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Background: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)–piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. Methods: Participants were recruited through Health Care Provider’s safety registry in 15 centres across 6 European countries in the period 2013–2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett’s (QTcB) or Fridericia’s (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. Results: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). Conclusions: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Disease epidemiology of (re-)emerging infectious diseases is changing rapidly, rendering surveillance of travel-associated illness important. Methods We evaluated travel-related illness encountered at EuroTravNet clinics, the European surveillance sub-network of GeoSentinel, between March 1, 1998 and March 31, 2018. Findings 103,739 ill travellers were evaluated, including 11,239 (10.8%) migrants, 89,620 (86.4%) patients seen post-travel, and 2,880 (2.8%) during and after travel. Despite increasing numbers of patient encounters over 20 years, the regions of exposure by year of clinic visits have remained stable. In 5-year increments, greater proportions of patients were migrants or visiting friends and relatives (VFR); business travel-associated illness remained stable; tourism-related illness decreased. Falciparum malaria was amongst the most-frequently diagnosed illnesses with 5,254 cases (5.1% of all patients) and the most-frequent cause of death (risk ratio versus all other illnesses 2.5:1). Animal exposures requiring rabies post-exposure prophylaxis increased from 0.7% (1998-2002) to 3.6% (2013-2018). The proportion of patients with seasonal influenza increased from zero in 1998-2002 to 0.9% in 2013-2018. There were 44 cases of viral haemorrhagic fever, most during the past five years. Arboviral infection numbers increased significantly as did the range of presenting arboviral diseases, Dengue and chikungunya diagnoses increased by 2.6% and 1%, respectively. Interpretation Travel medicine must adapt to serve the changing profile of travellers, with an increase in migrants and persons visiting relatives and friends and the strong emergence of vector-borne diseases, with potential for further local transmission in Europe. Funding This project was supported by a cooperative agreement (U50CK00189) between the Centers for Disease Control and Prevention to the International Society of Travel Medicine (ISTM) and funding from the ISTM and the Public Health Agency of Canada.

Leptospirosis is a potentially fatal emerging zoonosis with worldwide distribution and a broad range of clinical presentations and exposure risks. It typically affects vulnerable populations in (sub)tropical countries but is increasingly reported in travelers as well. Diagnostic methods are cumbersome and require further improvement. Here, we describe leptospirosis among travelers presenting to the GeoSentinel Global Surveillance Network. We performed a descriptive analysis of leptospirosis cases reported in GeoSentinel from January 1997 through December 2016. We included 180 travelers with leptospirosis (mostly male; 74%; mostly tourists; 81%). The most frequent region of infection was Southeast Asia (52%); the most common source countries were Thailand (N = 52), Costa Rica (N = 13), Indonesia, and Laos (N = 11 each). Fifty-nine percent were hospitalized; one fatality was reported. We also distributed a supplemental survey to GeoSentinel sites to assess clinical and diagnostic practices. Of 56 GeoSentinel sites, three-quarters responded to the survey. Leptospirosis was reported to have been most frequently considered in febrile travelers with hepatic and renal abnormalities and a history of freshwater exposure. Serology was the most commonly used diagnostic method, although convalescent samples were reported to have been collected infrequently. Within GeoSentinel, leptospirosis was diagnosed mostly among international tourists and caused serious illness. Clinical suspicion and diagnostic workup among surveyed GeoSentinel clinicians were mainly triggered by a classical presentation and exposure history, possibly resulting in underdiagnosis. Suboptimal usage of available diagnostic methods may have resulted in additional missed, or misdiagnosed, cases. Published version

Hemostasis disorders are one of the major clinical conditions of snakebites and are because of mechanisms which may disrupt vessels, platelets, clotting factors and fibrinolysis. Thromboelastography (TEG) could help to understand these effects in the clinical practice. A retrospective study reports a series of patients presenting a snakebite-related coagulopathy, treated with antivenom and monitored with conventional tests and TEG in a French military treatment facility (Republic of Djibouti, East Africa) between August 2011 and September 2013. Conventional coagulation assays (platelets, prothrombin time, activated partial thromboplastin time, fibrinogen) and TEG measurements were taken on arrival and at various times during the first 72 h of hospitalization, at the discretion of the physician. The study included 14 patients (median age 28 years). Bleedings were present in five patients. All patients received antivenom. A coagulopathy was present in all patients and was detected by both conventional assays and TEG. None exhibited thrombocytopenia. Prothrombin time and fibrinogen remained abnormal for most of patients during the first 72 h. The TEG profiles of 11 patients (79%) showed incoagulability at admission (R-time > 60 min). TEG distinguished 10 patients with a generalized clotting factor deficiency and 4 patients with an isolated fibrinogen deficiency after an initial profile of incoagulability. Hyperfibrinolysis was evident for 12 patients (86%) after Hour 6. Snake envenomations in Djibouti involve a consumption coagulopathy in conjunction with delayed hyperfibrinolysis. TEG could improve medical management of the condition and assessment of additional therapeutics associated with the antivenom.

