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Background: Recent studies demonstrate that rabies post-exposure prophylaxis (RPEP) in international travelers is suboptimal, with only 5-20% of travelers receiving rabies immune globulin (RIG) in the country of exposure when indicated. We hypothesized that travelers may not be receiving RIG appropriately, and practices may vary between countries. We aim to describe the characteristics of travelers who received RIG and/or RPEP during travel., Methodology/principal Findings: We conducted a multi-center review of international travelers exposed to potentially rabid animals, collecting information on RPEP administration. Travelers who started RPEP before (Group A) and at (Group B) presentation to a GeoSentinel clinic during September 2014-July 2017 were included. We included 920 travelers who started RPEP. About two-thirds of Group A travelers with an indication for rabies immunoglobulin (RIG) did not receive it. Travelers exposed in Indonesia were less likely to receive RIG in the country of exposure (relative risk: 0.30; 95% confidence interval: 0.12-0.73; P = 0.01). Travelers exposed in Thailand [Relative risk (RR) 1.38, 95% Confidence Interval (95% CI): 1.0-1.8; P = 0.02], Sri Lanka (RR 3.99, 95% CI: 3.99-11.9; P = 0.013), and the Philippines (RR 19.95, 95% CI: 2.5-157.2; P = 0.01), were more likely to receive RIG in the country of exposure., Conclusions/significance: This analysis highlights gaps in early delivery of RIG to travelers and identifies specific countries where travelers may be more or less likely to receive RIG. More detailed country-level information helps inform risk education of international travelers regarding appropriate rabies prevention., Competing Interests: The authors have declared that no competing interests exist.

Background: Zika virus (ZIKV) was first isolated in Africa; decades later, caused large outbreaks in the Pacific, and is considered endemic in Asia. We aim to describe ZIKV disease epidemiology outside the Americas, the importance of travelers as sentinels of disease transmission, and discrepancies in travel advisories from major international health organizations., Methods and Findings: This descriptive analysis using GeoSentinel Surveillance Network records involves sixty-four travel and tropical medicine clinics in 29 countries. Ill returned travelers with a confirmed or probable diagnosis of ZIKV disease acquired in Africa, Asia and the Pacific seen between 1 January 2012 and 31 December 2016 are included, and the frequencies of demographic, trip, and diagnostic characteristics described. ZIKV was acquired in Asia (18), the Pacific (10) and Africa (1). For five countries (Indonesia, Philippines, Thailand, Vietnam, Cameroon), GeoSentinel patients were sentinel markers of recent Zika activity. Additionally, the first confirmed ZIKV infection acquired in Kiribati was reported to GeoSentinel (2015), and a probable case was reported from Timor Leste (April 2016), representing the only case known to date. Review of Zika situation updates from major international health authorities for country risk classifications shows heterogeneity in ZIKV country travel advisories., Conclusions: Travelers are integral to the global spread of ZIKV, serving as sentinel markers of disease activity. Although GeoSentinel data are collected by specialized clinics and do not capture all imported cases, we show that surveillance of imported infections by returned travelers augments local surveillance system data regarding ZIKV epidemiology and can assist with risk categorization by international authorities. However, travel advisories are variable due to risk uncertainties.

We evaluated EuroTravNet (a GeoSentinel subnetwork) data from June 2013 to May 2016 on 508 ill travellers returning from Brazil, to inform a risk analysis for Europeans visiting the 2016 Olympic and Paralympic Games in Brazil. Few dengue fever cases (n = 3) and no cases of chikungunya were documented during the 2013-15 Brazilian winter months, August and September, the period when the Games will be held. The main diagnoses were dermatological (37%), gastrointestinal (30%), febrile systemic illness (29%) and respiratory (11%)., (This article is copyright of The Authors, 2016.)

Screening of 488 Syrian unaccompanied minor refugees (< 18 years-old) in Berlin showed low prevalence of intestinal parasites (Giardia, 7%), positive schistosomiasis serology (1.4%) and absence of hepatitis B. Among 44 ill adult Syrian refugees examined at GeoSentinel clinics worldwide, cutaneous leishmaniasis affected one in three patients; other noteworthy infections were active tuberculosis (11%) and chronic hepatitis B or C (9%). These data can contribute to evidence-based guidelines for infectious disease screening of Syrian refugees.

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 Pearson's 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: According to WHO, 1.5 million cases of malaria are reported annually in Pakistan. Malaria distribution in Pakistan is heterogeneous, and some areas, including Punjab, are considered at low risk for malaria. The aim of this study is to describe the trend of imported malaria cases from Pakistan reported to the international surveillance systems from 2005 to 2012., Methods: Clinics reporting malaria cases acquired after a stay in Pakistan between January 1, 2005, and December 31, 2012, were identified from the GeoSentinel (http://www.geosentinel.org) and EuroTravNet (http://www.Eurotravnet.eu) networks. Demographic and travel-related information was retrieved from the database and further information such as areas of destination within Pakistan was obtained directly from the reporting sites. Standard linear regression models were used to assess the statistical significance of the time trend., Results: From January 2005 to December 2012, a total of 63 cases of malaria acquired in Pakistan were retrieved in six countries over three continents. A statistically significant increasing trend in imported Plasmodium vivax malaria cases acquired in Pakistan, particularly for those exposed in Punjab, was observed over time (p = 0.006)., Conclusions: Our observation may herald a variation in malaria incidence in the Punjab province of Pakistan. This is in contrast with the previously described decreasing incidence of malaria in travelers to the Indian subcontinent, and with reports that describe Punjab as a low risk area for malaria. Nevertheless, this event is considered plausible by international organizations. This has potential implications for changes in chemoprophylaxis options and reinforces the need for increased surveillance, also considering the risk of introduction of autochthonous P. vivax malaria in areas where competent vectors are present, such as Europe., (© 2014 International Society of Travel Medicine.)

