[A multi-resistant bacterium before the era of antibiotics: the agent of melioidosis]. / Une bactérie multirésistante avant l'ère des antibiotiques : l'agent de la mélioïdose.

Melioidosis is an infectious, tropical and emerging disease, due to a bacterium of the hydrotelluric environment, Burkholderia pseudomallei, which is considered as a potential biological weapon because of its exceptional resistance and virulence capacities. Its worldwide spread, outside the original endemic foci of Southeast Asia and Australia, is favoured by global warming and the diabetes mellitus pandemic, which is the main predisposing factor.In humans, melioidosis is an opportunistic infection, following professional (rice farmers, soldiers) or accidental contamination, by inhalation or inoculation. B. pseudomallei is a facultative intracellular bacterium that can overcome host immune defences, induce acute, subacute, or chronic invasive infection, or remain latent for years. The acute infection is polymorphic, bacteraemic in more than 50% of cases, frequently complicated by shock, and revealed by visceral abscesses, most often pulmonary. It is fatal in 20 to 50% of cases, the prognosis depending on the delay before the establishment of effective first-line antibiotic therapy, using ceftazidime or carbapenems, and therefore on the speed of bacteriological diagnosis.B. pseudomallei is a saprophytic bacterium, resident of the rhizosphere where it has developed and accumulated capacities to overcome environmental stresses and competition with organisms living in such ecosystem. These adaptation mechanisms are also the virulence factors that make melioidosis serious, in particular the efflux pumps that are the main support for its multi-resistance to antibiotics.

La mélioïdose est une maladie infectieuse, tropicale et émergente, due à une bactérie de l'environnement hydrotellurique, Burkholderia pseudomallei, qui est considérée comme arme biologique potentielle en raison de ses exceptionnelles capacités de résistance et de virulence. Son extension mondiale, en dehors des foyers endémiques originels d'Asie du Sud-Est et d'Australie, est favorisée par le réchauffement climatique et par la pandémie de diabète de type 2 qui en est le principal facteur prédisposant.Chez l'Homme, la mélioïdose est une infection opportuniste, consécutive à une contamination professionnelle (riziculteurs, militaires) ou accidentelle, par inhalation ou par inoculation. B. pseudomallei est une bactérie intracellulaire facultative qui peut déjouer les défenses immunitaires de l'hôte, induire une infection invasive, aiguë, subaiguë ou chronique, ou rester latente pendant des années. L'infection aiguë est polymorphe, bactériémique dans plus de 50 % des cas, fréquemment compliquée de choc, et révélée par des abcès viscéraux le plus souvent pulmonaires. Elle est mortelle dans 20 à 50 % des cas, le pronostic dépendant du délai avant la mise en place d'une antibiothérapie efficace, utilisant la ceftazidime ou les carbapénèmes, donc de la rapidité du diagnostic bactériologique.B. pseudomallei est une bactérie saprophyte, résidente de la rhizosphère où elle a développé et accumulé des capacités pour supporter les stress environnementaux et la compétition avec les organismes vivant dans cet écosystème. Ces mécanismes d'adaptation sont aussi les facteurs de virulence qui font toute la gravité de la mélioïdose, en particulier les pompes d'efflux qui sont le support principal de sa multirésistance aux antibiotiques.

[Laveran and the French Academy of Medicine]. / Laveran et l'Académie nationale de médecine.

In November 1880, Alphonse Laveran, stationed at the Constantine military hospital, addressed to the Academy of Medicine a "Note on a new parasite found in the blood of several patients with malaria fever". Léon Colin, professor at the Val-de-Grâce school, is the rapporteur, but he is not convinced by these observations, nor by two additional notes sent by Laveran in December 1880 and October 1881. This skepticism is shared by other academicians such as Joseph Laboulbène and Émile Duclaux.Twelve years will be necessary for Laveran to overcome the disbelief of the French scientific community. Three fundamental books donated to the Academy testify to the tenacity with which he gradually succeeded in convincing most of his colleagues: Traité des fièvres palustres avec la description des microbes du paludisme in 1884, Des hématozoaires du paludisme in 1887, and Du paludisme et de son hématozoaire in 1891.Laveran was elected to the Academy of Medicine on December 26, 1893. His resignation from the Military Health Corps enabled him to participate assiduously in meetings and to intervene in debates concerning infectious and tropical diseases, hygiene and prophylaxis. Obtaining the Nobel Prize in 1907 for his work on malaria, trypanosomiasis and colonial diseases crowned his work while honoring the Academy. Laveran was elected vice-president for the year 1919 and president for 1920, the year of the centenary of the Academy, the celebration of which he organized to the detriment of his health. He died two years later, having fulfilled his duty to the end of his strength.