International audience; Background: There is no consensus on the most accurate combination of diagnostic criteria to define community acquired pneumonia (CAP). We describe inclusion criteria in randomized controlled trials (RCT) of CAP and assess their performance for the diagnosis of formally identified CAP.Methods: RCTs related to CAP recorded on ClinicalTrials.gov were analysed. Due to high heterogeneity, we divided close CAP inclusion criteria into patterns (i.e. combinations of inclusion criteria). To assess their diagnostic performances, these CAP definition patterns were applied to a reference population of 319 suspected CAP patients, in whom the CAP diagnosis had been confirmed (n = 163) or excluded (n = 156) by an adjudication committee after a systematic thoracic CT-scan and a 28-day follow-up period.Results: In the 47 RCTs included in the analysis, 42 different CAP inclusion criteria combinations were identified and 8 patterns created. This heterogeneity was not explained either by the trials’ methodology or by their objectives. When applied to the reference population, the performance ranges of the 8 definition patterns were 9.8–56.4% for sensitivities, 56.4 97.4% for specificities, 63.6 83.6% for positive predictive values and 50.8–66.7% for negative predictive values. None of the CAP definitions had both sensitivity and specificity superior to 65%. Depending on the CAP definition, the rate of included patients without CAP (“false positives”) ranged from 1 to 21%.Conclusions CAP diagnostic criteria within RCTs are heterogeneous, which may have far-reaching consequences on validity of RCT results.

BACKGROUND The pathogenesis of Ebola virus disease (EVD) remains unclear. The sporadic nature of Ebola outbreaks and their occurrence in resource-limited settings have precluded the acquisition of extensive clinical and laboratory data. Rhabdomyolysis during EVD has been suggested to occur in previous studies showing increased aspartate aminotransferase-alanine aminotransferase ratios, but, to date, has not been confirmed with creatine kinase (CK) assays. METHODS We performed an observational study of 38 patients admitted to an Ebola treatment center from January to April 2015. CK values from patients with confirmed EVD were compared with those in patients without confirmed EVD. A panel of other analyses were also performed. In patients with EVD, characteristics were compared between survivors and nonsurvivors. RESULTS High levels of CK were more frequent in patients with EVD than in those without (P = .002), and rhabdomyolysis was more frequent (59% vs 19%, respectively; P = .03). CK levels >5000 U/L were observed in 36% of patients with EVD. Also in patients with EVD, fatal outcome was significantly associated with higher creatinine and bilirubin levels, international normalized ratio, and viral load. CONCLUSIONS Rhabdomyolysis is a frequent disorder in EVD and seems to be more common than in other viral infections. It may contribute to the renal failure observed in nonsurviving patients. More studies are needed to determine the impact of rhabdomyolysis on EVD outcome.

For administration of multiple live attenuated vaccines, the Advisory Committee on Immunization Practices recommends either simultaneous immunization or period of at least 28 days between vaccines, due to a possible reduction in the immune response to either vaccine. The main objective of this study was to compare the immune response to measles (alone or combined with mumps and rubella) and yellow fever vaccines among infants aged 6–24 months living in a yellow fever non-endemic country who had received measles and yellow fever vaccines before travelling to a yellow fever endemic area. Subjects and methods: A retrospective, multicenter case-control study was carried out in 7 travel clinics in the Paris area from February 1st 2011 to march 31, 2015. Cases were defined as infants immunized with the yellow fever vaccine and with the measles vaccine, either alone or in combination with mumps and rubella vaccine, with a period of 1–27 days between each immunization. For each case, two controls were matched based on sex and age: a first control group (control 1) was defined as infants having received the measles vaccine and the yellow fever vaccine simultaneously; a second control group (control 2) was defined as infants who had a period of more than 27 days between receiving the measles vaccine and yellow fever vaccine. The primary endpoint of the study was the percentage of infants with protective immunity against yellow fever, measured by the titer of neutralizing antibodies in a venous blood sample. Results: One hundred and thirty-one infants were included in the study (62 cases, 50 infants in control 1 and 19 infants in control 2). Of these, 127 (96%) were shown to have a protective titer of yellow fever antibodies. All 4 infants without a protective titer of yellow fever antibodies were part of control group 1. Discussion: The measles vaccine, alone or combined with mumps and rubella vaccines, appears to have no influence on humoral immune response to the yellow fever vaccine when administered between 1 and 27 days. The absence of protective antibodies against yellow fever was observed only among infants who received both vaccines simultaneously. Conclusion: These results may support a revision of current vaccination recommendations concerning the administration of these two live attenuated vaccines either on the same day or at least 28 days apart. Our findings show no statistically significant difference if the interval between both vaccines is more than 24 h, but the immune response seems to be reduced when the two vaccines are given at the same time.

