Hélène Savini

Human schistosomiasis: an emerging threat for Europe

1094 www.thelancet.com Vol 384 September 20, 2014 to acknowledge that schistosomiasis is now becoming a European disease. The Mediterranean area is a former settlement of Bulinus and climate warming creates favourable conditions for local transmission in southern Europe. The emergence of urinary schistosomiasis in Corsica (France), with a decade of native cases around Europe, might mean that schistosomiasis is now a cause for concern in Europe. Also, many travellers (migrants or tourists) come back from endemic areas after being contaminated through contact with water. Among travellers, the European armed forces have many cases of schistosomiasis because of their deployments in Africa (especially Cote d’Ivoire, Mali, and Central African Republic). Clinical examination has low sensibility and specifi city (one of three people are asymptomatic). European physicians have to manage this new situation. Medical education enhancement would improve their clinical sensibility. Nowadays, unexplained chronic urinary or digestive symptoms should evoke suspicion of schistosomiasis. Biological screening should be systematically done in these patients and in travellers with water contact in endemic countries, whatever their symptomatology. Finally, epidemiological surveillance should permit the detection of clusters around cases and monitor the spread of the local transmission.

Atorvastatin treatment is effective when used in combination with mefloquine in an experimental cerebral malaria murine model

BackgroundOne of the major complications of Plasmodium falciparum infection is cerebral malaria (CM), which causes one million deaths worldwide each year, results in long-term neurological sequelae and the treatment for which is only partially effective. Statins are recognized to have an immunomodulatory action, attenuate sepsis and have a neuroprotective effect. Atorvastatin (AVA) has shown in vitro anti-malarial activity and has improved the activity of mefloquine (MQ) and quinine.MethodsThe efficiency of 40 mg/kg intraperitoneal AVA, alone or in association with MQ, was assessed in an experimental Plasmodium berghei ANKA rodent parasite model of CM and performed according to different therapeutic schemes. The effects on experimental CM were assessed through the evaluation of brain histopathological changes and neuronal apoptosis by TUNEL staining.ResultsAVA alone in the therapeutic scheme show no effect on survival, but the prophylactic scheme employing AVA associated with MQ, rather than MQ alone, led to a significant delay in mouse death and had an effect on the onset of CM symptoms and on the level of parasitaemia. Histopathological findings show a correlation between brain lesions and CM onset. A neuronal anti-apoptotic effect of AVA in the AVA + MQ combination was not shown.ConclusionsThe combination of AVA and MQ therapy led to a significant delay in mouse mortality. There were differences in the incidence, time to cerebral malaria and the level of parasitaemia when the drug combination was administered to mice. When used in combination with MQ, AVA had a relevant effect on the in vivo growth inhibition and clinical outcome of P. berghei ANKA-infected mice.

First Case of Emergence of Atovaquone-Proguanil Resistance in Plasmodium falciparum during Treatment in a Traveler in Comoros