Covid-19, an unfinished story.

The Covid-19 pandemic appeared in China in December 2019 as a cluster of transmissible pneumonia caused by a new betacoronavirus. On March 11, 2020, the World Health Organization (WHO) declared it a pandemic. Covid-19 is a mild infection in 80% of cases, serious in 15% and critical in 5%. Symptomatic forms include a first phase of flu-like viral invasion, and at times a second phase, dysimmune and inflammatory, with acute respiratory distress syndrome, multiorgan failure and thromboembolic complications. Degree of severity is related to age and comorbidities. SARS-CoV-2 is the third highly pathogenic Betacoronavirus to cross the species barrier. Its genome, an RNA of 29,903 nucleotides, shows strong homogeneity with bat coronaviruses from southern China, but the conditions for its passage in humans have yet to be elucidated. Mutations can give rise to variants of concern (VOC) that are more transmissible and able to evade the host's immune response. Several VOCs have succeeded and replaced one another: Alpha in October 2020, Beta and Gamma in December 2020, Delta in spring 2021 and Omicron in November 2021. The Covid-19 pandemic has evolved in five waves of unequal amplitude and severity, with geographical disparities. Worldwide, it has caused 395,000,000 confirmed cases including 5,700,000 deaths. Epidemiological surveillance applies several indicators (incidence rate, test positivity rate, effective R and occupancy rate of intensive care beds) supplemented by genomic monitoring to detect variants by sequencing. Non-pharmacological measures, particularly face mask wearing, have been effective in preventing the transmission of SARS-CoV-2. Few currently available drugs have proven useful, with the exception of dexamethazone for patients requiring oxygen therapy. Development of SARS-CoV-2 vaccines began early on many platforms. Innovation was brought about by the Pfizer-BioNTech and Moderna messenger RNA vaccines, which claim protective efficacy of 95% and 94.1% respectively, far higher than the 70% minimum set by the WHO. Governments have hesitated between two strategies, mitigation and suppression. The second has been favored in critical periods such as April 2020, when 2.5 billion people throughout the world were confined. Vaccination campaigns got underway at the end of December 2020 and progressed without reaching sufficient herd immunity, leading some nations to consider compulsory vaccination or to require a vaccine or health pass, in order for persons to access different activities. Will the pandemic stop with Omicron and become endemic? This part of the Covid-19 story remains to be told.

COVID-19 pandemic: lessons learned from more than a century of pandemics and current vaccine development for pandemic control.

Pandemic dynamics and health care responses are markedly different during the COVID-19 pandemic than in earlier outbreaks. Compared with established infectious disease such as influenza, we currently know relatively little about the origin, reservoir, cross-species transmission and evolution of SARS-CoV-2. Health care services, drug availability, laboratory testing, research capacity and global governance are more advanced than during 20th century pandemics, although COVID-19 has highlighted significant gaps. The risk of zoonotic transmission and an associated new pandemic is rising substantially. COVID-19 vaccine development has been done at unprecedented speed, with the usual sequential steps done in parallel. The pandemic has illustrated the feasibility of this approach and the benefits of a globally coordinated response and infrastructure. Some of the COVID-19 vaccines recently developed or currently in development might offer flexibility or sufficiently broad protection to swiftly respond to antigenic drift or emergence of new coronaviruses. Yet many challenges remain, including the large-scale production of sufficient quantity of vaccines, delivery of vaccines to all countries and ensuring vaccination of relevant age groups. This wide vaccine technology approach will be best employed in tandem with active surveillance for emerging variants or new pathogens using antigen mapping, metagenomics and next generation sequencing.

Impact of vaccines on antimicrobial resistance.