Background Plasmodium vivax is the second most common species among cases of imported malaria diagnosed in Europe. The objective of this study is to describe the sensitivity of the parasitological tests in imported P. vivax malaria, and the impact of chemoprophylaxis and attack type (primary infection or relapse). Methods A retrospective study included the imported vivax malaria cases admitted in a French military hospital between 2001 and 2013. The reference diagnosis method was microscopy corrected by polymerase chain reaction (PCR). Thin and thick blood films examination, quantitative buffy coat (QBC) test, and a rapid diagnostic test (RDT) had been systematically performed. PCR had been carried out for ambiguous profiles. Results Eighty-nine cases recorded from 78 patients were included, 65 of them having recently traveled to French Guyana. Forty-two patients had properly followed chemoprophylaxis. Forty-six cases were primary infections while 43 were relapses. The sensitivity was 91% for the thin blood smear, 96% for the concentration techniques (Giemsa thick blood smear and QBC test), and 76% for the RDT. The combination of the three conventional tools has an imperfect sensitivity, both for the positive diagnosis of malaria (96%) and for the diagnosis of vivax species (80%). In 4% of the cases, the positive diagnosis was established only by the PCR. The species identification was established in 20% by the PCR. The sensibility of thin blood smear and of RDT decreased significantly with full compliance of chemoprophylaxis or primary infection, whereas the decrease of sensibility of concentration techniques was not significant. Conclusions This study illustrates the difficulties encountered in vivax malaria diagnosis, especially in patients who properly followed chemoprophylaxis or with primary infection due to a lower parasitemia. It underlines the lack of sensitivity of RDT for P. vivax and emphasizes the need for systematically combining various diagnosis methods.

To understand geographic variation in travel-related illness acquired in distinct African regions, we used the GeoSentinel Surveillance Network database to analyze records for 16,893 ill travelers returning from Africa over a 14-year period. Travelers to northern Africa most commonly reported gastrointestinal illnesses and dog bites. Febrile illnesses were more common in travelers returning from sub-Saharan countries. Eleven travelers died, 9 of malaria; these deaths occurred mainly among male business travelers to sub-Saharan Africa. The profile of illness varied substantially by region: malaria predominated in travelers returning from Central and Western Africa; schistosomiasis, strongyloidiasis, and dengue from Eastern and Western Africa; and loaisis from Central Africa. There were few reports of vaccine-preventable infections, HIV infection, and tuberculosis. Geographic profiling of illness acquired during travel to Africa guides targeted pretravel advice, expedites diagnosis in ill returning travelers, and may influence destination choices in tourism.

The main objective of this study was to evaluate the contribution of a newly implemented daily surveillance system to the management of the 2009 A(H1N1) influenza pandemic by the military decision-makers at different levels in the French Department of Defence.The study sample included all medical advisors in the Ministry of Defence and the French Armed Forces Staff and also the members of the specific committee dedicated to flu pandemic control. The variables studied were mental representation of epidemiology, relevance, usefulness, and real-time use of surveillance data using quantitative questionnaires and qualitative face-to-face semistructured interviews.Among the risk managers of the flu pandemic in the Armed Forces, 84% responded. The data generated by epidemiological surveillance were considered relevant and useful, and were reported as effectively used. On the basis of the information produced, concrete actions were planned and implemented in the French Armed Forces.In a pandemic situation involving low mortality, the daily monitoring of the disease did not target public health issues, but it was mainly used to assess the availability of the Armed Forces in real time. For the military staff, epidemiological surveillance represents an essential information tool for the conduct of operations.

Ebola virus disease (EVD) went in the space of a few months from being a forgotten tropical disease to a global "health emergency". The scope of this Ebola virus epidemic (Zaire strain), which has broken out in West Africa, its spread and the high number of deaths reported among frontline health workers are unprecedented. This article describes how a specialist hospital deals with imported cases of EVD.

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

To describe patient characteristics and disease spectrum among foreign visitors to Haiti before and after the 2010 earthquake, we used GeoSentinel Global Surveillance Network data and compared 1 year post-earthquake versus 3 years pre-earthquake. Post-earthquake travelers were younger, predominantly from the United States, more frequently international assistance workers, and more often medically counseled before their trip than pre-earthquake travelers. Work-related stress and upper respiratory tract infections were more frequent post-earthquake; acute diarrhea, dengue, and Plasmodium falciparum malaria were important contributors of morbidity both pre- and post-earthquake. These data highlight the importance of providing destination- and disaster-specific pre-travel counseling and post-travel evaluation and medical management to persons traveling to or returning from a disaster location, and evaluations should include attention to the psychological wellbeing of these travelers. For travel to Haiti, focus should be on mosquito-borne illnesses (dengue and P. falciparum malaria) and travelers' diarrhea.

