Jean-Philippe Chippaux

Recommandations pour la production, le contrôle et l'enregistrement des immunoglobulines antivenimeuses

Although frequent and severe, envenomations represent a neglected public health problem in most of the developing countries. Access to antivenoms is poor, mainly in Sub-Saharan Africa, and remains a major concern to World Health Organization (WHO). Since 2007, WHO committed international experts to propose guidelines aiming to improve the manufacture, quality control, registration and use of antivenoms. These guidelines, which will published soon, should promote access to antivenoms, and their use by health services, leading in the short term to a significant decrease of snakebite morbidity and mortality.

Epidemiology of snakebites in Europe: a systematic review of the literature.

Snakebites are rare medical emergency cases in Europe but may sometimes be severe and lead to complications. A better knowledge of snakebite epidemiology may help health authorities to better understand therapeutic requirements, especially concerning antivenoms, and thus improve treatment of snakebite. An extensive literature search for studies and articles published between 1970 and 2010 was performed. Both indexed and non-indexed articles were examined, the analysis of which took into account the heterogeneity between the studies and weighted the studies according to size of the study population covered. Most of the articles involved hospitalized patients who represented more than 90% of snakebites. Incidence, mortality and population at risk were estimated after stratification into three regions (northern, central and southern Europe) based both on viper species distribution and climatic characteristics. There was no significant variation in incidence from the north to the south of Europe. In the whole of Europe, including European Russia and Turkey, the annual number of snakebite cases was estimated at 7992 [CI 95%xa0=xa06860-9178] bites, out of which approximately 15% were considered severe (grade 3). These bites usually occurred between May and September, with a more dispersed distribution in southern Europe. The average number of deaths per annum was 4 [0.7-7.7]. Children and male victims are more affected, contrary to what one would expect given their respective proportion in the entire population. Both upper and lower limb bites were recorded at an equal frequency while the bites in other parts of the body were very rare. Immunotherapy was prescribed in one out of three snakebites in Europe, with a very high geographical variability, in spite of excellent tolerance, at least considering highly-purified immunoglobulin fragments. Snakebites are uncommon in Europe but can cause life-threatening envenomation. Fragments of highly-purified immunoglobulins are now very well tolerated and dramatically reduce both severity and mortality of snakebites when used in treatment.

Outbreaks of Ebola virus disease in Africa: the beginnings of a tragic saga

The tremendous outbreak of Ebola virus disease occurring in West Africa since the end of 2013 surprises by its remoteness from previous epidemics and dramatic extent. This review aims to describe the 27 manifestations of Ebola virus that arose after its discovery in 1976. It provides an update on research on the ecology of Ebola viruses, modes of contamination and human transmission of the disease that are mainly linked to close contact with an infected animal or a patient suffering from the disease. The recommendations to contain the epidemic and challenges to achieve it are reminded.

Snakebite envenomation turns again into a neglected tropical disease

On June 9th, 2017 WHO categorized snakebite envenomation into the Category A of the Neglected Tropical Diseases. This new situation will allow access to new funding, paving the way for wider and deeper researches. It should also expand the accessibility of antivenoms. Let us hope that it also leads to cooperation among stakeholders, aiming at improving the management of snakebites in developing countries.

The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine

The disease caused by Plasmodium falciparum (Pf) involves different clinical manifestations that, cumulatively, kill hundreds of thousands every year. Placental malaria (PM) is one such manifestation in which Pf infected erythrocytes (IE) bind to chondroitin sulphate A (CSA) through expression of VAR2CSA, a parasite-derived antigen. Protection against PM is mediated by antibodies that inhibit binding of IE in the placental intervillous space. VAR2CSA is a large antigen incompatible with large scale recombinant protein expression. Vaccines based on sub-units encompassing the functionally constrained receptor-binding domains may, theoretically, circumvent polymorphisms, reduce the risk of escape-mutants and induce cross-reactive antibodies. However, the sub-unit composition and small differences in the borders, may lead to exposure of novel immuno-dominant antibody epitopes that lead to non-functional antibodies, and furthermore influence the folding, stability and yield of expression. Candidate antigens from the pre-clinical development expressed in High-Five insect cells using the baculovirus expression vector system were transitioned into the Drosophila Schneider-2 cell (S2) expression-system compliant with clinical development. The functional capacity of antibodies against antigens expressed in High-Five cells or in S2 cells was equivalent. This enabled an extensive down-selection of S2 insect cell-expressed antigens primarily encompassing the minimal CSA-binding region of VAR2CSA. In general, we found differential potency of inhibitory antibodies against antigens with the same borders but of different var2csa sequences. Likewise, we found that subtle size differences in antigens of the same sequence gave varying levels of inhibitory antibodies. The study shows that induction of a functional response against recombinant subunits of the VAR2CSA antigen is unpredictable, demonstrating the need for large-scale screening in order to identify antigens that induce a broadly strain-transcending antibody response.

