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Compared to the previous 2013–2014 outbreak, dengue 2016–2017 outbreak in New Caledonia was characterized by an increased number of severe forms associated with hepatic presentations. In this study, we assessed the virological factors associated with this enhanced severity. Whole-genome sequences were retrieved from dengue virus (DENV)-1 strains collected in 2013–2014 and from severe and non-severe patients in 2016–2017. Fitness, hepatic tropism and cytopathogenicity of DENV 2016–2017 strains were compared to those of 2013–2014 strains using replication kinetics in the human hepatic cell line HuH7. Whole-genome sequencing identified four amino acid substitutions specific to 2016–2017 strains and absent from 2013–2014 strains. Three of these mutations occurred in predicted T cell epitopes, among which one was also a B cell epitope. Strains retrieved from severe forms did not exhibit specific genetic features. DENV strains from 2016–2017 exhibited a trend towards reduced replicative fitness and cytopathogenicity in vitro compared to strains from 2013–2014. Overall, the 2016–2017 dengue outbreak in New Caledonia was associated with a viral genetic evolution which had limited impact on DENV hepatic tropism and cytopathogenicity. These mutations, however, may have modified DENV strains antigenicity, altering the anti-DENV immune response in some patients, in turn favoring the development of severe forms. Trial registration: ClinicalTrials.gov identifier: NCT04615364.

Members of the BIRDY study group : Bodonirina Tanjona Raheliarivao, Frédérique Randrianirina, Perlinot Herindrainy, Zafitsara Zo Andrianirina, Feno Manitra Jacob Rakotoarimanana, Benoit Garin, Jean-Marc Collard, Agathe de Lauzanne, Laurence Borand, Patrice Piola, Alexandra Kerléguer, Thida Chon, Sok Touch, Arnaud Tarantola, Sophie Goyet, Siyin Lach, Veronique Ngo, Muriel Vray, Marguerite Diatta, Joseph Faye, Abibatou Ndiaye, Vincent Richard, Abdoulaye Seck, Raymond Bercion, Amy Gassama Sow, Jean Baptiste Diouf, Pape Samba Dieye, Balla Sy, Bouya Ndao, Didier Guillemot, Bich-tram Huynh, Maud Seguy, Laurence Watier, Abdou Armya Youssouf and Michael Padget.; International audience; BACKGROUND:Salmonella enterica is a leading cause of human gastroenteritis. S. enterica strains that produce ESBLs (ESBL-Salm) remain rare in Europe and North America, but less is known about their prevalence among animal-derived foods in countries with weaker food safety practices and unregulated veterinary antibiotic use.OBJECTIVES:To examine the prevalence and characteristics of ESBL-Salm from retail meats in Phnom Penh, Cambodia.METHODS:We tested fish, pork and chicken from two markets for ESBL- and carbapenemase-producing Salmonella from September-December 2016, using cefotaxime- and ertapenem-supplemented media, respectively. ESBL-Salm were sequenced and their genomes characterized. We performed plasmid conjugation experiments to assess the co-transferability of ESBL-encoding genes and MDR phenotypes.RESULTS:Twenty-six of 150 fish and meat samples (17%) were positive for ESBL-Salm, including 10/60 fish (17%), 15/60 pork (25%) and 1/30 chicken (3%). Carbapenemase-producing Salmonella strains were not detected. Pork-origin ESBL-Salm were primarily serotypes Rissen (10/15) or a monophasic variant of Typhimurium 4,5,12:i:- (3/15), whereas Saintpaul (3/10) and Newport (4/10) were more common among fish. Most ESBL enzymes were encoded by blaCTX-M-55 genes (24/26) harboured on conjugative IncA/C2 (n = 14) or IncHI2 (n = 10) plasmids. Resistance to up to six additional drug classes was co-transferred by each plasmid type. ESBL-Salm were resistant to almost every antibiotic recommended for severe salmonellosis treatment.CONCLUSIONS:CTX-M-55-type S. enterica are highly prevalent among pork and fish from Phnom Penh markets and their spread appears to be mediated by MDR IncA/C2 and IncHI2 plasmids. Food safety must be improved and veterinary antibiotic use should be regulated to protect public health.