Only a few late cases of Plasmodium ovale presentation have been reported in literature. We describe two cases of late P. ovale presentation occurring in two French military personnel, 47 and 69 months, respectively, after a stay in Côte d'Ivoire and in the absence of new intercurrent malaria exposure.

Tuberculosis remains a public-health problem in 2010 with 9 millions cases and 1,7 million deaths worldwide each year. Tuberculosis meningitis is rare (0.5 to 1%) but is associated with high mortality and disability among survivors. An early starting of treatment is crucial. Despite molecular biology methods, microbiological diagnosis remains a challenge for the biologist. We report here 2 cases of tuberculous meningitis with different clinical and biological presentations, which underline diagnosis and therapeutic difficulties encountered in the management of this disease. The first one occurred in an HIV infected patient and the second one was caused by a multidrug-resistant strain. Clinical issues were severe with important neurological residual disability and death. Biological methods available for tuberculous meningitis diagnosis are exposed.

Summary Background Splenic rupture during acute malaria is rare but underreported. Because splenic rupture occurs mostly in non-immune adults, ongoing malaria elimination efforts may paradoxically increase the proportion of Plasmodium -infected patients suffering from this life-threatening complication. The pathogenesis and optimal patient management are still debated. Method We collected and analysed reports of pathological rupture of the spleen associated with malaria published over the last 50 years in five languages. Results Fifty-five cases were reported, due to Plasmodium falciparum ( n = 26), Plasmodium vivax ( n = 23), Plasmodium ovale ( n = 2), Plasmodium malariae ( n = 2), or P. vivax–falciparum ( n = 2), and occurred in travellers ( n = 24), locals ( n = 21), expatriates ( n = 6) or migrants ( n = 4). Median age was 31.5 years and sex ratio M/F 3.2. Splenic rupture was complete with hemoperitoneum ( n = 50), or partial ( n = 5). Death occurred in 12 patients (22%), 8 of whom from early irreversible collapse ( n = 7) or unexpected death ( n = 1). Death rate was higher among travellers than in other patients (9/24, 38%, versus 3/31, 10%, p = 0.01). Clinical features of P. falciparum - or P. vivax -associated splenic rupture were strikingly similar. Treatment included in-hospital medical observation without surgery (conservative management, n = 14), immediate splenectomy ( n = 29), delayed splenectomy ( n = 4), or none (patients dying at admission, n = 8). The type of treatment, conservative or not, had no influence on prognosis. The median duration of malaria symptoms before diagnosis was longer in our review (5–6 days) than in previous reports on imported malaria (3–4 days), suggesting that early diagnosis and therapy of malaria may reduce the incidence of splenic rupture. Conclusions Abdominal pain, collapse, or fainting is warning symptoms. Fourteen published observations support conservative management in carefully selected patients. Spleen preservation likely reduces the risk of future severe malaria attacks in patients with potential further exposition to Plasmodium sp., and also that of overwhelming sepsis in all.

Hemolysis occurred in a low proportion of patients and did not increase transfusion requirements., Artesunate is the most effective treatment for severe malaria. However, delayed-onset hemolytic anemia has been observed in ≈20% of travelers who receive artesunate, ≈60% of whom require transfusion. This finding could discourage physicians from using artesunate. We prospectively evaluated a cohort of 123 patients in France who had severe imported malaria that was treated with artesunate; our evaluation focused on outcome, adverse events, and postartesunate delayed-onset hemolysis (PADH). Of the 123 patients, 6 (5%) died. Overall, 97 adverse events occurred. Among the 78 patients who received follow-up for >8 days after treatment initiation, 76 (97%) had anemia, and 21 (27%) of the 78 cases were recorded as PADH. The median drop in hemoglobin levels was 1.3 g/dL; 15% of patients with PADH had hemoglobin levels of

Background. French military surveillance identified an increase in Plasmodium ovale attacks among soldiers in Ivory Coast. This emergence and the low sensitivity of biological tests raise the question of a possible role of P. ovale variant species. Methods. Epidemiological data about P. ovale attacks from 1993 to 2012 were studied; the species diagnosis was based on a thin blood smear and/or a quick diagnostic test. Clinical and biological features in soldiers hospitalized in 2 French military hospitals were also reviewed. Malaria polymerase chain reaction followed by genotyping was performed when available. Results. French military physicians declared 328 P. ovale attacks over the 20-year study. A peak of incidence occurred in 2005. Among patients with positive blood smears, the quick diagnostic test was positive in 33 of 101 tests performed. The hospital study showed that symptoms and biological changes were not specific, which made diagnosis challenging: fever, anemia, and thrombocytopenia were not present in 20%, 71%, and 23% of the 45 confirmed cases, respectively. It was possible to perform molecular investigations on 19 clinical isolates: 18 were classic haplotypes with additional polymorphism and 1 was variant. Conclusions. This emergence of P. ovale malaria enabled a good description to be made in nonimmune patients. The lack of sensitivity of both clinical features and quick diagnostic tests suggests an underestimation. Reasons for this outbreak are especially intense exposure to the vectors and the insufficient efficacy of doxycycline against P. ovale. The polymorphism of classic haplotypes of P. ovale rather than variant forms could be involved.