Incidence and mortality due to snakebite in the Americas

Background Better knowledge of the epidemiological characteristics of snakebites could help to take measures to improve their management. The incidence and mortality of snakebites in the Americas are most often estimated from medical and scientific literature, which generally lack precision and representativeness. Methodology/Principal findings Authors used the notifications of snakebites treated in health centers collected by the Ministries of Health of the American countries to estimate their incidence and mortality. Data were obtained from official reports available on-line at government sites, including those of the Ministry of Health in each country and was sustained by recent literature obtained from PubMed. The average annual incidence is about 57,500 snake bites (6.2 per 100,000 population) and mortality is close to 370 deaths (0.04 per 100,000 population), that is, between one third and half of the previous estimates. The incidence of snakebites is influenced by the abundance of snakes, which is related to (i) climate and altitude, (ii) specific preferences of the snake for environments suitable for their development, and (iii) human population density. Recent literature allowed to notice that the severity of the bites depends mainly on (i) the snake responsible for the bite (species and size) and (ii) accessibility of health care, including availability of antivenoms. Conclusions/Significances The main limitation of this study could be the reliability and accuracy of the notifications by national health services. However, the data seemed consistent considering the similarity of the incidences on each side of national boundaries while the sources are distinct. However, snakebite incidence could be underestimated due to the use of traditional medicine by the patients who escaped the reporting of cases. However, gathered data corresponded to the actual use of the health facilities, and therefore to the actual demand for antivenoms, which should make it possible to improve their management.

Evaluation of compliance to congenital Chagas disease treatment: results of a randomised trial in Bolivia.

BACKGROUNDnA randomised, unblinded, clinical trial comparing two benznidazole regimens for congenital Chagas disease was carried out to determine whether simplification and reduction in the length of treatment could lead to better treatment compliance.nnnMETHODSnThis study was conducted in Santa Cruz, Bolivia. Serological screening was carried out in pregnant women, and parasites were sought in the blood of newborns from seropositive mothers. Infected infants were randomly assigned to two treatment groups. Recovery was assessed by parasite seeking at 1 month and 2 months as well as serological tests at 9 months. Assessment of treatment adherence was based on weekly home visits and use of electronic monitors.nnnRESULTSnBenznidazole was given to 63 newborns in group A (5 mg/kg in two daily doses for 60 days) and 61 newborns in group B (7.5 mg/kg in a single daily dose for 30 days). There was no difference in compliance between the two groups. The study confirmed the efficacy and good tolerance of both benznidazole regimens in the treatment of congenital Chagas disease.nnnCONCLUSIONSnThe short treatment should be preferred as it allows reducing the dose of benznidazole as well as the cost of treatment.

Evolution of malaria mortality and morbidity after the emergence of chloroquine resistance in Niakhar, Senegal

BackgroundRecently, it has been assumed that resistance of Plasmodium to chloroquine increased malaria mortality. The study aimed to assess the impact of chemoresistance on mortality attributable to malaria in a rural area of Senegal, since the emergence of resistance in 1992, whilst chloroquine was used as first-line treatment of malaria, until the change in national anti-malarial policy in 2003.MethodsThe retrospective study took place in the demographic surveillance site (DSS) of Niakhar. Data about malaria morbidity were obtained from health records of three health care facilities, where diagnosis of malaria was based on clinical signs. Source of data concerning malaria mortality were verbal autopsies performed by trained fieldworkers and examined by physicians who identified the probable cause of death.ResultsFrom 1992 to 2004, clinical malaria morbidity represented 39% of total morbidity in health centres. Mean malaria mortality was 2.4‰ and 10.4‰ among total population and children younger than five years, respectively, and was highest in the 1992-1995 period. It tended to decline from 1992 to 2003 (Trend test, total population p = 0.03, children 0-4 years p = 0.12 - children 1-4 years p = 0.04- children 5-9 years p = 0.01).ConclusionContrary to what has been observed until 1995, mortality attributable to malaria did not continue to increase dramatically in spite of the growing resistance to chloroquine and its use as first-line treatment until 2003. Malaria morbidity and mortality followed parallel trends and rather fluctuated accordingly to rainfall.

Anti-malarial prescriptions in three health care facilities after the emergence of chloroquine resistance in Niakhar, Senegal (1992-2004).