DRIVERS OF ANTIMICROBIAL RESISTANCE: Antibiotic use drives the development and spread of resistant bacterial infections. Antimicrobial resistance (AMR) has become a prolific global issue, due to significant increases in antibiotic use in humans, livestock and agriculture, inappropriate use (under-dosing and over-prescribing), and misuse of antibiotics (for viral infections where they are ineffective). Fewer new antibiotics are being developed. THE PROBLEM OF AMR: AMR is now considered a key threat to global health, leading to more mortality and increased healthcare costs threatening future conduct of routine medical procedures. Traditional approaches to address AMR include antibiotic stewardship, better hygiene/infection control, promoting antibiotic research and development, and restricting use for agricultural purposes. VACCINES AS A TOOL TO REDUCE AMR: While antibiotic development is declining, vaccine technology is growing. This review shows how vaccines can decrease AMR by preventing bacterial and viral infections, thereby reducing the use/misuse of antibiotics, and by preventing antibiotic-resistant infections. Vaccines are less likely to induce resistance. Some future uses and developments of vaccines are also discussed. CONCLUSIONS: Vaccines, along with other approaches, can help reduce AMR by preventing (resistant) infections and reducing antibiotic use. Industry and governments must focus on the development of novel vaccines and drugs against resistant infections to successfully reduce AMR. A graphical abstract is available online.

Seroprevalence and risk factors of hepatitis E among women of childbearing age in the Xieng Khouang province (Lao People's Democratic Republic), a cross-sectional survey.

BACKGROUND: Endemic hepatitis E in Southeast Asia increases the risk of death in pregnant women. In Lao People's Democratic Republic, infection with hepatitis E virus (HEV) is widespread in pig farms. No human data are available yet. This study determined the prevalence and risk factors for HEV infection among women of reproductive age living in urban and rural areas. METHODS: A cross-sectional study was conducted in Xieng Khouang province, selected for its high prevalence of HEV in pig farms, after a two-stage random sampling. Blood eluates of filter paper samples were tested by enzyme-linked immunosorbent assay for anti-HEV immunoglobulin G (IgG). Risk factors were investigated by bivariate and multivariate analyses. RESULTS: Of 226 women (112 rural and 114 urban), anti-HEV IgG was detected in 66 (29.2%), with more in rural than in urban areas (38.4% vs 20.2%; p=0.005). Age (25-29 y) and farming profession were associated with HEV positivity. Living in an urban area, a supply of clean drinking water and raw duck blood consumption were protective. CONCLUSIONS: Risks of HEV infection are more related to lack of drinking water resources than to promiscuity with pigs. Women of childbearing age could be targeted by future vaccination programs. Consumption of drinking water should be recommended during pregnancy.

Seroprevalence and risk factors of hepatitis B and C virus infections in female workers of Lao garment factories.

The prevalence of hepatitis B and C virus infections may be higher in vulnerable populations or in individuals likely to be exposed through risk behaviors such as female garment factory workers in Lao People's Democratic Republic. A cross-sectional study was performed on 400 female garment workers in Vientiane Capital. Women were tested for hepatitis B virus surface antigen and antibodies against hepatitis B core, surface antigen and hepatitis C virus using commercial Enzyme-linked immuno-absorbent assays. Participants completed a standardized questionnaire about potential risk factors for both infections. Sixteen women (4±1.9%) were HBsAg carriers, 187 (47%) had anti-HBc, 116 (29%) anti-HBs and 7 (1.8±1.3%) anti-HCV antibodies. Three factors were significantly associated with the presence of anti-HBc (indicating previous exposure to HBV): (i) residence in dormitories, (ii) more than one sexual partner, (iii) history of abortion. Despite a high risk of exposure, the prevalence of anti HBV and anti HCV infection markers in this sample of female workers was not higher than in the Lao general population. Our data suggest that exposure to HBV happens later during life and was significantly associated with sexual risk behavior. Thus, this study highlights the vulnerability of these women who were mostly young, uneducated, unvaccinated, of rural origin and were not aware of the risk of infections. An occupational health program targeting the female factory workers should be implemented in Lao PDR.

Chikungunya virus emergence in the Lao PDR, 2012-2013.