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.

To the Editor: Doxycycline is an effective antimalarial prophylactic drug when administered as a monotherapy 1 day before, daily during, and for 4 weeks after travel to an area where malaria is endemic (1). Doxycycline is currently a recommended chemoprophylactic regimen for travelers visiting areas where malaria is endemic and has a high prevalence of chloroquine or multidrug resistance (2). The World Health Organization also recommends doxycycline in combination with quinine or artesunate as the second-line treatment for uncomplicated Plasmodium falciparum malaria (3). Prophylactic and clinical failures of doxycycline against P. falciparum have been associated with both inadequate doses (4) and poor patient compliance (5). However, resistance can also explain failures of prophylaxis. Cycline resistance in Plasmodium spp. has been documented as a consequence of selective drug pressure in a P. berghei murine malaria model (6). The administration of increasing doses of minocycline to mice infected with 1 × 107 parasites for 86 successive passages over 600 days made it possible to obtain a resistant P. berghei strain with a median drug inhibitory concentration (IC50) of 600 mg/kg/d, which is 6-fold higher than that of the susceptible starting strain (100 mg/kg/d) (6). A Bayesian mixture modeling approach identified 3 different phenotypes (low, medium, and high doxycycline IC50 phenotypic groups) among P. falciparum clinical isolates (7,8). Using 90 isolates from 14 countries, we demonstrated that increases in copy numbers of P. falciparum metabolite drug transporter gene (Pfmdt, PFE0825w) and P. falciparum GTPase TetQ gene (PfTetQ, PFL1710c) are associated with reduced susceptibility to doxycycline (9); this association was later confirmed (7). In addition, isolates with PfTetQ KYNNNN motif repeats are associated with in vitro reduced susceptibility to doxycycline and with a significantly higher probability of having an IC50 above the doxycycline resistance threshold of 35 μM (9,10). We report a case of documented malaria prophylactic failure with doxycycline in a 26-year-old soldier from France who was infected during a 6-week peacekeeping mission in the Central African Republic in 2014. According to his colleagues and the collective prophylaxis intake, the patient had been compliant with doxycycline prophylaxis. On admission to a hospital in Bangui, Central African Republic, the patient had fever (temperature 40°C), alteration of consciousness, and hypotension. The diagnosis of severe P. falciparum malaria was made on the basis of a rapid diagnostic test confirmed by a blood smear test (parasitemia 8% on day 0). Intravenous artesunate was immediately started, in accordance with World Health Organization recommendations (3). The patient’s clinical condition worsened, and kidney failure developed. Twenty-four hours later (day 1), he was transported by airplane to Begin Military Teaching Hospital (Saint-Mande, France). On admission, he had cerebral edema and a P. falciparum parasitemia level of 0.7%. The patient died 1 day later (day 2). A blood sample obtained from the patient on day 1 in France showed a doxycycline concentration of 195 μg/mL plasma. This concentration, which was determined by liquid chromatography coupled with tandem mass spectrometry, was compatible with a last doxycycline uptake 1 day before diagnosis (day −1). The finding of the expected doxycycline plasma concentration, together with assurances (colleague’s statements and collective intake of doxycycline) that the patient had followed the drug regimen, was sufficient to suggest prophylaxis failure in a treatment-compliant patient. The P. falciparum sample obtained from the patient on arrival in France was evaluated for in vitro susceptibility to doxycycline, but the evaluation was unsuccessful. The number of copies of PfTetQ and Pfmdt genes were evaluated relative to the single-copy P. falciparum β-tubulin gene (pfβtubulin), as previously described (7,8). The sample was assayed in triplicate. The 2–ΔΔCt method (where Ct indicates cycle threshold) of relative quantification was used and adapted to estimate the number of copies of Pfmdt and PfTetQ by using the formula ΔΔCt = (Ct (PfTetQ or Pfmdt) − Ct (Pfβtubulin))Sample – (Ct (PfTetQ or Pfmdt) − Ct (Pfβtubulin))Calibrator. Genomic DNA extracted from 3D7 P. falciparum, which has a single copy of each gene, was used for calibrator sample; Pfβtubulin served as the control housekeeping gene. The experiment was assayed twice. The sample had 2 copies of PfTetQ and Pfmdt genes, which suggested decreased in vitro susceptibility of the sample to doxycycline (8,9). The genotyping of PfTetQ sequence polymorphisms was done by using conventional methods with the primers PfTetQ forward (5′-TCACGACAAATGTGCTAGATAC-3′) and PfTetQ reverse (5′-ATCATCATTTGTGGTGGATAT-3′), as previously described (10). Two PfTetQ KYNNNN motif repeats were found in the sample; 35 μM (odds ratio 15) (10). The 2 copies of Pfmdt and the 2 KYNNNN motif repeats have been shown to be associated with parasites with in vitro resistance to doxycycline (9,10). The association of doxycycline resistance (prophylactic failure with statement of correct intake and the presence of an expected concentration) with increased Pfmdt copies and decreased PfTetQ KYNNNN motif repeats suggest that these molecular markers are predictive markers of doxycycline resistance that can be used for resistance surveillance.

