Jean-Baptiste Meynard

In Vitro Monitoring of Plasmodium falciparum Drug Resistance in French Guiana: a Synopsis of Continuous Assessment from 1994 to 2005

ABSTRACT Implemented as one arm of the malaria control program in French Guiana in the early 1990s, our laboratory has since established in vitro profiles for parasite drug susceptibility to a panel of eight antimalarials for more than 1,000 Plasmodium falciparum isolates from infected patients. The quinine-doxycycline combination was introduced in 1995 as the first-line drug treatment against uncomplicated P. falciparum malaria, replacing chloroquine, and the first-line drug combination was changed to the artemether-lumefantrine combination in 2002. Resistance to chloroquine declined 5 years after it was dropped in 1995 as the first-line drug, but unlike similar situations in Africa, there was a rapid halt to this decline. Doxycycline susceptibility substantially decreased from 2002 to 2005, suggesting parasite selection under quinine-doxycycline drug pressure. Susceptibility to mefloquine decreased from 1997 onward. Throughout the period from 1994 to 2005, most isolates were sensitive in vitro to quinine, amodiaquine, and atovaquone. Susceptibility to amodiaquine was strongly correlated with that to chloroquine and to a lesser extent with that to mefloquine and halofantrine. Susceptibilities to mefloquine and to halofantrine were also strongly correlated. There were two alerts issued for in vitro artemether resistance in the period from 2002 to 2003 and again in 2005, both of which could be associated with the presence of an S769N polymorphism in the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)-type P. falciparum ATPase6 (PfATPase6) gene. Analysis of susceptibility to lumefantrine, conducted for the first time in 2005, indicates an alarming rate of elevated 50% inhibitory concentrations. In vitro monitoring of parasite drug susceptibility should be pursued to further document the consequences of specific drug policies on the local parasite population and, in particular, to establish profiles of susceptibility to individual components of drug combinations to provide early warning signs of emerging parasite resistance.

Resistance to Dihydroartemisinin

The original title of our article was “Lack of Plasmodium falciparum in Vitro and Genomic Resistance to Dihydroartemisinin in Travelers Returning to France from Africa.” EID’s shortening of the title (1) led to the perception that the letter title was misleading, but it was not on purpose. We have recently tested the 50% inhibitory concentration for artemether of the S769N PfATPase6 isolate that we had kept in liquid nitrogen, and it showed susceptibility. We underline that the previously reported clinical or parasitologic failures to some artemisinin-based combination therapies (2,3) were not synonymous with the emergence of resistance to artemisinin compounds. In the study by Grandesso et al., a combination of artesunate plus amodiaquine was given to children <5 years of age who lived in an area in which amodiaquine alone was ineffective to adequately treat uncomplicated falciparum malaria in 1 of 3 cases at day 28 (2). Such a combination (artesunate plus amodiaquine) was nearly equivalent in 1 of 3 cases to a 3-day artesunate monotherapy, which may fail to completely cure children because of the short half-life of artesunate. In the study by Bukirwa et al., no recrudescence occurred in patients treated with artesunate plus amodiaquine and only 2 of 199 patients treated with artemether plus lumefantrine experienced recrudescence at day 28 (3). As Birkiwa et al. themselves acknowledged, artemether plus lumefantrine was not administered with food, and it is known that lumefantrine is absorbed better when it is taken with a small amount of fat. Thus, the clinical failures observed did not necessarily reflect P. falciparum resistance to artemisinin compounds.

Clinical and virological study of dengue cases and the members of their households: the multinational DENFRAME Project.

Background Dengue has emerged as the most important vector-borne viral disease in tropical areas. Evaluations of the burden and severity of dengue disease have been hindered by the frequent lack of laboratory confirmation and strong selection bias toward more severe cases. Methodology A multinational, prospective clinical study was carried out in South-East Asia (SEA) and Latin America (LA), to ascertain the proportion of inapparent dengue infections in households of febrile dengue cases, and to compare clinical data and biological markers from subjects with various dengue disease patterns. Dengue infection was laboratory-confirmed during the acute phase, by virus isolation and detection of the genome. The four participating reference laboratories used standardized methods. Principal Findings Among 215 febrile dengue subjects—114 in SEA and 101 in LA—28 (13.0%) were diagnosed with severe dengue (from SEA only) using the WHO definition. Household investigations were carried out for 177 febrile subjects. Among household members at the time of the first home visit, 39 acute dengue infections were detected of which 29 were inapparent. A further 62 dengue cases were classified at early convalescent phase. Therefore, 101 dengue infections were found among the 408 household members. Adding these together with the 177 Dengue Index Cases, the overall proportion of dengue infections among the study participants was estimated at 47.5% (278/585; 95% CI 43.5–51.6). Lymphocyte counts and detection of the NS1 antigen differed significantly between inapparent and symptomatic dengue subjects; among inapparent cases lymphocyte counts were normal and only 20% were positive for NS1 antigen. Primary dengue infection and a specific dengue virus serotype were not associated with symptomatic dengue infection. Conclusion Household investigation demonstrated a high proportion of household members positive for dengue infection, including a number of inapparent cases, the frequency of which was higher in SEA than in LA.