Atovaquone-proguanil (Malarone; GlaxoSmithKline) is now commonly used for the treatment and prophylaxis of falciparum malaria in France. We report here a treatment failure of atovaquone-proguanil in a patient who was infected during a 33-day visit without antimalarial prophylaxis in Comoros. The patient presented with fever 10 days after the end of his trip, and a diagnosis of falciparum malaria was made. Treatment with atovaquone-proguanil was well tolerated. Isolated fever in association with falciparum parasites appeared 23 days after therapy. The patient was successfully treated with quinine. In vitro susceptibility tests performed on blood samples from day 0 and day 23 showed a 50% inhibitory concentration (IC50) value for atovaquone that was more than 100-fold greater on day 23 than on day 0 (Table ​(Table1).1). In addition, the IC50 for cycloguanil was increased by 18-fold. TABLE 1. In vitro drug susceptibility profiles and changes in genotyping profiles of the day 0 and day 23 P. falciparum parasitesa Sequencing of the cyt b gene, encoding the atovaquone target (12), showed a wild-type P. falciparum strain on day 0 and a Y268S mutation on day 23. Genotyping of the dhfr gene, encoding the proguanil target (5), showed a double mutation, C59R and S108N, on day 0, while a triple mutation, N51I, C59R, and S108N, was observed on day 23. However, proguanil likely does not act by itself in atovaquone-proguanil treatment but only facilitates the atovaquone activity (11). Genotyping of the Pfcrt gene (wild type, K76), encoding a transport protein involved in chloroquine resistance, and of the dhps gene (wild type, S436, A437, K540, A581, and A613), encoding the sulfadoxine target (5), showed wild-type, identical alleles. The genotyping of the two isolates, using three of six microsatellite loci (7A11, Pf2802, C4M79, Pf2689, TRAP, and C4M69) (1), msp1, and msp2 (5), showed differences between days 0 and 23 (Table ​(Table11). The day 23 parasites presented a high IC50 for atovaquone associated with a Y268S mutation in Cyt b. Since 2002, fewer than 20 cases of genetically confirmed clinical resistance to atovaquone-proguanil had been reported (2-4, 6, 7, 9, 13, 14). Clinical failures were associated with in vitro-increased IC50s for atovaquone between day 0 and the failure day only in five isolates (4, 7, 9). In some cases, the increased IC50 was moderate (7, 8). An in vitro atovaquone threshold of 1,900 nM was recommended to discriminate resistant isolates (10). Considering our results, this cutoff must be adjusted to >350 nM. We were unable to detect Cyt b mutations on codon 268 and high IC50 to atovaquone in the pretreatment isolate. Reinfection was excluded because the patient was treated after returning to France. The atovaquone-resistant strain was probably present in the initial isolate but in the minority, making it undetectable by classical genotyping methods and in vitro testing. The isolate was polyclonal on day 0 and monoclonal on day 23. This is the first observation of the clinical failure of atovaquone-proguanil treatment of P. falciparum infection in a traveler in Comoros, an area where the in vitro prevalences of isolates with reduced susceptibilities to classical antimalarial drugs were <7% (12). Although clinical failures of atovaquone-proguanil therapy remain rare in travelers, an increased vigilance is required during their treatment followup, and surveillance of the parasite population should be reinforced as well.

Atorvastatin as a Potential Antimalarial Drug: In Vitro Synergy in Combinational Therapy with Dihydroartemisinin

Atorvastatin (AVA) is a synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A. AVA has lipid-lowering ability, a long plasma half-life, and an excellent safety record. In addition to the previously mentioned positive aspects of AVA, this drug has also shown in vitro antimalarial activity (10). AVA showed no in vitro cross-resistance with the commonly used antimalarials. In addition, the 50% inhibitory concentrations (IC50s) of AVA were found to be unrelated to mutations occurring in transport protein genes involved in quinoline antimalarial drug resistance, including the pfcrt, pfmdr1, pfmrp, and pfnhe-1 genes (8). Nevertheless, AVA treatment alone, at a dose of 20 mg/kg of body weight, failed to prevent death due to cerebral malaria and was not able to affect parasitemia in infected mice (1). One possibility is that AVA could act as an adjuvant therapy. Wong and Davis recently showed that AVA did not potentiate the in vitro activity of dihydroartemisinin (DHA) in the 3D7 strain of P. falciparum (13) and also posited that AVA had no clinical relevance because AVA IC50s were well above the plasma concentrations achievable in humans taking high-dose AVA (0.1 to 0.5 μM) (2). In the present study, we tested the effects of AVA at six concentrations (0.1, 0.5, 1, 2, 4, and 8 μM). We used 13 well-established strains of P. falciparum for the analysis (Table ​(Table1)1) (6). The methodology of the in vitro potentiation test was previously described (5). The combination of AVA and DHA had synergistic effects (Fig. ​(Fig.1).1). The differences in DHA IC50 between AVA concentrations groups have first been tested using analysis of variance for repeated measures to take into account the fact that observations made within each strain were not independent. Using the most conservative correction for interdependence between observations (i.e., Boxs conservative epsilon), the differences in DHA IC50 were highly significant (P < 0.001) in the range of AVA plasma concentrations achievable in patients taking 80 mg of AVA daily (Table ​(Table1).1). Using a random-effect linear regression approach, the regression coefficients for the log-transformed DHA IC50 indicated that the mean fold change in the DHA IC50 when adding AVA at concentrations of 0.1, 0.5, and 1.0 μM (0.90, 0.82, and 0.72, respectively) were also highly significant (P < 0.001). The DHA IC50 was reduced by 10% (range, 0 to 24%; 95% confidence interval [CI], 5 to 15%), 18% (range, 8 to 38%; 95% CI, 14 to 22%), and 28% (range, 15 to 43%; 95% CI, 24 to 32%) in the presence of AVA at concentrations of 0.1, 0.5, and 1.0 μM, respectively. These reductions were all significant (P < 0.001). Another finding was that the synergy of the effects of DHA was AVA dose dependent. The reductions in DHA IC50 were also significant (P < 0.001) between 0.1 and 0.5 μM AVA and between 0.5 and 1.0 μM AVA. FIG. 1. In vitro synergy of AVA with DHA against 13 strains of P. falciparum. TABLE 1. In vitro susceptibilities of 13 P. falciparum strains to AVA alone, DHA alone, and combinations of DHA and different concentrations of AVA In contrast to previously published studies on 3D7 (13), we showed that AVA had a synergistic effect on DHA activity. These controversial findings could be explained by differences in the isotopic method used; Wrong and Davis used a modified microdilution isotopic method with 50% plasma (versus 10% in commonly used in vitro test). In addition, their IC50 of DHA alone was 12.5 nM, while the commonly accepted IC50 on 3D7 was <4 nM. We also illustrated that this synergy occurred at AVA plasma concentrations achievable in patients taking 80 mg of AVA daily (0.1 to 0.5 μM) (2). Furthermore, the doses of AVA administered to humans could be increased to 120 mg daily with only limited additional side effects (9). A dose of 120 mg of AVA increased the maximal plasma concentration (Cmax) after oral administration by 4- to 10-fold. Cerebral malaria has pathophysiological features in common with sepsis, especially with regard to the pathology of the endothelium (4), and critically ill patients with sepsis had a significantly higher Cmax than healthy volunteers (110.5 versus 5.9 ng/ml) (7). Artemisinin-based combination therapy is beginning to fail in southern Cambodia and Thailand, particularly the mefloquine-artesunate drug combination (3, 11, 12). AVA could improve the activity of artemisinin derivatives. All of these observations support calls for both an in vivo evaluation with a pharmacokinetic component and clinical trials of AVA as an antimalarial therapy.