Background: Limited data exist on infectious diseases imported to various locations in Europe, particularly after travel within the continent., Methods: To investigate travel-related disease relevant to Europe that is potentially preventable through pre-travel intervention, we analyzed the EuroTravNet database of 5,965 ill travelers reported by 16 centers in "Western" Europe in 2011., Results: There were 54 cases of vaccine-preventable disease, mostly hepatitis A (n = 16), typhoid fever (n = 11), and measles (n = 8); 6 cases (including 3 measles cases) were associated with travel within "Western" Europe. Malaria was the most commonly diagnosed infection (n = 482, 8.1% of all travel-related morbidity). Among patients with malaria, the military most commonly received pre-travel advice (95%), followed by travelers for missionary, volunteer, research, or aid work (81%) but travelers visiting friends and relatives (VFRs) were least likely to receive pre-travel advice (21%). The vast majority (96%) of malaria patients were resident in "Western" Europe, but over half (56%) were born elsewhere. Other significant causes of morbidity, which could be reduced through advice and behavioral change, include Giardia (n = 221, 3.7%), dengue (n = 146, 2.4%), and schistosomiasis (n = 131, 2.2%). Of 206 (3.5%) travelers with exposure in "Western" Europe, 75% were tourists; the highest burden of disease was acute gastrointestinal infection (35% cases). Travel from "Eastern" Europe (n = 132, 2.2%) was largely associated with migration-related travel (53%); among chronic infectious diseases, tuberculosis was frequently diagnosed (n = 20). Travelers VFRs contributed the largest group of malaria patients (46%), but also had the lowest documented rate of pre-travel health advice in this subset (20%). Overall, 44% of nonimmigrant ill travelers did not receive pre-travel advice., Conclusion: There is a burden of infectious diseases in travelers attending European health centers that is potentially preventable through comprehensive pre-travel advice, chemoprophylaxis, and vaccination. Targeted interventions for high-risk groups such as travelers VFRs and migration-associated travelers are of particular importance., (© 2014 International Society of Travel Medicine.)

Background: Brazil will host the 2014 FIFA World Cup and the 2016 Olympic and Paralympic Games, events that are expected to attract hundreds of thousands of international travelers. Travelers to Brazil will encounter locally endemic infections as well as mass event-specific risks., Methods: We describe 1586 ill returned travelers who had visited Brazil and were seen at a GeoSentinel Clinic from July 1997 through May 2013., Results: The most common travel-related illnesses were dermatologic conditions (40%), diarrheal syndromes (25%), and febrile systemic illness (19%). The most common specific dermatologic diagnoses were cutaneous larva migrans, myiasis, and tungiasis. Dengue and malaria, predominantly Plasmodium vivax, were the most frequently identified specific causes of fever and the most common reasons for hospitalization after travel. Dengue fever diagnoses displayed marked seasonality, although cases were seen throughout the year. Among the 28 ill returned travelers with human immunodeficiency virus (HIV) infection, 11 had newly diagnosed asymptomatic infection and 9 had acute symptomatic HIV., Conclusions: Our analysis primarily identified infectious diseases among travelers to Brazil. Knowledge of illness in travelers returning from Brazil can assist clinicians to advise prospective travelers and guide pretravel preparation, including itinerary-tailored advice, vaccines, and chemoprophylaxis; it can also help to focus posttravel evaluation of ill returned travelers. Travelers planning to attend mass events will encounter other risks that are not captured in our surveillance network.