Background In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. Methods The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. Results The proposed weight-based regimen has 5 dosing bands: (i) 5–7 kg, 5 mg, resulting in 0.71–1.0 mg/kg/day; (ii) 8–16 kg, 7.5 mg, 0.47–0.94 mg/kg/day; (iii) 17–40 kg, 15 mg, 0.38–0.88 mg/kg/day; (iv) 41–80 kg, 30 mg, 0.37–0.73 mg/kg/day; and (v) 81–100 kg, 45 mg, 0.45–0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6–11 months, 5 mg, 0.43–1.0 mg/kg/day; (ii) 1–5 years, 7.5 mg, 0.35–1.25 mg/kg/day; (iii) 6–14 years, 15 mg, 0.30–1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35–1.07 mg/kg/day. Conclusion The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Background In 2017, New Caledonia experienced an outbreak of severe dengue causing high hospital burden (4379 cases, 416 hospital admissions, 15 deaths). We decided to build a local operational model predictive of dengue severity, which was needed to ease the healthcare circuit. Methods We retrospectively analyzed clinical and biological parameters associated with severe dengue in the cohort of patients hospitalized at the Territorial Hospital between January and July 2017 with confirmed dengue, in order to elaborate a comprehensive patient’s score. Patients were compared in univariate and multivariate analyses. Predictive models for severity were built using a descending step-wise method. Results Out of 383 included patients, 130 (34%) developed severe dengue and 13 (3.4%) died. Major risk factors identified in univariate analysis were: age, comorbidities, presence of at least one alert sign, platelets count 9/L, prothrombin time 10 N, and previous dengue infection. Severity was not influenced by the infecting dengue serotype nor by previous Zika infection. Two models to predict dengue severity were built according to sex. Best models for females and males had respectively a median Area Under the Curve = 0.80 and 0.88, a sensitivity = 84.5 and 84.5%, a specificity = 78.6 and 95.5%, a positive predictive value = 63.3 and 92.9%, a negative predictive value = 92.8 and 91.3%. Models were secondarily validated on 130 patients hospitalized for dengue in 2018. Conclusion We built robust and efficient models to calculate a bedside score able to predict dengue severity in our setting. We propose the spreadsheet for dengue severity score calculations to health practitioners facing dengue outbreaks of enhanced severity in order to improve patients’ medical management and hospitalization flow.

International audience; With over one million cases worldwide annually and a high fatality in symptomatic forms, human leptospirosis is a growing public health concern for the most vulnerable populations, especially in the context of global warming and unplanned urbanization. Although the Asia-Pacific region is particularly affected, accurate epidemiological data are often lacking. We conducted an eleven-year retrospective laboratory-based epidemiological survey of human leptospirosis in New Caledonia. From 2006 to 2016, 904 cases were laboratory-confirmed, including 29 fatalities, corresponding to an average annual incidence of 30.6/100,000 and a case fatality rate of 3.2%. Over the period, there was a major shift from indirect serological diagnosis by MAT to direct diagnosis by real-time PCR, a more specific and sensitive test when performed early in the course of the disease. The systematic implementation of genotyping informed on the variety of the infective strains involved, with a predominance of serogroups Icterohaemorrhagiae and Pyrogenes. The epidemiological pattern showed a marked seasonality with an annual peak in March-April. Interestingly, the seasonal peak in children of school age was significantly earlier and corresponded to school holidays, suggesting that attending school from February on could protect children from environmentborne leptospirosis.

International audience

Comment in : Improving human rabies post-exposure prophylaxis. / Blumberg L, Rupprecht CE. Lancet Infect Dis. 2019 Dec;19(12):1273-1274. doi: 10.1016/S1473-3099(19)30525-0. Epub 2019 Sep 27. PMID: 31570310; International audience; Background: The international health authorities are backing an effort to eliminate canine-mediated rabies in humans by 2030. This effort will require improving access to adequate and timely rabies post-exposure prophylaxis as compliance is low with WHO-recommended regimens (given in four to five visits over 1 month). Access could be substantially improved by an abridged regimen to reduce doses, direct and indirect costs, and improve vaccine equity by better sharing of available vaccine. We aimed to compare rabies virus neutralising antibody titres before and after the fourth visit to determine whether that session was needed or the current regimen could be abridged.Methods: In this observational cohort study, we measured rabies virus neutralising antibody titres using rapid fluorescent focus inhibition tests in 116 people bitten by dogs with laboratory-confirmed rabies and 20 control individuals. Percentages of circulating plasmablasts were determined by flow cytometry. All individuals had been referred to the rabies prevention clinic at Institut Pasteur in Cambodia and received two intradermal injections of post-exposure prophylaxis on days 0, 3, 7, and 28 (Thai Red Cross regimen) with or without equine rabies immunoglobulin, as per 2010 WHO recommendations.Findings: All individuals had rabies virus neutralising antibody titres considered protective (≥0·5 IU/mL) and plasmablast activation on day 28 before the last injection. The median rabies virus neutralising antibody concentration in the group of individuals bitten by rabies virus-positive dogs was 1·08 IU/mL (IQR 0·37-3·09) on day 7, 26·86 (22·68-49·50) on day 28, and 26·74 (11·78-49·06) on day 42. No significant differences were observed in titres between days 28 and 42, after titres reached a plateau. These titres were reached notwithstanding equine rabies immunoglobulin use, age, sex, nutrition status as indicated by upper-arm circumference in children or BMI in adults, or dog infection status. Titres or plasmablast percentages did not increase between the day of the last injection and 2 weeks later. All patients were alive 1 year after post-exposure prophylaxis.Interpretation: The fourth vaccine session on day 28 provides no additional benefit. Rabies post-exposure prophylaxis can be abridged to a two-dose, three-session, 1 week regimen to improve post-exposure prophylaxis coverage and equity at no risk to patients.