Inflammation of the external ear in acute chikungunya infection: Experience from the outbreak in Johor Bahru, Malaysia, 2008

The re-emerging invalidating chikungunya disease has recently extended to temperate areas. Other alphaviruses can also present with febrile arthalgias. Dengue virus transmitted by the same species of mosquitoes may cocirculate, leading to dual infections and concurrent epidemics. Although these diseases share similar clinical features, their prognoses considerably differ. Prominent and prolonged articular disorders are more consistent with chikungunya virus, whereas haemorrhages make the gravity of dengue infection. Specific symptoms are required, especially when diagnostic tests are not available or performable at a large scale. Indeed, early clinical suspicion of a vector-borne disease is crucial to isolate the first cases in the course of an outbreak, and discrimination between arboviruses help to optimal management of patients. No specific chikungunya clinical sign has been yet reported. We highlight here the high prevalence (about 25%) of acute ear redness in infected people during the 2008 chikungunya outbreak in Jahor Bahru in Malaysia. Nine consenting patients are more precisely described. Ear chondritis could be sensitive diagnostic criterion of the acute stage of chikungunya, every physician - even in occidental non endemic areas - should be aware of.

Moderate Thermal Strain in Healthcare Workers Wearing Personal Protective Equipment During Treatment and Care Activities in the Context of the 2014 Ebola Virus Disease Outbreak

The extent of thermal strain while wearing personal protective equipment (PPE) during care activities for Ebola virus disease patients has not yet been characterized. From January to March 2015, 25 French healthcare workers (HCWs) in Conakry, Guinea, volunteered to be monitored while wearing PPE using an ingestible thermal sensor. The mean (standard deviation) working ambient temperature and relative humidity were 29.6 °C (2.0 °C) and 65.4% (10.3%), respectively; the mean time wearing PPE was 65.7 (13.5) minutes; and the mean core body temperature increased by 0.46 °C (0.20 °C). Four HCWs reached or exceeded a mean core body temperature of ≥ 38.5 °C. HCWs wearing PPE for approximately 1 hour exhibited moderate but safe thermal strain.