Background: Leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania. Clinical manifestations of leishmaniasis include cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). About 90% of cases occur in the tropics or subtropics but the disease is also endemic in the Mediterranean area. No systematic analysis on leishmaniasis in travellers visiting endemic areas in Europe is available., Methods: Within the European travel medicine network EuroTravNet, we performed a retrospective analysis in travellers who acquired leishmaniasis within Europe diagnosed between 2000 and 2012., Results: Forty cases of leishmaniasis (30 CL and 10 VL) were identified; the majority were acquired in Spain (n = 20, 50%), Malta and Italy (each n = 7, 18%). Median age was 48 years (range 1-79). Three of eight (37.5%) of the VL patients were on immunosuppressive therapy. The most frequent reason for travel was tourism (83%). Median duration of travel for patients with CL and VL was 2 weeks with ranges of 1-21 weeks in CL and 1-67 weeks in VL, respectively (P = 0.03)., Conclusions: Health professionals should include leishmaniasis in the differential diagnosis in patients returning from southern Europe - including short-term travellers - with typical skin lesions or systemic alterations like fever, hepatosplenomegaly and pancytopenia., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Based on their essential role in concerting immunological and inflammatory responses we hypothesized that the homeostatic chemokines CCL19 and CCL21 may play a pathogenic role in rickettsiae infection., Methods: Serum levels of CCL19 and CCL21 in patients with R. africae and R. conorii infection were analyzed by enzyme immunoassays. Lungs from R. conorii infected mice were examined for CCL19, CCL21 and CCR7 expression by immunohistochemistry., Results: We found that patients with R. africae infection (n = 15) and in particular those with R. conorii infection (n = 16) had elevated serum levels of CCL19 on admission, with a decline during follow-up. While a similar pattern was seen for CCL21 in R. africae infection, patients with R. conorii infection showed persistently increased CCL21 levels during follow-up. In experimental R. conorii infection, we found strong immunostaining of CCL19 and CCL21 in the lungs, particularly in individuals that had received lethal doses. Immunofluorescence showed co-localization of CCR7 to endothelial cells, macrophages and fibroblasts within the lung tissue of R. conorii infected mice., Conclusions: Our findings suggest that the CCL19/CCL21/CCR7 axis is up-regulated during R. africae and in particular during R. conorii infection, which may potentially contribute to the pathogenesis of these disorders.

We performed a descriptive analysis of acute and potentially life-threatening tropical diseases among 82,825 ill western travelers reported to GeoSentinel from June of 1996 to August of 2011. We identified 3,655 patients (4.4%) with a total of 3,666 diagnoses representing 13 diseases, including falciparum malaria (76.9%), enteric fever (18.1%), and leptospirosis (2.4%). Ninety-one percent of the patients had fever; the median time from travel to presentation was 16 days. Thirteen (0.4%) patients died: 10 with falciparum malaria, 2 with melioidosis, and 1 with severe dengue. Falciparum malaria was mainly acquired in West Africa, and enteric fever was largely contracted on the Indian subcontinent; leptospirosis, scrub typhus, and murine typhus were principally acquired in Southeast Asia. Western physicians seeing febrile and recently returned travelers from the tropics need to consider a wide profile of potentially life-threatening tropical illnesses, with a specific focus on the most likely diseases described in our large case series.

Background: Acute schistosomiasis constitutes a rare but serious condition in individuals experiencing their first prepatent Schistosoma infection. To circumvent costly and time-consuming diagnostics, an early and rapid diagnosis is required. So far, classic diagnostic tools such as parasite microscopy or serology lack considerable sensitivity at this early stage of Schistosoma infection. To validate the use of a blood based real-time polymerase chain reaction (PCR) test for the detection of Schistosoma DNA in patients with acute schistosomiasis who acquired their infection in various endemic regions we conducted a European-wide prospective study in 11 centres specialized in travel medicine and tropical medicine., Methods: Patients with a history of recent travelling to schistosomiasis endemic regions and freshwater contacts, an episode of fever (body temperature ≥38.5°C) and an absolute or relative eosinophil count of ≥700/μl or 10%, were eligible for participation. PCR testing with DNA extracted from serum was compared with results from serology and microscopy., Results: Of the 38 patients with acute schistosomiasis included into the study, PCR detected Schistosoma DNA in 35 patients at initial presentation (sensitivity 92%). In contrast, sensitivity of serology (enzyme immunoassay and/or immunofluorescence assay) or parasite microscopy was only 70% and 24%, respectively., Conclusion: For the early diagnosis of acute schistosomiasis, real-time PCR for the detection of schistosoma DNA in serum is more sensitive than classic diagnostic tools such as serology or microscopy, irrespective of the region of infection. Generalization of the results to all Schistosoma species may be difficult as in the study presented here only eggs of S. mansoni were detected by microscopy. A minimum amount of two millilitre of serum is required for sufficient diagnostic accuracy.

To investigate trends in travel-associated morbidity with particular emphasis on emerging infections with the potential for introduction into Europe, diagnoses of 7,408 returning travellers presenting to 16 EuroTravNet sites in 2010 were compared with 2008 and 2009. A significant increase in reported Plasmodium falciparum malaria (n=361 (6% of all travel-related morbidity) vs. n=254 (4%) and 260 (5%); p<0.001), P. vivax malaria (n=51 (1%) vs. n=31 (0.5%) and 38 (1%); p=0.027) and dengue fever (n=299 (5%) vs. n=127 (2%) and 127 (2%); p<0.001) was observed. Giardia lamblia was identified in 16% of patients with acute diarrhoea, with no significant annual variation. The proportion of acute diarrhoea due to Campylobacter increased from 7% in 2008 to 12% in 2010 (p=0.001). We recorded 121 patients with pulmonary tuberculosis in 2010, a threefold increase in the proportionate morbidity from 2008 to 2010. In 2010, 60 (0.8%) cases of chronic Chagas disease, 151 (2%) cases of schistosomiasis and 112 (2%) cases of cutaneous larva migrans were reported. Illness patterns in sentinel travellers, captured by EuroTravnet, continue to highlight the potential role of travellers in the emergence of infectious diseases of public health concern in Europe and the relevance of offering medical travel advice and enforcing specific and adequate prophylaxis.

Background: Europeans represent the majority of international travellers and clinicians encountering returned patients have an essential role in recognizing, and communicating travel-associated public health risks., Methods: To 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., Results: Gastro-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., Conclusions: In 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.