Objectives In this study, we document the clinical characteristics and investigated risk factors for uncomplicated and severe forms of EV-A71 disease in Cambodian children. Methods From March to July 2014 inclusive, all patients with suspicion of EV-A71 infection presenting to Kantha Bopha Hospitals in Phnom Penh and Siem Reap and confirmed by the Virology Unit at the Institut Pasteur du Cambodge were prospectively enrolled in this study. Throat swabs, rectal swabs and serum samples were collected from all consecutive patients with suspected EV-A71 infection. In addition, CSF was also collected from patients with suspected EV-A71 associated encephalitis. A total of 122 patients (29 with uncomplicated disease and 93 with severe disease) with confirmed EV-A71 infection with all available demographic and clinical data for clinical classification and further analysis were included in the study. Results In this prospective EV-A71 study in Cambodia, we confirmed the previously reported association of male gender and absence of mouth or skin lesions with severe disease. We also highlighted the strong association of neutrophils in blood, but also in CSF in patients with pulmonary oedema. More importantly, we identified new putative nutrition-related risk factors for severe disease. Conclusions EV-A71 is an important cause of encephalitis in the Asia-Pacific region. Further studies to determine the risk factors associated with severe EV-A71 disease are needed.

International audience; OBJECTIVES:This study aimed to investigate proteinuria occurring during dengue disease in children and assess if measurement of this parameter can help physicians in the clinical management of patients.METHODS:Proteinuria was assessed by dipstick and quantified by urine protein:creatinine ratio (UPCR) in samples from patients hospitalized with a confirmed dengue infection and in healthy controls.RESULTS:The dipstick tested positive in 42.9% of the patients presenting at hospital with dengue versus 20.0% in healthy controls. UPCR increased during the critical phase of the disease; peaking one week after fever onset then decreasing as the patients recovered. Patients with warnings signs or severe dengue were more likely to present with proteinuria detected by UPCR at the time of hospital admission compared to patients without warning signs. The sensitivity of this marker, however, was limited as only 16.1% of the patients with warning signs had proteinuria.CONCLUSIONS:Urine dipstick and UPCR do not seem to be very valuable for the triage of the patients at the time of the initial consultation but the observation of a decrease of the UPCR during the course of the illness appears to indicate an evolution towards recovery.

International audience; We describe a retrospective study on circulation of Zika virus in Cambodia during 2007-2016 among patients with dengue-like symptoms and Aedes aegypti mosquitoes. Our findings suggest that Zika virus in Cambodia belongs to the Asia genotype, is endemic, has low prevalence, and has had low-level impact on public health.

International audience; The Pacific region, also referred to as Oceania, is a geographically widespread region populated by people of diverse cultures and ethnicities. Indigenous people in the region (Melanesians, Polynesians, Micronesians, Papuans, and Indigenous Australians) are over-represented on national, regional, and global scales for the burden of infectious and non-communicable diseases. Although social and environmental factors such as poverty, education, and access to health-care are assumed to be major drivers of this disease burden, there is also developing evidence that genetic and microbiotic factors should also be considered. To date, studies investigating genetic and/or microbiotic links with vulnerabilities to infectious and non-communicable diseases have mostly focused on populations in Europe, Asia, and USA, with uncertain associations for other populations such as indigenous communities in Oceania. Recent developments in personalized medicine have shown that identifying ethnicity-linked genetic vulnerabilities can be important for medical management. Although our understanding of the impacts of the gut microbiome on health is still in the early stages, it is likely that equivalent vulnerabilities will also be identified through the interaction between gut microbiome composition and function with pathogens and the host immune system. As rapid economic, dietary, and cultural changes occur throughout Oceania it becomes increasingly important that further research is conducted within indigenous populations to address the double burden of high rates of infectious diseases and rapidly rising non-communicable diseases so that comprehensive development goals can be planned. In this article, we review the current knowledge on the impact of nutrition, genetics, and the gut microbiome on infectious diseases in indigenous people of the Pacific region.