Among causes of fever in travelers, Q fever is rarely documented. 1-6 However, Coxiella burnetii, the agent responsible for the disease, has a worldwide distribution. 7 We report 10 cases of Q fever seen in our department within 4 years (October 1999-September 2003), of which 4 were observed from a military unit in Bosnia.

We compared a latex agglutination test (LAT) with enzyme-linked immunosorbent assay and indirect hemagglutination assay in the diagnosis of invasive amoebiasis. A retrospective biological records review has included 639 patients for whom these three serological tests were performed. The sensitivity of the LAT was 97.8% and the specificity was 97%.

Summary Snakebites are an infrequent but real risk for travelers. We report a case of envenomation by Bothrops atrox in a traveler to Manaus, Brazil. Rapid administration of specific antivenom prevented the expected systemic disorders. This case gives opportunity to review prevention and first aid measures of snakebites in travelers.

Amebiasis, the parasitic disease caused by Entamoeba histolytica, may result in extra-intestinal diseases among which liver abscess is the most common manifestation. We report two cases of amebic liver abscess illustrating the inequal sensitivity of serologic tests detecting anti-amebic antibodies.

Shigella bacteremias are uncommon in immune-competent adults. We report two cases of Shigella flexneri bacteremia that occurred in healthy young travelers, who recovered. Self-medication with loperamide and ibuprofen without antibiotics (case 1) and concomitant falciparum malaria (case 2) were the only co-morbidities found in our two patients.

Context Non- falciparum malaria is less studied than Plasmodium falciparum malaria, both in endemic and non-endemic zones. Patients and method A retrospective study was made of the medical files of patients managed for attacks of malaria due to Plasmodium vivax or Plasmodium ovale , between 2000 and 2009, in two French military teaching hospitals. Results Seventy-five percent of attacks occurred after a stay in French Guiana, in the Comoros Archipelago, or in the Ivory Coast Republic. The most frequent symptoms two months after coming back were a flu-like syndrome with headaches, and occasional digestive symptoms, without any difference between the first attack and recurrence. One third of patients presented with anemia, 78% with thrombocytopenia, and 12% with liver dysfunction. Discussion This study was the most important made in France on imported non- falciparum malaria. Military patients and immigrants accounted for a majority of patients due to the specificity of military hospitals and local recruitment. Clinical and biological features were not specific and did not allow guiding the diagnosis. Diagnostic tools were less sensitive for P. ovale . Conclusion Patient management could be optimized by more efficient diagnostic tools, specific guidelines for the diagnostic and therapeutic management, and a dedicated medical training for family practitioners as well as hospitals practice.

Case Description A 42-year-old woman was admitted with fever. Two weeks prior, she had returned from a 1-month stay in the Comoros archipelago (islands situated to the east of Mozambique), during which she had not taken antimalarial prophylaxis. Her medical history included a total splenectomy during surgery for a gastrointestinal stromal tumor 2 years before. A thin smear of blood revealed the findings seen in Fig. 1 (highlighted by arrows), and test results …

Background Plasmodium ovale is responsible for 5% of imported malaria in French travellers. The clinical and biological features of six clustered cases of P. ovale malaria in an army unit of 62 French soldiers returning from the Ivory Coast are reported. Case report All patients were symptomatic and developed symptoms on average 50 days after their return and 20 days after the end of chemoprophylaxis (doxycycline). Clinical features included fever (6/6), mostly tertian (4/6), aches (6/6), nausea (3/6), abdominal pain (2/6), diarrhoea (2/6), or cough (2/6). Thrombocytopaenia was lower than 100,000/mm3 in half the cases only, and the haemoglobin count was normal for all patients. The diagnosis was made after at least three thick and thin blood smear searches. Parasitaemia was always lower than 0.5%. All rapid diagnostic tests were negative for HRP2 and pLDH antigens. Discussion Plasmodium ovale malaria is currently a problem to diagnose in travellers, notably in French soldiers returning from the Ivory Coast. Early attempts at diagnosis are difficult due to the lack of specific clinical features, the rarity of biological changes and the poor sensitivity of diagnostic tools to detect low parasitaemia. Thus, the diagnosis is commonly delayed or missed. Physicians should be aware of this diagnostic challenge to avoid relapses and provide prompt and adequate treatment with chloroquine and radical cure with primaquine.