Using the GeoSentinel database, an analysis of ill patients returning from throughout sub-Saharan Africa over a 13-year period was performed. Systemic febrile illness, dermatologic, and acute diarrheal illness were the most common syndromic groupings, whereas spotted fever group rickettsiosis was the most common individual diagnosis for travelers to South Africa. In contrast to the rest of sub-Saharan Africa, only six cases of malaria were documented in South Africa travelers. Vaccine-preventable diseases, typhoid, hepatitis A, and potential rabies exposures were uncommon in South Africa travelers. Pre-travel advice for the travelers to the 2010 World Cup should be individualized according to these findings.

We investigated epidemiologic and clinical aspects of rickettsial diseases in 280 international travelers reported to the GeoSentinel surveillance Network during 1996-2008. Of these 280 travelers, 231 (82.5%) had spotted fever (SFG) rickettsiosis, 16 (5.7%) scrub typhus, 11 (3.9%) Q fever, 10 (3.6%) typhus group (TG) rickettsiosis, 7 (2.5%) bartonellosis, 4 (1.4%) indeterminable SFG/TG rickettsiosis, and 1 (0.4%) human granulocytic anaplasmosis. One hundred ninety-seven (87.6%) SFG rickettsiosis cases were acquired in sub-Saharan Africa and were associated with higher age, male gender, travel to southern Africa, late summer season travel, and travel for tourism. More than 90% of patients with rickettsial disease were treated with doxycycline, 43 (15.4%) were hospitalized, and 4 had a complicated course, including 1 fatal case of scrub typhus encephalitis acquired in Thailand.

Objectives: Mediterranean spotted fever (MSF) caused by Rickettsia conorii (R. conorii) is a potential lethal disease while African tick bite fever (ATBF) caused by Rickettsia africae is a self-limiting flu-like illness. We hypothesized that different inflammatory potential in endothelial cells could contribute to the different clinical features in these rickettsioses., Methods: We analyzed the effect of heat-inactivated R. africae and R. conorii on the mRNA and protein levels of monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8 and adhesion molecules in endothelial cells. Serum samples from patients with MSF (n=16) and ATBF (n=15) were collected before and after therapy., Results: R. conorii induced a marked increase in MCP-1, IL-8, and adhesion molecules in endothelial cells, involving toll-like receptor 4 activation. In contrast, R. africae induced MCP-1 expression, but only modest or no responses were seen on IL-8 and adhesion molecules. Comparable to the in vitro response, levels of IL-8 and adhesion molecules showed no or only a modest increase in ATBF patients while these inflammatory markers were markedly elevated during MSF., Conclusions: Our findings suggest a superior inflammatory potential of R. conorii as compared to R. africae in endothelial cells, potentially related to the more severe inflammation in MSF comparing ATBF.

In the field of tick-borne rickettsioses, discussion is ongoing about new vectors and the geographic zones of the diseases. New Rickettsia spp. that cannot yet be linked to human disease are sometimes detected in arthropods. In Africa, in addition to R. conorii and R. africae, seven distinct species of tick-borne rickettsiae are considered to be human pathogens. A combination of clinical alertness and molecular tools such as PCR base detection of DNA and sequencing help to describe new diseases.

In this paper, a supervised neural network training technique based on constrained optimization is developed for preserving prior knowledge of an input-output mapping during repeated incremental training sessions. The prior knowledge, referred to as long-term memory (LTM), is expressed in the form of equality constraints obtained by means of an algebraic training technique. Incremental training, which may be used to learn new short-term memories (STMs) online, is then formulated as an error minimization problem subject to equality constraints. The solution of this problem is simplified by implementing an adjoined error gradient that circumvents direct substitution and exploits classical backpropagation. A target application is neural network function approximation in adaptive critic designs. For illustrative purposes, constrained training is implemented to update an adaptive critic flight controller, while preserving prior knowledge of an established performance baseline that consists of classical gain-scheduled controllers. It is shown both analytically and numerically that the LTM is accurately preserved while the controller is repeatedly trained over time to assimilate new STMs.

Hookworm-related cutaneous larva migrans is a common dermatosis in travellers to the tropics and typically presents as one or a few migrating serpiginous lesions on the lower extremities or buttocks. We present two Norwegian holidaymakers who developed extensive disease after returning from Brazil and Tanzania, respectively. Both patients responded to the treatment with ivermectin.

We present a Norwegian female in her thirties who acquired dengue fever caused by dengue virus serotype 2 while travelling to Mexico. When hospitalised 3 days after symptom onset, the patient had severe headache, fever, rash and a positive tourniquet test, but did not fulfil the criteria of dengue haemorrhagic fever (DHF). Five days later she developed a fatal subarachnoidal haemorrhage. A post-mortem examination failed to reveal any intracranial arterial aneurysm. Our case was consistent with so called 'dengue fever with haemorrhages', a recently described entity that mainly affects adults and may cause severe bleedings also in the absence of DHF.