International audience; Several diseases and vulnerabilities associated with genetic or microbial factors are more frequent among populations of Oceanian, Non-European, Non-Asian descent (ONENA). ONENA are specific and have long been isolated geographically. To our knowledge, there are no published official, quantitative, aggregated data on the populations impacted by these excess vulnerabilities in Oceania. We searched official census reports for updated estimates of the total population for each of the Pacific Island Countries and Territories (including Australia) and the US State of Hawaii, privileging local official statistical or censual sources. We multiplied the most recent total population estimate by the cumulative percentage of the ONENA population as determined in official reports. Including Australia and the US State of Hawaii, Oceania counts 27 countries and territories, populated in 2016 by approximately 41 M inhabitants (17 M not counting Australia) among which approximately 12.5 M (11.6 M not counting Australia) consider themselves of entire or partial ONENA ancestry. Specific genetic and microbiome traits of ONENA may be unique and need further investigation to adjust risk estimates, risk prevention, diagnostic and therapeutic strategies, to the benefit of populations in the Pacific and beyond.

International audience; Arboviruses are viruses transmitted to humans by the bite of infected mosquito vectors. Over the last decade, arbovirus circulation has increasingly been detected in New Caledonia (NC), a French island territory located in the subtropical Pacific region. Reliable epidemiological, entomological, virological and climate data have been collected in NC over the last decade. Here, we describe these data and how they inform arboviruses' epidemiological profile. We pinpoint areas which remain to be investigated to fully understand the peculiar epidemiological profile of arbovirus circulation in NC. Further, we discuss the advantages of conducting studies on arboviruses dynamics in NC. Overall, we show that conclusions drawn from observations conducted in NC may inform epidemiological risk assessments elsewhere and may be vital to guide surveillance and response, both in New Caledonia and beyond.

This work was presented at the following congresses: SFRA, September 2017 and SRLF, January 2018; International audience; Introduction: Hypermucoviscous Klebsiella pneumoniae (KP) strains are responsible for complicated bacteremia with multiple septic sites (liver, central nervous system, muscles). We aimed to compare the clinical severity of patients presenting with KP bacteremia based on the hypermucoviscous or non-hypermucoviscous characteristic of the strains.Methods: Observational retrospective study successively including all patients with KP bacteremia from May 2013 to March 2015 at the tertiary medical center of New Caledonia. The hypermucoviscous characteristic was defined by the string test results and molecular analysis to determine the capsular serotype.Results: A total of 55 bacteremic patients were included in the study; 27% of isolated strains were hypermucoviscous. Hypermucoviscous strains accounted for two-thirds of community-acquired infections (72.5% vs. 33.4%, p=0.01). The rate of intensive care hospitalization was high (hypermucoviscous 46.7%; standard 52.5%) without any difference between the two groups. No significant difference was observed in case fatality (hypermucoviscous 46.7% vs. standard 15%, p=0.07) but patients with hypermucoviscous strains had longer hospital stays (73.5 days versus 50.7 days, p=0.04) and longer persistence of positive blood cultures despite an appropriate treatment (OR 1.41, 95% CI: 1.0-1.96, p=0.045).Conclusion: Hypermucoviscous KP bacteremia account for most community-acquired Klebsiella infections in New Caledonia and are associated with longer hospital stay and persistence of positive blood cultures despite the implementation of an appropriate treatment.

International audience; Early names for leptospirosis often indicate occupational or environmental exposure. Leptospirosis is hard to identify in the tropical setting because of co-circulating diseases. This is not the case in the temperate setting, such as Europe, where the few differential diagnoses at the time are malaria, typhoid, and viral hepatitis. Leptospirosis presumably caused community epidemics in Europe before 1900 and military epidemiologists carefully documented outbreaks in "constrained settings." Achille Kelsch (1841-1911) synthesized available military data and epidemiological perspectives to define "epidemic jaundice" as a nosological continuum, caused by an infectious agent found in muds and water. He viewed Weil's disease as being only one form of that now well-identified disease continuum. The causative pathogen and epidemiological determinants were identified years later. The role of soils and muds as intermediate reservoirs, as suggested by Kelsch, deserves further investigation.