Background. The etiological spectrum of cerebro-meningeal infections (CMI) in travelers has never been specifically analyzed. Objectives. To assess the etiologies of CMI in hospitalized travelers and to propose a diagnostic approach to travel-related CMI. Methods. During an 8-year period, we retrospectively collected data on all travelers hospitalized in our department for a CMI occurring during travel or in the month after their return. Results. Fifty-six patients (35 men and 21 women; mean age 29 years (16–83); 44.6% tourists, 26.8% military, 16% immigrants, 12.5% expatriates) were included. The main destinations were Africa (57.2%), Europe (19.5%), and Asia (12.5%). The median duration of travel was 24 days (5–550). Symptoms occurred during travel in 20 patients (11 of which required a medical evacuation). In the remaining 36 patients, the median duration between return and clinical onset was 10 days. The median time from clinical onset to hospitalization was 4 days (0.5–96). Twenty-four patients presented with a meningeal syndrome and 20 others with encephalitic features. The remaining 12 patients had an incomplete clinical presentation (headaches or fever). The etiology was confirmed in 42 cases (75%) of which tropical diseases (n = 14) were less common than cosmopolitan ones (n = 28). Sub-Saharan Plasmodium falciparum malaria (n = 12) was the leading tropical infection, whereas viral infections (enterovirus, herpesviridae, HIV) were the main cosmopolitan etiologies. Only four bacterial infections were reported (Neisseria meningitidis, Mycoplasma pneumoniae, Brucella melitensis, Salmonella typhi). Sixteen patients were admitted to intensive care for a median time of 9.5 days (1–63). The average duration of hospitalization was 14 days (3–63). One death by herpes simplex virus 1 encephalitis was recorded. Four patients (7%) had neurological sequelae. Conclusions. Among the diversified etiological spectrum of CMI, cosmopolitan infections are widely predominant, particularly viral infections, followed by tropical causes, of which malaria is the leading disease in returnees from endemic areas. The diagnostic approach should be driven by history and physical examination. Key investigations include: blood smear, cerebrospinal fluid polymerase chain reaction and culture as well as neuroimaging. Management should focus on curable causes.

Acute lymphocytic meningitis, seen in France in summer, is often due to enteroviruses. Arboviruses as West Nile and tick-borne encephalitis do exist in Europe, but other viruses are rarely considered in patients unless they have had recent tropical travel. Toscana virus infection, which is endemic, especially in Italy,1-3 has been documented in some European travelers returning from Italy,4-6 but surprisingly was not documented in France until recently.7 We report a case of meningitis caused by Toscana virus imported to France.

Lymphogranuloma venereum (LGV) cases are currently re-emerging in the homosexual community, particularly in HIV-seropositive patients. The standard treatment for this infection, which is caused by Chlamydia trachomatis L1, L2 and L3 serotypes, is a 3-week doxycycline regimen. The case is reported of a male patient presenting with LGV, who was rapidly cured with moxifloxacin treatment after failure of extended treatment with cyclines. This fluoroquinolone is known to be highly active in vitro on the LGV pathogenic agent. Thus it may be a useful alternative when doxycycline treatment results in failure.

Dear Sir: We read with great interest the study on the abdominal computed tomography (CT) scan during acute vivax malaria in South Korea by Kim and others.1 In our recent analysis of 55 cases of pathological rupture on the spleen in malaria,2 we found that 23 (42%) were caused by Plasmodium vivax. We therefore agree with Kim and others that infection with P. vivax—less prevalent worldwide than Plasmodium falciparum—likely carry a higher risk of splenic complications than infection with P. falciparum. Acute splenic enlargement, which is as frequent in P. vivax as in P. falciparum infection despite lower mean parasitemia in the former,3 is likely to be a major determinant of both splenic infarction and splenic rupture in malaria. Splenic enlargement during lethal falciparum malaria likely results from splenic congestion with surface-altered and mechanically altered red blood cells (either infected or uninfected), and with migration or local multiplication of white blood cells.4–6 Because patients with vivax malaria rarely die, post-mortem data on the spleen in this context are very limited.7 The mechanistic connections between malaria, splenic infarction, and pathological splenic rupture are not clearly established. Although splenic infarction leads to splenic rupture in a small number of patients, 53 of the 55 malaria patients with pathological splenic rupture had no obvious signs of pre-existing infarction.8 Not least, pathological rupture of the spleen and other splenic complications may occur well beyond the acute phase of the malaria attack (median time from fever onset to rupture: 5 d, range: 0–37; median time from malaria diagnosis to rupture: 0 d, range: 0–31).2 Because Kim and others excluded patients in whom the CT scan had been performed more than 3 days after the diagnosis of malaria, a proportion of splenic complications was likely to be ignored in their study.1 Clinicians should be aware of the (small but life-threatening) risk of a delayed splenic rupture after a malaria attack.