The pathophysiological hallmark of spotted fever group rickettsioses comprises infection of endothelial cells with subsequent infiltration of inflammatory cells. Based on its ability to promote inflammation and endothelial cell activation, we investigated the role of CD40L in African tick bite fever (ATBF), caused by Rickettsia africae, using different experimental approaches. Several significant findings were revealed. 1) Patients with ATBF (n = 15) had increased serum levels of soluble CD40 ligand (sCD40L), which decreased during follow-up. 2) These enhanced sCD40L levels seem to reflect both direct and indirect (through endothelial cell activation involving CX3CL1-related mechanisms) effects of R. africae on platelets. 3) In combination with sCD40L, R. africae promoted a procoagulant state in endothelial cells by up-regulating tissue factor and down-regulating thrombomodulin expression. 4) Although the R. africae-mediated activation of platelets involved TLR2, the combined procoagulant effects of R. africae and sCD40L on endothelial cells involved TLR4. 5) Doxycycline counteracted the combined procoagulant effects of R. africae and sCD40L on endothelial cells. Our findings suggest an inflammatory interaction between platelets and endothelial cells in ATBF, involving TLR-related mechanisms. This interaction, which includes additive effects between sCD40L and R. africae, may contribute to endothelial inflammation and hypercoagulation in this disorder.

Introduction: To avoid the use of unnecessary broad-spectrum antibiotics, empirical therapy of bacteraemia should be adjusted according to the results of blood cultures., Objectives: To investigate whether the results of blood cultures led to changes in antibiotic use and costs in a tertiary-care university hospital in Norway., Methods: Medical records from all patients with positive blood cultures in 2001 were analysed retrospectively. Factors predisposing to infections, results of blood cultures, antibiotic use and outcome were recorded. The influence of blood culture results on antibiotic treatment and costs were analysed., Results: The antibiotic use in 226 episodes of bacteraemia in 214 patients was analysed. According to the guidelines empirical antibiotic treatment should be adjusted in 166 episodes. Antibiotic use was adjusted in 146 (88%) of these 166 episodes, which led to a narrowing of therapy in 118 (80%) episodes. Compared with empirical therapy there was a 22% reduction in the number of antibiotics. Adjustment of therapy was more often performed in Gram-negative bacteraemia and polymicrobial cultures than in Gram-positive bacteraemia. In bacteraemia caused by ampicillin-resistant Escherichia coli, ampicillin was mostly replaced by ciprofloxacin. The cost for 7 days adjusted therapy in 146 episodes was euro19,800 (23%) less than for 7 days of empirical therapy., Conclusions: Adjustment of antibiotic therapy according to the results of blood cultures led to a reduction in the number of antibiotics and a narrowing of antibiotic therapy. The costs for antibiotics decreased.

We present the first 3 cases of confirmed scrub typhus imported to Scandinavia. The patients were infected in Thailand, Laos and Sri Lanka, respectively. Treatment with ciprofloxacin and doxycycline lead to rapid cure in 2 of the patients, while the third patient, who was not treated, had a prolonged convalescence. Specific antibodies against Orientia tsutsugamushi, the causative agent of scrub typhus, were detected in all 3 cases.

African tick bite fever (ATBF) caused by Rickettsia africae is an emerging health problem in travellers to sub-Saharan Africa. We here present 6 patients with evidence of long-lasting sub-acute neuropathy following ATBF contracted during safari trips to southern Africa. Three patients developed radiating pain, paresthaesia and/or motor weakness of extremities, 2 had hemi-facial pain and paresthaesia, and 1 developed unilateral sensorineural hearing loss. When evaluated 3-26 months after symptom onset, cerebrospinal fluid samples from 5 patients were negative for R. africae PCR and serology, but revealed elevated protein content in 3 and mild pleocytosis in 1 case. Despite extensive investigations, no plausible alternative causes of neuropathy could be identified. Treatment with doxycycline in 2 patients had no clinical effect. Given the current increase of international safari tourism to sub-Saharan Africa, more cases of sub-acute neuropathy following ATBF may well be encountered in Europe and elsewhere in the y to come.

To date, 14 tick-borne diseases have been reported in international travellers, the majority of cases being Lyme borreliosis caused by Borrelia burgdorferi sensu lato in North America and Eurasia, African tick bite fever caused by Rickettsia africae in sub-Saharan Africa and eastern Caribbean, and Central European encephalitis caused by tick-borne encephalitis virus in Europe. The clinical presentation is frequently non-specific, and tick-borne diseases should always, in the absence of other likely diagnoses, be suspected in travellers with flu-like symptoms following a recent visit to tick-infested areas. Feasible microbiological diagnostic tests are widely unavailable, at least outside areas of endemicity where many infected travellers present. Empiric treatment with doxycycline should be considered in suspected cases of tick-borne bacterial diseases. Since ecotourism and adventure travel are increasingly popular worldwide, the incidence of travel-associated tick-borne diseases is likely to increase in the future.

African tick bite fever, caused by Rickettsia africae, is an emerging zoonotic infection in rural sub-Saharan Africa and the French West Indies. We tested the repellent efficacy of four commercial diethyl-3-methylbenzamide (DEET) lotions against Amblyomma hebraeum Koch, the principal vector of R. africae in southern Africa, by using a human bioassay in which repellent-treated fingers were presented to questing tick nymphs hourly for 4h. Three lotions with 19.5, 31.6 and 80% DEET concentrations, respectively, had a repellent efficacy of > or =90% at 1h post-application, of > or =77% at 2h post-application and of <70% during the rest of the experiment. By contrast, a lotion with 2% DEET plus 1% citronella oil provided only a 59% repellency at 1h post-application, with a drop to <22% during the following hours. Hourly negative control trials repelled <5% of tick attacks. Our results suggest that commercial repellents containing > or =19.5% DEET provide a significant but short-lasting protection against questing A. hebraeum ticks.