International audience; Rabies circulates intensely in Cambodia, mainly affecting rural populations. We conducted a prospective study to estimate the baseline incidence of potentially infective dog bites in rural villages of Siem Reap province, Cambodia. The study was conducted in a convenience sample of 844 families totaling 1779 persons in four villages. The study collected data in a total of 802.3 person-years. Trained village health workers (VHW) exhaustively documented consecutive dog bites at the end of each month. Between May 15th and November 15th, 2011, a total of 40 attacks (43 bites; 1.07 bites per attack) were notified by 39 persons (50% female; one suffered two distinct incidents) to VHW. The all-age attack rate for bites over this 6-month period was 2.3% (CI95%: 1.7-3.1%), with a global incidence rate estimated at 4.84 bites/100 person-years (CI95%: 3.5-6.6). The mean age in bite victims was 20.8±18.9years (median 12.5; interquartile range 6-36; range 1-63). The dog was identified in 39 (97.5%) of cases, being the household dog in 9 (22.5%) of cases. Bites were classified as severe (WHO Category III-broken skin with bleeding) in 33 (82.5%) of cases with a severe dog bites incidence estimated at 4/100 person-years (CI95%: 2.8-5.6). The bites involved the hand or face in 1 (2.5%) case each (both Category III). In 20 incidents (50%), only rice was applied to the wounds. There were no suspected or confirmed human rabies deaths during the study period but one dog died after biting (2 others were lost to follow-up and 14 were put down by their owner). Our study documented an extremely high incidence of dog bites in of rural Cambodian adults and children. Adapted control policies for canine vaccination are urgently needed.

International audience; BACKGROUND:The diagnosis of tuberculosis in human immunodeficiency virus (HIV)-infected children is challenging. We assessed the performance of alternative specimen collection methods for tuberculosis diagnosis in HIV-infected children using Xpert MTB/RIF (Xpert).METHODS:HIV-infected children aged ≤13 years with suspected intrathoracic tuberculosis were enrolled in 8 hospitals in Burkina Faso, Cambodia, Cameroon, and Vietnam. Gastric aspirates were taken for children aged

International audience; In a 10-year incidence survey of breast cancer in the City of Boston, 14 cases in American Chinese women were observed, while approximately 13 were expected on the basis of age-specific incidence in the white population. In Hawaii, on the other hand, while breast cancer incidence rates for ethnic Chinese are approximately three times as high as those of indigenous Chinese populations, data indicate that they are still 35% lower than those of whites in Hawaii or on the US mainland. We have compared estrogen concentrations in the urine of Chinese women in the Orient, Honolulu, and Boston. Levels of estrone (E1) and estradiol (E2) increased greatly from the low to the high risk group. The increase was evident among both the younger (15-19 years) and the older (20-24 years) women, in both follicular and luteal phase specimens. The crude unweighted average increase from Oriental to continental US Chinese was about 38% and 34% for E1 and E2, respectively. On the other hand, levels of E3 decreased from the low-risk to the high-risk group, but the decrease was modest (16%) and not always regular. There were no systematic or significant differences in the frequency of ovulation in the three groups of women. These results are compatible with the hypothesis that high levels of estrone and estradiol are important to breast carcinogenesis. Whether E3 has some additional "protective" effect or is irrelevant is unclear. The data do not support the hypothesis that total urine estrogens (E1 + E2 + E3) are predictive of population groups at high risk for breast cancer and they appear inconsistent with the hypothesis that frequency of ovulation (or anovulation) is an important aspect of breast carcinogenesis.

Japanese encephalitis is mainly considered a rural disease, but there is growing evidence of a peri-urban and urban transmission in several countries, including Cambodia. We, therefore, compared the epidemiologic dynamic of Japanese encephalitis between a rural and a peri-urban setting in Cambodia. We monitored two cohorts of 15 pigs and determined the force of infection–rate at which seronegative pigs become positive–in two study farms located in a peri-urban and rural area, respectively. We also studied the mosquito abundance and diversity in proximity of the pigs, as well as the host densities in both areas. All the pigs seroconverted before the age of 6 months. The force of infection was 0.061 per day (95% confidence interval = 0.034–0.098) in the peri-urban cohort and 0.069 per day (95% confidence interval = 0.047–0.099) in the rural cohort. Several differences in the epidemiologic dynamic of Japanese encephalitis between both study sites were highlighted. The later virus amplification in the rural cohort may be linked to the later waning of maternal antibodies, but also to the higher pig density in direct proximity of the studied pigs, which could have led to a dilution of mosquito bites at the farm level. The force of infection was almost identical in both the peri-urban and the rural farms studied, which shifts the classic epidemiologic cycle of the virus. This study is a first step in improving our understanding of Japanese encephalitis virus ecology in different environments with distinct landscapes, human and animal densities., Author summary The number of Japanese encephalitis cases has decreased substantially over the past decades with the implementation of childhood vaccination programs. Japanese encephalitis virus, however, remains the most important cause of acute viral encephalitis in Eastern and Southern Asia, with an estimated 68,000 cases reported annually worldwide. Our results demonstrate that Japanese encephalitis virus circulates intensely both in a rural and a peri-urban setting in Cambodia, which raises important public health concerns as peri-urban areas are densely populated. These results support the importance of changing vaccination recommendations for travelers and of not focusing national immunization programs against Japanese encephalitis solely on rural areas.