Primary effusion lymphoma (PEL) is a rare high-grade B-cell non-Hodgkin lymphoma associated with Kaposi sarcoma-associated Herpesvirus/Human Herpesvirus 8 (KSHV/HHV-8) infection, and mostly observed in the course of HIV infection. The prognosis is poor with reported median survival time shorter than 6 months. To date, no prognostic factor has been identified in this subset of lymphoma. We described here the largest series of HIV-infected patients with PEL, including 30 cases diagnosed in six French centers over a 15-year time period. Prognosis analysis was performed using a Cox proportional hazard regression model. Statistically significant covariates were further analyzed in a forward, stepwise multivariate model. After a median follow-up of 3.2 years (range, 10 months-8.2 years), 9 patients (30%) were still alive, and 8 of them remained progression free. The overall median survival was 5.5 months and the 1-year overall survival rate was 36.7%. Fourteen patients (47%) achieved complete remission, with a 1-year disease-free survival rate at 78.6%. In multivariate analysis, only a performance status > 2 [hazard ratio 6.27, 95% confidence intervals (CI),1.91–20.58] and the absence of highly active antiretroviral therapy (HAART) before PEL diagnosis [hazard ratio 0.28, 95% CI, 0.10–0.77] were found to be independent predictors for shorter survival. Based on a retrospective series of 30 patients, two prognostic factors were identified as being independently associated with impaired clinical outcome in HIV-related PEL, (i) a poor performance status and (ii) the absence of HAART prior to PEL diagnosis.

Introduction Malaria is a notifiable disease in all European Union and European Economic Area countries except Belgium and France, where only autochthonous malaria is notifiable. Although morbidity caused by malaria has been assessed, little is known about mortality incidence. Objective Our aim was to estimate the number of imported malaria-related deaths in hospital in metropolitan France. Methods We matched individual deaths reported between 1 January 2005 and 31 December 2014 to the French National Reference Centre for malaria (FNRCm) with malaria-related deaths from two other sources: the French National Registry on medical causes of death and the French national hospital discharge database. A capture–recapture method with log-linear modelling was used. Age, sex and place of death stratification were applied to remove heterogeneity. Results The estimated malaria-related deaths in metropolitan France during the study period were 205 (95% confidence interval (CI): 191–219). The annual mean number of malaria-related deaths was estimated at 21 (95% CI: 19–22). The FNRCm malaria-related deaths surveillance had a 38% sensitivity (95% CI: 32–44). Among 161 in-hospital individual malaria-related deaths reported from three data sources, the sex ratio (male to female) was 2.6. Median age of the patients was 57 years, ranging from 1 to 89 years. Conclusion The pertinent finding of this report is that malaria-related death records were significantly less* complete than case records. Therefore, data comparison of imported malaria morbidity and mortality between countries should imperatively be assessed using standard indicators weighted according to the completeness of health surveillance systems.

International audience; Background: Doxycycline is an antibiotic used in combination with quinine or artesunate for malaria treatment or alone for malaria chemoprophylaxis. Recently, one prophylactic failure has been reported, and several studies have highlighted in vitro doxycycline decreased susceptibility in Plasmodium falciparum isolates from different areas. The genetic markers that contribute to detecting and monitoring the susceptibility of P. falciparum to doxycycline, the pfmdt and pftetQ genes, have recently been identified. However, these markers are not sufficient to explain in vitro decreased susceptibility of P. falciparum to doxycycline. In this paper, the association between polymorphism of the small sub-unit ribosomal RNA apicoplastic gene pfssrRNA (PFC10_API0057) and in vitro susceptibilities of P. falciparum isolates to doxycycline were investigated.Methods: Doxycycline IC50 determinations using the hypoxanthine uptake inhibition assay were performed on 178 African and Thai P. falciparum isolates. The polymorphism of pfssrRNA was investigated in these samples by standard PCR followed by sequencing.Results: No point mutations were found in pfssrRNA in the Thai or African isolates, regardless of the determined IC50 values.Conclusions: The pfssrRNA gene is not associated with in vitro decreased susceptibility of P. falciparum to doxycycline. Identifying new in vitro molecular markers associated with reduced susceptibility is needed, to survey the emergence of doxycycline resistance.