against Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi, but these species can be treated with chloroquine. Treatment of persistent liver forms in P. vivax and P. ovale with primaquine is indicated after excluding glucose 6 phosphate dehydrogenase deficiency. There are modified schedules and drug options for the treatment of malaria in special patient groups, such as children and pregnant women. The potential for drug interactions and the role of food in the absorption of anti-malarials are important considerations in the choice of treatment.Complicated malaria is treated with intravenous artesunate resulting in a much more rapid decrease in parasite density compared to quinine. Patients treated with intravenous artesunate should be closely monitored for haemolysis for four weeks after treatment. There is a concern in some countries about the lack of artesunate produced according to Good Manufacturing Practice (GMP).