International audience; Rabies causes 60,000 deaths worldwide annually. Rabies post-exposure prophylaxis is highly effective but often geographically and financially beyond reach in endemic developing countries. We conducted a retrospective study on clinical outcome at ≥6 months in 3318 Cambodians who received intradermal Vero cell vaccine post-exposure prophylaxis after a bite by a rabid or sick-looking but untested dog in 2003-2014. An external expert panel examined verbal autopsy reports to identify rabies deaths. 1739 (93.65%) persons bitten by rabid- and 1066 (72.96%) bitten by sick-looking but untested dogs were traced and 513 were lost to follow-up. Among the former, 1591 (91.49%) and 129 (7.42%) patients referred for 4+ and 3 post-exposure prophylaxis sessions, respectively. Three persons died of probable rabies so that the overall percentage of survival was 99.83% (95% exact confidence interval: 99.49-99.96%) in post-exposure prophylaxis recipients bitten by confirmed rabid dogs. No significant difference was found in survival among patients who received 3 vs. 4+ sessions (with or without rabies immunoglobin). The power of the study, however, was limited. The current four sessions/one month intradermal regimen can be reduced to a three sessions/one week at no detectable added risk to patients, with the limitation of study power at 49%. A clinical follow-up system should be adopted by rabies prevention centers, especially to monitor implementation of an abridged course. The Institut Pasteur in Cambodia regimen will improve vaccine equity by treating 33% more patients with available doses, reduce direct cost of vaccination, transportation and other indirect costs to vaccinees.

The development of human rabies vaccines has evolved dramatically from the first crude nerve tissue vaccine produced then administered in the presence of Louis Pasteur in 1885. New cell culture technology has enabled highly potent and well-tolerated rabies vaccines to be produced that have reduced the volume and number of doses required to save human lives after exposure. However, these highly potent vaccines are still unaffordable to many patients living at risk of exposure on a daily basis. The cost of post-exposure prophylaxis (PEP) is not only related to the direct cost of rabies biologicals and equipment but is also associated with indirect costs that patients incur as a result of travel, loss of work time (income loss), and accommodation over the period of time that a PEP regimen requires to be completed. This paper summarizes the particular criteria that the SAGE Working Group and WHO personnel reviewed as part of the evaluation process for recommending the new one-week intradermal vaccination regimen (2-2-2-0-0) for rabies post-exposure prophylaxis. These criteria included: Cost-effectiveness; evaluation of number of doses; seroconversion after vaccination; efficacy; safety; and patient follow-up.

Background Estimates of leptospirosis morbidity identified Oceania as the region with highest burden. Besides Australia and New Zealand, Oceania is home of Pacific Island Countries and Territories, most of which are developing countries facing a number of challenges. Their archipelago geography notably affects health infrastructure and access to healthcare. Although human leptospirosis was formerly identified in Vanuatu, there is a lack of knowledge of this disease in the country. We aimed to identify leptospirosis in outpatients visiting the hospital. Methodology/Principal findings We conducted a clinical study to investigate leptospirosis as a cause of non-malarial acute febrile illness in Vanuatu. A total 161 outpatients visiting the outpatient clinics at Port Vila Central Hospital for internal medicine were recruited over 20 month. We showed that leptospirosis significantly affects humans in Vanuatu: 12 cases were confirmed by real-time PCR on acute blood samples (n = 5) or by high serology titers evidencing a recent infection (MAT titer ≥800 or ELISA≥18 Units, n = 7). A high rate of positive serology was also evidenced, by MAT (100, Author summary Leptospirosis is thought to impose its highest burden to tropical island populations, especially in the Pacific region of Oceania. Yet, very few information has ever been reported from some of the Pacific Island Countries and Territories, including Vanuatu. In this study, we aimed at evidencing leptospirosis in a convenience sample of outpatients visiting Port Vila Central Hospital, the major hospital of this archipelago country in the South Pacific. Using reference laboratory techniques, our study confirms a significant number of acute leptospirosis cases, as well as a high level of previous exposure in outpatients visiting this hospital. Risk factor analysis point to livestock and lifestyle as important factors exposing to leptospirosis in this developing country. Furthermore, there is evidence that the disease probably has a higher incidence in remote islands outside of the capital of Efate in this very wide archipelago. Taken together, our results point to a need of increased awareness, notably in peripheral health centers and of better access to laboratory confirmation for surveillance.