We report 3 cases of fascioliasis imported to Norway: a 24-y-old male Vietnamese immigrant and a 51-y-old female Vietnamese immigrant with acute fascioliasis, and a 2-y-old male Ethiopian adoptee with chronic fascioliasis. Diagnosis was confirmed by detection of specific antibodies to Fasciola hepatica in the 2 first cases and by demonstration of Fasciola hepatica eggs in stool samples in the latter case. Treatment with oral triclabendazole led to prompt cure in all 3 patients. Imported fascioliasis is rarely reported but should be suspected in patients with a travel history to endemic areas, abdominal symptoms and hypereosinophilia of the blood.

The rickettsioses--zoonotic bacterial infections transmitted to humans by arthropods--were for many years considered to be oddities in travel medicine. During the previous 2 decades, however, reports of >450 travel-associated cases have been published worldwide, the vast majority being murine typhus caused by Rickettsia typhi, Mediterranean spotted fever caused by Rickettsia conorii, African tick bite fever caused by Rickettsia africae, and scrub typhus caused by Orientia tsutsugamushi. Most patients present with a benign febrile illness accompanied by headache, myalgia, and cutaneous eruptions, but severe complications and fatalities are occasionally seen. Current microbiological tests include culture, polymerase chain reaction, and serological analysis, of which only the latter method is widely available. Tetracyclines are the drugs of first choice and should be prescribed whenever a case of rickettsiosis is suspected. Preventive measures rely on minimizing the risk of arthropod bites when traveling in areas of endemicity.

Purpose of Review: Recent developments in cell-culture techniques and molecular methods have led to the description of several new rickettsial diseases. An update on these new infections should be of interest to health workers with patients who are international travellers., Recent Findings: Epidemic typhus was reported last year in the United States when an outbreak of murine typhus was recorded in Hawaii. Among spotted fever group rickettsioses, African tick bite fever is now probably the most common rickettsial infection in Africa with numerous cases also reported in international travellers. For the first time the Astrakhan fever rickettsia has been described outside Europe, in a French patient returning from Chad. Similarly, the first case of Rickettsia sibirica mongolotimonae infection in Africa was reported in 2004. Finally, a newly recognized agent of a spotted fever rickettsiosis, Rickettsia parkeri, has been reported in the United States during 2004., Summary: Because results of serological testing are only presumptive, sophisticated methods are crucial for the diagnosis and description of new rickettsial diseases, especially in atypical cases. Modern diagnostic tools include cross-adsorption assays, Western blot testing, and cell-culture and molecular-biological methods.

Until very recently, Mediterranean spotted fever caused by Rickettsia conorii was the only spotted fever group (SFG) rickettsioses recognized in southern Africa. However, increasing medical awareness of tick-borne infections, together with the introduction of improved isolation methods and the availability of molecular techniques, have led to the identification of several new SFG rickettsioses in the region. African tick bite fever, caused by Rickettsia africae, is currently the most important of these new rickettsioses, affecting large numbers of international travellers each year, but infections due to Rickettsia aeschlimannii and Rickettsia mongolotimonae have also been recently encountered. In this review, we describe the current status of the epidemiology, microbiology, clinical presentation, diagnosis, treatment, and prevention of SFG rickettsioses in southern Africa.

In testing paired serum samples from 40 consecutive cases of African tick bite fever, we detected diagnostic antibodies against spotted fever group rickettsiae in 45% of the patients by immunofluorescence assay (IFA) and in 100% of the patients by Western blotting (WB) (P < 0.01). A specific diagnosis of Rickettsia africae infection could be established in 15% of the patients by IFA and in 73% of the patients by a combination of WB and cross-adsorption assays (P < 0.01).

Background: Tick-borne rickettsioses are of emerging importance in today's travel medicine but have until recently received little attention. We describe the current knowledge of tick-borne rickettsioses as they relate to international travel, their microbiological diagnosis, treatment, possible prevention, and future prospects., Methods: Literature-based review and personal observations., Results: During the last decade, some 400 cases of tick-borne rickettsioses have been reported in international travellers, the vast majority being African tick bite fever caused by Rickettsia africae and Mediterranean spotted fever caused by Rickettsia conorii. Only a minority of infected travellers can recall a preceding tick bite. Most patients present with a mild-to-moderately severe flu-like illness typically accompanied by a cutaneous rash and an inoculation eschar at the site of the tick bite, but potentially life-threatening disease with disseminated vaculitis is occasionally seen. Definite microbiological confirmation of tick-borne rickettsioses by isolation or antigen detection is only available at reference laboratories and diagnosis must in most cases rely on clinical and epidemiological data supported by serology. Doxycycline is the recommended treatment for tick-borne rickettsioses and prevention is based on personal protective measures against tick bites when travelling in endemic areas., Conclusion: Tick-borne rickettsiosis should be suspected in febrile returnees from endemic areas, especially in cases with skin eruptions. Travellers to endemic areas should be encouraged to use personal protective measures against tick bites.