In May 2012, the first authenticated cases of active chikungunya virus infection were detected in Champasak Province, Southern Laos. Analysis of series of human samples and mosquito specimens collected during the outbreak and over the year that followed the emergence enabled the drawing up of a map of the progression of CHIKV and the establishment of a full genetic characterization of the virus.

Prevalence of Hepatitis B Virus Infection among Pregnant Women Attending Antenatal Clinics in Vientiane, Laos, 2008-2014.

The Lao People's Democratic Republic (PDR) is still considered a highly endemic country for hepatitis B, mainly due to perinatal transmission of hepatitis B virus (HBV), despite efforts made since 2004 for universal immunization of newborns. The prevalence of HBV surface antigen (HBsAg) carriage in pregnant women is a relevant marker for the risk of mother-to-child HBV transmission. This study aimed to assess the changes in prevalence of HBV infection among pregnant women attending the Mahosot Prenatal Clinic (Vientiane Capital). Methods. A retrospective study was performed in the Mahosot Hospital Laboratory to collect and analyze all the results of HBsAg testing in pregnant women from 2008 to 2014. Results. Of a total of 13,238 tested women of mean age of 26 years, 720 women (5,44% [95 CI: 5.1-5.8%]) were found HBsAg positive, the annual prevalence ranging from 4.6% to 6.2%. A slight but steady and significant decrease in prevalence over the 7 years of the study could be documented. Conclusion. Although below the 8% hyperendemic threshold, the HBsAg prevalence observed in pregnant women in Vientiane reflects a high risk of HBV perinatal transmission and call for a widespread infant immunization with an HBV vaccine birth dose.

High prevalence of intestinal worms in children up to 5 years of age in Huaphan province, Lao People's Democratic Republic (PDR).

BACKGROUND: The prevalence of soil-transmitted helminth infection is high in Lao People's Democratic Republic (PDR), reaching 62% among school-children. However, this prevalence presents wide regional variations, due to differences in healthcare access and environmental factors. Curiously, there are few studies on helminth infections in pre-school children - an age group targeted by the national de-worming campaign. Therefore, a preliminary study was conducted in a remote region of Huaphan Province, North Laos, to determine the prevalence of helminth infections in pre-school children. RESULTS: A total of 74 pre-school aged children provided stool samples for this study. Parasite eggs were detected in 41.9% with Ascaris lumbricoides being most common (32.4%). Presence of parasites was significantly associated with distance from health centres. CONCLUSIONS: Such a high prevalence of helminth infection indicates that the national deworming campaign is not adequate in the remote areas, in particular in villages distant from health care centres. It is necessary to ensure the proper administration of anti-helminthics to all children and to adapt the implementation of deworming campaigns to the specificities of each province.

Hydrological Regime and Water Shortage as Drivers of the Seasonal Incidence of Diarrheal Diseases in a Tropical Montane Environment.

BACKGROUND: The global burden of diarrhea is a leading cause of morbidity and mortality worldwide. In montane areas of South-East Asia such as northern Laos, recent changes in land use have induced increased runoff, soil erosion and in-stream suspended sediment loads, and potential pathogen dissemination. To our knowledge, few studies have related diarrhea incidences to catchment scale hydrological factors such as river discharge, and loads of suspended sediment and of Fecal Indicator Bacteria (FIB) such as Escherichia coli, together with sociological factors such as hygiene practices. We hypothesized that climate factors combined with human behavior control diarrhea incidence, either because higher rainfall, leading to higher stream discharges, suspended sediment loads and FIB counts, are associated with higher numbers of reported diarrhea cases during the rainy season, or because water shortage leads to the use of less safe water sources during the dry season. Using E. coli as a FIB, the objectives of this study were thus (1) to characterize the epidemiological dynamics of diarrhea in Northern Laos, and (2) to identify which hydro-meteorological and sociological risk factors were associated with diarrhea epidemics. METHODS: Considering two unconnected river catchments of 22 and 7,448 km2, respectively, we conducted a retrospective time series analysis of meteorological variables (rainfall, air temperature), hydrological variables (discharge, suspended sediments, FIB counts, water temperature), and the number of diarrheal disease cases reported at 6 health centers located in the 5 southern districts of the Luang Prabang Province, Lao PDR. We also examined the socio-demographic factors potentially affecting vulnerability to the effect of the climate factors, such as drinking water sources, hygiene habits, and recreational water exposure. RESULTS: Using thus a mixed methods approach, we found E. coli to be present all year long (100-1,000 Most Probable Number or MPN 100 mL-1) indicating that fecal contamination is ubiquitous and constant. We found that populations switch their water supply from wells to surface water during drought periods, the latter of which appear to be at higher risk of bacterial contamination than municipal water fountains. We thus found that water shortage in the Luang Prabang area triggers diarrhea peaks during the dry and hot season and that rainfall and aquifer refill ends the epidemic during the wet season. The temporal trends of reported daily diarrhea cases were generally bimodal with hospital admissions peaking in February-March and later in May-July. Annual incidence rates were higher in more densely populated areas and mostly concerned the 0-4 age group and male patients. CONCLUSIONS: We found that anthropogenic drivers, such as hygiene practices, were at least as important as environmental drivers in determining the seasonal pattern of a diarrhea epidemic. For diarrheal disease risk monitoring, discharge or groundwater level can be considered as relevant proxies. These variables should be monitored in the framework of an early warning system provided that a tradeoff is found between the size of the monitored catchment and the frequency of the measurement.