Evaluation of a syndromic surveillance for the early detection of outbreaks among military personnel in a tropical country

BACKGROUND To evaluate a new military syndromic surveillance system (2SE FAG) set up in French Guiana. METHODS The evaluation was made using the current framework published by the Centers for Disease Control and Prevention, Atlanta, USA. Two groups of system stakeholders, for data input and data analysis, were interviewed using semi-structured questionnaires to assess timeliness, data quality, acceptability, usefulness, stability, portability and flexibility of the system. Validity was assessed by comparing the syndromic system with the routine traditional weekly surveillance system. RESULTS Qualitative data showed a degree of poor acceptability among people who have to enter data. Timeliness analysis showed excellent case processing time, hindered by delays in case reporting. Analysis of stability indicated a high level of technical problems. System flexibility was found to be high. Quantitative data analysis of validity indicated better agreement between syndromic and traditional surveillance when reporting on dengue fever cases as opposed to other diseases. CONCLUSIONS The sophisticated technical design of 2SE FAG has resulted in a system which is able to carry out its role as an early warning system. Efforts must be concentrated on increasing its acceptance and use by people who have to enter data and decreasing the occurrence of the frequency of technical problems.

Tolerability of doxycycline monohydrate salt vs. chloroquine–proguanil in malaria chemoprophylaxis

The resistance of Plasmodium falciparum to the chloroquine–proguanil association (C/P) as antimalarial chemoprophylaxis is becoming increasingly common in Africa. Daily oral doxycycline hyclate 100 mg is effective as malaria prophylaxis. But the hyclate salts adverse effects combined with the capsules galenic form are incompatible with good chemoprophylaxis compliance. We conducted a randomized group study of 522 French soldiers deployed in Gabon and Chad for 4 months to determine the tolerability of short‐term malaria chemoprophylaxis with a 100‐mg daily tablet of a monohydrate doxycycline salt compared with a daily C/P capsule. At days 7 and 120, compliance was better in the doxycycline group [respectively 98.5%vs. 73.9% (P < 0.001) and 90.5%vs. 74% (P < 0.001)]. No major event (evacuation, hospitalization) was related to the medications. Epigastralgia, diarrhoea, urticaria, mouth ulcers, sun sensitization and desquamation were significantly more frequent in the C/P group (P < 0.05). There was no statistical difference for malaria incidence, vertigo, nausea and hair loss. These results suggest that doxycycline monohydrate may be safely used in short‐term malaria chemoprophylaxis. With the same efficacy as a hyclate doxycycline, doxycycline monohydrate could be a good chemoprophylaxis for short‐term travellers at particular risk of C/P resistant P. falciparum malaria.

Value of syndromic surveillance within the Armed Forces for early warning during a dengue fever outbreak in French Guiana in 2006.

BackgroundA dengue fever outbreak occured in French Guiana in 2006. The objectives were to study the value of a syndromic surveillance system set up within the armed forces, compared to the traditional clinical surveillance system during this outbreak, to highlight issues involved in comparing military and civilian surveillance systems and to discuss the interest of syndromic surveillance for public health response.MethodsMilitary syndromic surveillance allows the surveillance of suspected dengue fever cases among the 3,000 armed forces personnel. Within the same population, clinical surveillance uses several definition criteria for dengue fever cases, depending on the epidemiological situation. Civilian laboratory surveillance allows the surveillance of biologically confirmed cases, within the 200,000 inhabitants.ResultsIt was shown that syndromic surveillance detected the dengue fever outbreak several weeks before clinical surveillance, allowing quick and effective enhancement of vector control within the armed forces. Syndromic surveillance was also found to have detected the outbreak before civilian laboratory surveillance.ConclusionMilitary syndromic surveillance allowed an early warning for this outbreak to be issued, enabling a quicker public health response by the armed forces. Civilian surveillance system has since introduced syndromic surveillance as part of its surveillance strategy. This should enable quicker public health responses in the future.