International audience; The aim of this review is to guide clinicians in the practical management of patients suffering from rabies encephalomyelitis. This condition is eminently preventable by modern post-exposure vaccination, but is virtually always fatal in unvaccinated people. In the absence of any proven effective antiviral or other treatment, palliative care is an imperative to minimise suffering. Suspicion of rabies encephalomyelitis depends on recognising the classic symptomatology and eliciting a history of exposure to a possibly rabid mammal. Potentially treatable differential diagnoses must be eliminated, notably other infective encephalopathies. Laboratory confirmation of suspected rabies is not usually possible in many endemic areas, but is essential for public health surveillance. In a disease as agonising and terrifying as rabies encephalomyelitis, alleviation of distressing symptoms is the primary concern and overriding responsibility of medical staff. Calm, quiet conditions should be created, allowing relatives to communicate with the dying patient in safety and privacy. Palliative management must address thirst and dehydration, fever, anxiety, fear, restlessness, agitation, seizures, hypersecretion, and pain. As the infection progresses, coma and respiratory, cardiovascular, neurological, endocrine, or gastrointestinal complications will eventually ensue. When the facilities exist, the possibility of intensive care may arise, but although some patients may survive, they will be left with severe neurological sequelae. Recovery from rabies is extremely rare, and heroic measures with intensive care should be considered only in patients who have been previously vaccinated, develop rabies antibody within the first week of illness, or were infected by an American bat rabies virus. However, in most cases, clinicians must have the courage to offer compassionate palliation whenever the diagnosis of rabies encephalomyelitis is inescapable.

International audience; Childhood vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in Cambodia in January 2015. Baseline data regarding circulating serotypes are scarce. All microbiology laboratories in Cambodia were contacted for identification of stored isolates ofStreptococcus pneumoniaefrom clinical specimens taken before the introduction of PCV13. Available isolates were serotyped using a multiplex polymerase chain reaction method. Among 166 identified isolates available for serotyping from patients with pneumococcal disease, 4% were isolated from upper respiratory samples and 80% were from lower respiratory samples, and 16% were invasive isolates. PCV13 serotypes accounted for 60% (95% confidence interval [CI] 52-67) of all isolates; 56% (95% CI 48-64) of noninvasive and 77% (95% CI 57-89) of invasive isolates. Antibiotic resistance was more common among PCV13 serotypes. This study of clinicalS. pneumoniaeisolates supports the potential for high reduction in pneumococcal disease burden and may serve as baseline data for future monitoring ofS. pneumoniaeserotypes circulation after implementation of PCV13 childhood vaccination in Cambodia.

International audience; Background:In Western settings, community-acquired pneumonia (CAP) due to Gram-negative bacilli (GNB) is relatively rare. Previous studies from Asia, however, indicate a higher prevalence of GNB in CAP, but data, particularly from Southeast Asia, are limited.Methods:This is a prospective observational study of 1451 patients ≥15 y of age with CAP from two hospitals in Cambodia between 2007 and 2010. The proportion of GNB was estimated. Risk factors and clinical characteristics of CAP due to GNB were assessed using logistic regression models.Results:The prevalence of GNB was 8.6% in all CAP patients and 15.8% among those with a valid respiratory sample. GNB infection was independently associated with diabetes, higher leucocyte count and CAP severity. Mortality was higher in patients with CAP due to GNB.Conclusions:We found a high proportion of GNB in a population hospitalized for CAP in Cambodia. Given the complex antimicrobial sensitivity patterns of certain GNBs and the rapid emergence of multidrug-resistant GNB, microbiological laboratory capacity should be strengthened and prospective clinical trials comparing empiric treatment algorithms according to the severity of CAP are needed

International audience; BACKGROUND:Tuberculosis is a major cause of morbidity and mortality in HIV-infected children, but is difficult to diagnose. We studied mortality and its determinants in antiretroviral treatment (ART)-naive HIV-infected children presenting with suspected tuberculosis.METHODS:In this observational cohort study, HIV-infected children aged 13 years or younger with suspected tuberculosis were followed up for 6 months as part of the ANRS 12229 PAANTHER 01 cohort in eight hospitals in four countries (Burkina Faso, Cambodia, Cameroon, and Vietnam). Children started ART and antituberculosis treatment at the clinician's discretion and were retrospectively classified into one of three groups by tuberculosis documentation: confirmed by culture or Xpert MTB/RIF, unconfirmed, and unlikely. We assessed mortality and associated factors using Kaplan-Meier methods and Cox proportional hazard models. The ANRS 12229 PAANTHER 01 study is registered at ClinicalTrials.gov, number NCT01331811.FINDINGS:266 (61%) of 438 children enrolled in the study between April 27, 2011, and May 31, 2014, were ART-naive and included in the analysis (40 had confirmed tuberculosis, 119 unconfirmed tuberculosis, and 107 unlikely tuberculosis). 112·5 person-years of follow-up were available. 154 children (58%) started antituberculosis treatment and 212 (80%) started ART. 50 children (19%) died. Mortality by 6 months was higher in children with confirmed tuberculosis (14 deaths; 2 month survival probability 65·0% [95% CI 50·2-79·8]) compared with unconfirmed tuberculosis (19 deaths; 83·5% [76·8-90·3]) and unlikely tuberculosis (17 deaths; 83·5% [76·3-90·7]; log-rank p=0·0141) and was lower in children with confirmed or unconfirmed tuberculosis who started antituberculosis treatment (p