Imported loiasis in France: A retrospective analysis of 47 cases

BACKGROUND French physicians occasionally encounter travelers (immigrants, expatriates, others) seeking care for loiasis. METHODS We describe the clinical and biological patterns and treatment of 47 cases of imported loiasis seen at three French hospitals over a 15-year period (1998-2012). RESULTS Most patients acquired their infection in Cameroon, Gabon, and Central African Republic. Overall, Calabar swellings were observed in 63% patients, and eye worm migration in 29%. Peripheral blood microfilariae were detected in 48% of patients and eosinophilia in 90% respectively. Calabar swellings and eosinophilia were more common among expatriates and travelers, whereas African immigrants were more likely to present with eye worm migration and have microfilaremia. First-line treatment was ivermectin in most cases (51%), followed by diethylcarbamazine (23%), albendazole (8%) or a combination of drugs (8%). Forty-one patients underwent clinical and parasitological follow-up for a mean period of 422 days [range 30-3600 days]. Clinical relapse and/or persistence/reappearance of blood microfilaria occurred in 10 patients. CONCLUSIONS Clinical and biological features were comparable with the largest monocentric series of imported loiasis. There was a marked rate of failure after first-line treatment and rare adverse effects were reported. The treatment of patients with imported loiasis would benefit from standardization with guidelines for the choice of first and second line drugs, the length of follow-up and criteria for cure.

Occupational Exposures to Ebola Virus in Ebola Treatment Center, Conakry, Guinea

We report 77 cases of occupational exposures for 57 healthcare workers at the Ebola Treatment Center in Conakry, Guinea, during the Ebola virus disease outbreak in 2014−2015. Despite the high incidence of 3.5 occupational exposures/healthcare worker/year, only 18% of workers were at high risk for transmission, and no infections occurred.

Surveillance of travel-associated diseases at two referral centres in Marseille, France: a 12-year survey

Abstract Background With increasing international travel and historically high numbers of residents visiting friends and relatives overseas, travel-associated illnesses are frequent in Marseille, France. We report the changing epidemiology of travel-related illnesses over a 12-year period. Methods A single site GeoSentinel surveillance analysis was undertaken for 3460 ill returned travellers presenting to two public hospitals in Marseille, France from March 2003 to October 2015, with travel-related illnesses. Demographic characteristics, travel history, presenting symptoms and information on pre-travel consultations were collected. Results There was a predominance of travel to sub-Saharan Africa, in particular to Comoros archipelago. Tourism was the main reason for travel (1591/3460, 46%), followed by visiting friends or relatives (VFR) (895/3460, 26%), with a mean duration of 29 days; 35% (1212/3460) of travellers reported a pre-travel health consultation. The most common syndromic diagnoses were febrile systemic illness (1343, 39%), dermatologic (716, 21%), gastrointestinal (340, 10%) and respiratory/ear–nose–throat (331, ENT) (10%). Hospitalization rates were highest amongst travellers from sub-Saharan Africa (858/ 1632, 53%), and VFR (573/ 895, 64%, P < 0.001). Frequent diagnoses included malaria (797, 23%), dengue (96, 2.77%) and chikungunya (75, 2.17%), reflecting global trends. Comparison of two periods (2003–10 to 2011–15) demonstrated an increase in chikungunya and decrease in malaria and influenza-like illness. We report an increase in ill travellers from the Caribbean, Middle East and South-East Asia. Conclusion Surveillance of travellers provides relevant sentinel information on the changing epidemiology of infectious diseases across the globe, most notably for malaria, dengue and chikungunya. We demonstrate the use of travel surveillance in improving pre-travel consultation needs and to address autochthonous vector-borne viral risks.

Anti-infective therapy without antimicrobials: Apparent successful treatment of multidrug resistant osteomyelitis with hyperbaric oxygen therapy

Infections due to multidrug-resistant bacteria have spread in the world and cause significant morbidity and mortality [1]. Bone and joint infection due to multidrug-resistant bacteria has become a major problem, limiting the efficacy of targeted treatment and compromising outcomes. Indeed, antimicrobial options are limited and extensive surgical procedures are required. Adjunctive hyperbaric oxygen therapy (HBO) has been reported as an effective treatment in soft tissue infection caused by anaerobic bacteria, such as gas gangrene, necrotizing fasciitis and Fournier’s gangrene. HBO has also been extensively used to improve wound healing in the treatment of diabetic foot infections and osteitis [2]. We report an apparent successful treatment of OXA-48 type carbapenemase-producing K. pneumonia osteomyelitis with HBO without any concomitant antimicrobial.