Proposal of a framework for evaluating military surveillance systems for early detection of outbreaks on duty areas

BackgroundIn recent years a wide variety of epidemiological surveillance systems have been developed to provide early identification of outbreaks of infectious disease. Each system has had its own strengths and weaknesses. In 2002 a Working Group of the Centers for Disease Control and Prevention (CDC) produced a framework for evaluation, which proved suitable for many public health surveillance systems. However this did not easily adapt to the military setting, where by necessity a variety of different parameters are assessed, different constraints placed on the systems, and different objectives required. This paper describes a proposed framework for evaluation of military syndromic surveillance systems designed to detect outbreaks of disease on operational deployments.MethodsThe new framework described in this paper was developed from the cumulative experience of British and French military syndromic surveillance systems. The methods included a general assessment framework (CDC), followed by more specific methods of conducting evaluation. These included Knowledge/Attitude/Practice surveys (KAP surveys), technical audits, ergonomic studies, simulations and multi-national exercises. A variety of military constraints required integration into the evaluation. Examples of these include the variability of geographical conditions in the field, deployment to areas without prior knowledge of naturally-occurring disease patterns, the differences in field sanitation between locations and over the length of deployment, the mobility of military forces, turnover of personnel, continuity of surveillance across different locations, integration with surveillance systems from other nations working alongside each other, compatibility with non-medical information systems, and security.ResultsA framework for evaluation has been developed that can be used for military surveillance systems in a staged manner consisting of initial, intermediate and final evaluations. For each stage of the process parameters for assessment have been defined and methods identified.ConclusionThe combined experiences of French and British syndromic surveillance systems developed for use in deployed military forces has allowed the development of a specific evaluation framework. The tool is suitable for use by all nations who wish to evaluate syndromic surveillance in their own military forces. It could also be useful for civilian mobile systems or for national security surveillance systems.

Discordant Temporal Evolution of Pfcrt and Pfmdr1 Genotypes and Plasmodium falciparum In Vitro Drug Susceptibility to 4-Aminoquinolines after Drug Policy Change in French Guiana

ABSTRACT Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falciparum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype. Pfdmr1 gene copy number correlated with 50% inhibitory concentrations of mefloquine and halofantrine (r = 0.64 and 0.47, respectively, n = 547); its temporal changes paralleled changes in in vitro mefloquine susceptibility. However, the molecular parameters studied did not account for the regained in vitro susceptibility to chloroquine and showed a poor correlation with susceptibility to artemether, lumefantrine, or quinine. Identification of novel markers of resistance to these antimalarials is needed in this South American area.

First human rabies case in French Guiana, 2008: epidemiological investigation and control.

Background Until 2008, human rabies had never been reported in French Guiana. On 28 May 2008, the French National Reference Center for Rabies (Institut Pasteur, Paris) confirmed the rabies diagnosis, based on hemi-nested polymerase chain reaction on skin biopsy and saliva specimens from a Guianan, who had never travelled overseas and died in Cayenne after presenting clinically typical meningoencephalitis. Methodology/Principal Findings Molecular typing of the virus identified a Lyssavirus (Rabies virus species), closely related to those circulating in hematophagous bats (mainly Desmodus rotundus) in Latin America. A multidisciplinary Crisis Unit was activated. Its objectives were to implement an epidemiological investigation and a veterinary survey, to provide control measures and establish a communications program. The origin of the contamination was not formally established, but was probably linked to a bat bite based on the virus type isolated. After confirming exposure of 90 persons, they were vaccinated against rabies: 42 from the cases entourage and 48 healthcare workers. To handle that emergence and the local populations increased demand to be vaccinated, a specific communications program was established using several media: television, newspaper, radio. Conclusion/Significance This episode, occurring in the context of a Department far from continental France, strongly affected the local population, healthcare workers and authorities, and the management team faced intense pressure. This observation confirms that the risk of contracting rabies in French Guiana is real, with consequences for population educational program, control measures, medical diagnosis and post-exposure prophylaxis.

Plasmodium vivax Malaria among Military Personnel, French Guiana, 1998–2008

We obtained health surveillance epidemiologic data on malaria among French military personnel deployed to French Guiana during 1998–2008. Incidence of Plasmodium vivax malaria increased and that of P. falciparum remained stable. This new epidemiologic situation has led to modification of malaria treatment for deployed military personnel.