BackgroundIn the rural zone of Niakhar in Senegal, the first therapeutic failures for chloroquine (CQ) were observed in 1992. In 2003, the national policy regarding first-line treatment of uncomplicated malaria was modified, replacing CQ by a transitory bi-therapy amodiaquine/sulphadoxine-pyrimethamine (AQ/SP), before the implementation of artemisinin-based combination therapy (ACT) in 2006.The aims of the study were to assess the evolution of anti-malarial prescriptions in three health care facilities between 1992 and 2004, in parallel with increasing CQ resistance in the region.MethodsThe study was conducted in the area of Niakhar, a demographic surveillance site located in a sahelo-sudanese region of Senegal, with mesoendemic and seasonal malaria transmission. Health records of two public health centres and a private catholic dispensary were collected retrospectively to cover the period 1992–2004.ResultsRecords included 110,093 consultations and 292,965 prescribed treatments. Twenty-five percent of treatments were anti-malarials, prescribed to 49% of patients. They were delivered all year long, but especially during the rainy season, and 20% of patients with no clinical malaria diagnosis received anti-malarials. Chloroquine and quinine represented respectively 55.7% and 34.6% of prescribed anti-malarials. Overall, chloroquine prescriptions rose from 1992 to 2000, in parallel with clinical malaria; then the CQ prescription rate decreased from 2000 and was concomitant with the rise of SP and the persistence of quinine use. AQ and SP were mainly used as bi-therapy after 2003, at the time of national treatment policy change.ConclusionThe results show the overall level of anti-malarial prescription in the study area for a considerable number of patients over a large period of time. Even though resistance to CQ rapidly increased from 1992 to 2001, no change in CQ prescription was observed until the early 2000s, possibly due to the absence of an obvious decrease in CQ effectiveness, a lack of therapeutic options or a blind follow-up of national guidelines.

Decreased prevalence and intensity of Loa loa infection in a community treated with ivermectin every three months for two years

Loiasis is a filarial disease with a defined geographical distribution; its main vectors, Chrysops silacea and C. diddiata, are confined to the great rainforest of Central Africa, from Zaire to Nigeria (HAWKING, 1977; FAIN, 1981). Within some endemic regions it is second only to malaria in contributing to the demand for medical consultation (PINDER, 1988). Humans are the only reservoir for Loa loa. Simian Loa is a sympatric but divergent species which has a different host-vector-parasite complex (RHODAIN, 1980). At present, no efficient method exists for controlling CItrysops and the only way to control loiasis is to treat the endemic community. At community level, this strategy is justifiable by the low population density of Chysops (c. 1000 flies per km2) and its short flight range (usually <5 km) (BEESLEY & CREWE, 1963; CHIPPAUX et al., in press). Both characteristics are conducive to a marked impact of community-based filaricidal treatment on the transmission of the parasite (NOIREAU, 1990). Ivermectin mass treatment for onchocerciasis, initiated in West Africa, has been used in loiasis endemic areas in Cameroon since 1991. It brought about a marked decrease in microfilarial loads, and the drug was safer than diethylcarbamazine (CARME et al., 1991; CHIPPAUX et al., 1992; MARTIN-PREVEL et al., 1993). Therefore, it seemed feasible to control both filariases with the same treatment. This study investigated the effect of repeated ivermectin treatments, over a period of 2 years, on the reservoir of L. loa in one village. The aim was to assess the feasibility of a large scale loiasis control programme. The study took place in Ngat, a village in the tropical rain forest of southern Cameroon (323N, 1134E), where loiasis is hyperendemic (30% microfilaraemia rate). The prevalence of Onchocerca volvulus was below 15%, and Mansonella perstans was the only other filarial parasite of importance (16% prevalence). In a previous longitudinal study carried out in Ngat during the year preceding the first ivermectin distribution, GARCIA et al. (1995) demonstrated the stability of the individuals L. Zoa microfilarial status. The population under study comprised about 700 inhabitants, of whom 450 were permanent residents, mostly field workers of the Ewondo tribe; 868 people were enrolled in the 2-year survey, including permanent residents, relatives living in nearby villages, and seasonal workers. The mean age was 28.6 years (range 0-87); the ma1e:female ratio was 0.94. Of the 320 subjects who left the study, 12 (3.7%) died, 40 (12.5%) refused treatment, and 268 (30.9%) left the village. Most of the latter were students who left to attend school and young women who left to get married. During the second year of treatment, 130 new inhabitants settled in the village. They therefore became part of the parasite reservoir and were included in the study.