International audience; Postexposure prophylaxis (PEP) prevents human rabies and is accessible in Cambodia principally in Phnom Penh, the capital. Timely, affordable access to PEP is a challenge for the mainly rural population. We aimed to identify districts independently associated with PEP noncompletion to position frontline vaccination centers. We analyzed the 2009–2013 database at the Rabies Prevention Center at the Institut Pasteur du Cambodge, Phnom Penh. Logistic regressions identified nongeographic determinants of PEP noncompletion as well as the districts that were independently associated with noncompletion after adjustment for these determinants. The influence of distance by road was estimated using a boosted regression-trees model. We computed a population attributable fraction (rabies index (RI)) for each district and developed a map of this RI distribution. A cartographic analysis based on the statistic developed by Getis and Ord identified clusters of high-RI districts. Factors independently associated with noncompletion were pa-tients' district of residence, male sex, age 15–49 years, initial visit during rice harvest, the dog's status (culled or disappeared), and a prescribed PEP protocol requiring more than 3 PEP sessions (4 or 5). Four clusters of high-RI districts were identified using this analytical strategy, which is applicable to many vaccination or other health services. Positioning frontline PEP centers in these districts could significantly widen access to timely and adequate PEP.

International audience; Chikungunya virus (CHIKV) is an alphavirus circulating worldwide. Its presence in Asia has been reported since the 1950s, constituting the Asian genotype. Since 2005, strains from the Eastern, Central, and Southern African (ECSA) genotype have caused several outbreaks across Asia. Viruses from the ECSA genotype were also detected in Cambodia in late 2011 and led to an outbreak in a rural community in 2012. A former investigation from 2012 found a higher risk of infection in people younger than 40 years, suggesting a pre-existing herd immunity in the older Cambodian population due to infection with an Asian genotype. In 2016, we collected serum from equivalent numbers of individuals born before 1975 and born after 1980 that were also part of the 2012 study. We analyzed the 154 serum samples from 2016 for neutralization against the Cambodian ECSA isolate and three strains belonging to the Asian genotype. This experiment revealed that 22.5% (18/80) of the younger study participants had no CHIKV antibodies, whereas 5.4% (4/74) of the older population remained naive. Study participants infected during the ECSA outbreak had twofold neutralizing titers against the ECSA and the most ancient Asian genotype virus (Thailand 1958) compared to the other two Asian genotype viruses. The neutralization data also support the older population's exposure to an Asian genotype virus during the 1960s. The observed cross-reactivity confirms that the investigated CHIKV strains belong to a single serotype despite the emergence of novel ECSA genotype viruses and supports the importance of the development of a Chikungunya vaccine.

International audience; Longitudinal surveillance of 2 live bird markets in Cambodia revealed year-round, high co-circulation of H5, H7, and H9 influenza viruses. We detected influenza A viruses in 51.3% of ducks and 39.6% of chickens, and co-infections, mainly by H5 and H9 viruses, in 0.8% of ducks and 4.5% of chickens.

International audience; Although antibiotics are too often used inappropriately in Cambodia, published data on antimicrobial resistance in this country are scarce. Epidemic dissemination and the transfer of resistance genes to other bacterial species put the population at risk. The aim of this study was to evaluate the frequency and characteristics of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) isolated in consecutive samples tested at Institut Pasteur du Cambodge over a 4-year period (2012-2015). Antimicrobial susceptibility testing was performed by disk diffusion on agar technique and the results were read automatically using an OSIRIS system. The Etest was used to determine minimum inhibitory concentrations (MIC) for some resistance phenotypes. The strain most commonly identified was Escherichia coli (63.9%). The proportion of ESBL-E increased gradually over the study period, from 23.8% to 38.4%. ESBL was detected in 42.7% of the E. coli strains and 33.7% of all Klebsiella pneumoniae isolated. The proportion of ESBL-producing E. coli increased significantly from 28.9% in 2012 to 48.2% in 2015, while the increase for K. pneumoniae remained non-significant. Multidrug resistance was high in this Cambodian series, with some strains displaying resistance to all antibiotics available in the country. There is currently no established system for the surveillance of antimicrobial resistance in Cambodia. Collecting samples from clinical settings throughout the country is critical to assess the impact of antimicrobial drug use in patients in Cambodia and in the Mekong Region.