African tick bite fever is an acute febrile illness that is frequently accompanied by headache, prominent neck muscle myalgia, inoculation eschars, and regional lymphadenitis. The disease is caused by Rickettsia africae, a recently identified spotted fever group rickettsia, which is transmitted by ungulate ticks of the Amblyomma genus in rural sub-Saharan Africa and the French West Indies. Whereas reports on African tick bite fever in indigenous populations are scarce, the number of reported cases in travellers from Europe and elsewhere has recently increased significantly. Treatment with doxycycline is associated with rapid recovery in most patients. An immunofluorescence assay is recommended for the diagnosis but seroconversion is commonly delayed and this limits the usefulness of the test. Travellers to endemic areas should be informed of the risk of contracting African tick bite fever and be encouraged to take personal protective measures against tick bites.

To estimate the incidence of, identify risk factors for, and describe the clinical presentation of travel-associated African tick bite fever (ATBF), a rapidly emerging disease in travel medicine, we prospectively studied a cohort of 940 travelers to rural sub-Equatorial Africa. Diagnosis was based on suicide polymerase chain reaction and the detection of specific antibodies to Rickettia africae in serum samples by multiple-antigen microimmunofluorescence assay, Western blotting, and cross-adsorption assays. Thirty-eight travelers, 4.0% of the cohort and 26.6% of those reporting flulike symptoms, had ATBF diagnosed. More than 80% of the patients had fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis, cutaneous rash, and aphthous stomatitis were seen in < or = 50% of patients. Game hunting, travel to southern Africa, and travel during November through April were found to be independent risk factors. Our study suggests that ATBF is not uncommon in travelers to rural sub-Saharan Africa and that many cases have a nonspecific presentation.

Information regarding the inflammatory response in African tick-bite fever (ATBF), an emerging spotted-fever-group rickettsiosis, in international travelers to sub-Saharan Africa, is scarce. Plasma/serum levels of von Willebrand factor (vWF), soluble (s) E-selectin, tumor necrosis factor-alpha, interleukin (IL)-6, interferon-gamma, IL-10, IL-13, IL-8, RANTES, macrophage inflammatory protein-1alpha, and C-reactive protein were studied, at both first presentation and follow-up, in 15 patients with travel-associated ATBF and in 14 healthy travelers who served as control subjects. Our main and novel findings are the following: (1) patients with ATBF had increased levels of vWF and sE-selectin, with a subsequent decrease at follow-up; (2) with the exception of IFN-gamma, levels of cytokines and chemokines were also increased in these patients at the first presentation; and (3) IL-10 and IL-13 tended to increase during follow-up, whereas most of the inflammatory cytokines decreased. The induction of these mediators and the balance between them may be critical both for the regulation of inflammation and for protective immunity in ATBF.

The bont tick, Amblyomma hebraeum Koch, is the principal vector of Rickettsia africae, the agent of African tick bite fever, in southern Africa. In contrast to most other hard ticks, members of the genus Amblyomma exhibit a characteristic attack host-seeking behavior. The efficacy of topically applied 20% lotions of DEET (diethyl-3-methylbenzamide), the currently considered reference repellent substance, and KBR 3023, a recently developed piperidine compound, was evaluated against laboratory-reared A. hebraeum nymphs on treated fingers. Both substances repelled >85% of nymph attacks at 0 and 1 h postapplication. At 2, 3, and 4 h, the repellent efficacies of DEET were 84%, 68% and 71%, whereas those of KBR 3023 were 56, 55, and 54%. The observed differences between the two test substances were statistically significant only at 2 h postapplication. This first study of topical repellents against A. hebraeum suggests that 20% lotions of DEET and KBR 3023 are effective for 2 and 1 h, respectively, but that the repellent efficacies decrease thereafter.

African tick-bite fever, caused by Rickettsia africae, is the most common tick-borne rickettsiosis in sub-Saharan Africa. Mediterranean spotted fever due to Rickettsia conorii also occurs in the region but is more prevalent in Mediterranean countries. Using microimmunofluorescence, we compared the development of immunoglobulin G (IgG) and IgM titers in 48 patients with African tick-bite fever and 48 patients with Mediterranean spotted fever. Doxycycline treatment within 7 days from the onset of disease significantly prevented the development of antibodies to R. africae. In patients with African tick-bite fever, the median times to seroconversion with IgG and IgM were 28 and 25 days, respectively, after the onset of symptoms. These were significantly longer by a median of 6 days for IgG and 9 days for IgM than the times for seroconversion in patients with Mediterranean spotted fever (P < 10(-2)). We recommend that sera collected 4 weeks after the onset of signs of patients with suspected African tick-bite fever should be used for the definitive serological diagnosis of R. africae infections.

Rickettsia africae is the causative agent of African tick bite fever (ATBF), an acute febrile illness frequently accompanied by inoculation eschars, regional lymphadenitis, myalgia and severe headache. Recently, ATBF has been recognized as an emerging health problem for international travellers to rural sub-Saharan Africa. To estimate the incidence, risk factors for and proportion of symptomatic cases of travel-associated R. africae infection, we performed a seroepidemiological study of 152 first-time Norwegian travellers to rural areas in sub-Equatorial Africa. Seropositivity was based on the detection of specific antibodies to R. africae in microimmunofluorescence and/or Western blotting assays. Thirteen (8.6%) travellers were seropositive to R. africae. Eight (62%) seropositive travellers reported symptoms consistent with ATBF; of these, 2 had received antirickettsial therapy. Using multiple logistic regression, the following factors were found to be significantly associated with seropositivity: hunting as the purpose of travel [odds ratio (OR) 10.1; 95% confidence interval (CI) 1.5-69; p=0.019] and stay in rural areas of > 7 d (OR 6.0; 95% CI 1.5-24; p=0.012). This first seroepidemiological study on travel-associated R. africae infection suggests that the infection may be common in international travellers to rural sub-Saharan Africa but that most cases are asymptomatic or clinically mild and self-limited.

Background: Imported falciparum malaria in an increasingly frequent health problem in many areas in which it is not endemic. Complications are commonly seen, and reported case-fatality rates may exceed 3%., Material and Methods: The study is a medical chart-based retrospective study of all cases of falciparum malaria diagnosed in Oslo and Akershus counties, south-eastern Norway, 1988-1997., Results: We identified 232 diagnosed cases; of these, records were available for 222 cases (95%). The incidence rate almost quadrupled during the study period. The two largest groups were immigrants visiting their country of origin (35%) and Norwegian tourists (29%). 95% of the cases were infected in Sub-Saharan Africa. There were no fatal cases, and only eight cases (3.6%) developed complicated falciparum malaria. In a statistical analysis, the following factors were found to be significantly associated with complicated disease: higher age, noncompliance to recommended chemoprophylaxis in assumed non-immune subjects, prolonged doctor's delay and prolonged diagnostic delay., Interpretation: The study suggests that complications in imported falciparum malaria may largely be prevented by a high rate of chemoprophylaxis compliance in non-immune travellers and a high awareness of this possibility among physicians evaluating febrile travellers from endemic areas.

We describe a case of culture-proven Brucella spondylitis in a 28-y-old Turkish male asylum seeker who had arrived to Norway 6 months earlier. Several diagnostic difficulties, including rapid in vitro growth and misidentification of the causative microorganism in biochemical gallery strip tests, resulted in late diagnosis.

Invasive infections caused by bacteria and fungi are common complications of intravenous drug abuse. Various vital organs and structures may be affected, e.g. the cardiac valves, the larger arteries, the bones, the joints and the central nervous system. However, due to the high frequency of low-virulent microbes of skin and oral origin, the clinical picture may be atypical with subacute course and few focal signs and symptoms. The complexity of this problem is illustrated by eight cases of serious bacterial and fungal infections recently diagnosed at our hospitals. All patients were HIV negative intravenous heroin addicts. The clinical spectrum was wide and included skin abscesses, pyomyositis, spondylodiscitis, septic arthritis, costal osteomyelitis, infective endocarditis, recurrent bacteraemia, and multiple brain abscesses.

We performed a retrospective study of 222 cases of falciparum malaria diagnosed in Oslo and Akerhus counties, Norway, from January 1988 to December 1997. Except for 12 cases, all had acquired the disease in sub-Saharan Africa. Sixty-four (28.8%) cases occurred in assumed non-immune individuals; of these, 41 (64.1%) were compliant to recommended antimalarial chemoprophylaxis. The mean time lag from first symptom to diagnosis (total diagnosis delay) was 4.6 d (median 3 d, range 0-30 d) and the mean time from presentation to diagnosis (doctor's delay) was 1.3 d (median 0 d, range 0-25 d). There were no fatal cases, and only 8 (3.6%) had a complicated course. The following factors were significantly associated with development of complicated disease: higher age, non-immunity combined with chemoprophylaxis non-compliance, prolonged doctor's delay and prolonged total diagnosis delay (p < or = 0.05). Our data suggest that complicated disease in imported falciparum malaria may largely be prevented by high chemoprophylaxis compliance rates in non-immune travellers and a high index of suspicion in physicians evaluating febrile travellers.

We report on 8 Norwegian travellers to Southern Africa with African tick-bite fever (ATBF), a recently described spotted fever group rickettsiosis. All patients had acute flu-like symptoms and developed I or multiple inoculation eschars. The patients were treated with either doxycycline or ciprofloxacin, and all recovered. The diagnosis of ATBF was confirmed by the detection of specific IgM antibodies to Rickettsia africae by microimmunofluoroscence in convalescent-phase serum samples.

Tick-borne rickettsioses are important zoonoses in many tropical and subtropical areas. There has recently been an increase in the number of reported cases among tourists returning to Scandinavia. In this article we present all five serologically confirmed cases of tick-borne rickettsioses imported into Norway in 1997. The patients were Norwegian tourists who had visited South Africa (three cases), Zimbabwe, and Italy. Four cases had typical eschar and three had maculopapular exanthema. The patients were treated with either doxycycline or ciprofloxacin. No complications were reported. The diagnosis of tick-borne rickettsiosis was confirmed by the detection of specific IgM antibodies to Rickettsia conorii using micro-immunofluorescence in serum samples.