Factors associated with the failure of first and second-line antiretroviral therapies therapy, a case control study in Cambodian HIV-1 infected children.

BACKGROUND: Little is known about the efficacy of first and and second-line antiretroviral therapies (ART) for HIV-1 infected children in resource limited Southeast Asian settings. Previous studies have shown that orphans are at a higher risk for virological failure (VF) in Cambodia. Consequently most of them required transfer to second-line ART. We assessed the factors associated with VF among HIV-1 infected children who were either under first-line (mostly 3TC + D4T + NVP) or under second-line (mostly ABC + DDI + LPV) therapies at a referral hospital in Cambodia. METHODS: A case-control study was conducted from February to July 2013 at the National Pediatric Hospital among HIV-1 infected children (aged 1-15 years) under second-line ART (cases) or first-line (matched controls at a ratio of 1:3) regimens. Children were included if a HIV-1 RNA plasma viral load (VL) result was available for the preceding 12 months. A standardized questionnaire explored family sociodemographics, HIV history, and adherence to ART. Associations between VF (HIV-1 RNA levels ≥1000 copies/ml) and the children's characteristics were assessed using bivariate and multivariate analyses. RESULTS: A total of 232 children, 175 (75.4 %) under first-line and 57 (24.6 %) under second-line ART, for a median of 72.0 (IQR: 68.0-76.0) months, were enrolled. Of them, 94 (40.5 %) were double orphans and 51 (22.0 %) single orphans, and 77 (33.2 %) were living in orphanages. A total of 222 children (95.6 %) were deemed adherent to ART. Overall, 18 (7.7 %; 95 % CI 4.6-11.9) showed a VF, 14 (8.6 %; 95 % CI 4.8-14.0) under first-line and 4 (7.0 %; 95 % CI 1.9-17.0) under second-line ART (p = 0.5). Their median CD4 percentage was 8 % (IQR 2.9-12.9) at ART initiation. Children under second-line ART were older; more often double orphans, and had lower CD4 cell counts at the last control. In the multivariate analysis, having the last CD4 percentage below 15 % was the only factor associated with VF for ART regimen separately or when combined (OR 40.4; 95 % CI 11-134). CONCLUSIONS: The pattern of risk factors for VF in children is changing in Cambodia. Improved adherence evaluation and intensified monitoring of children with low CD4 counts is needed to decrease the risk of VF.

Antibiotic prescription behaviours in Lao People's Democratic Republic: a knowledge, attitude and practice survey.

OBJECTIVE: To assess the antibiotic prescribing practices of doctors working in the Lao People's Democratic Republic and their knowledge of local antibiotic resistance patterns. METHODS: Doctors attending morning meetings in 25 public hospitals in four provinces were asked to complete a knowledge, attitude and practice survey. The questionnaire contained 43 multiple choice questions that the doctor answered at the time of the meeting. FINDINGS: The response rate was 83.4% (386/463). Two hundred and seventy doctors (59.8%) declared that they had insufficient information about antibiotics. Only 14.0% (54/386) recognized the possibility of cephalosporin cross-resistance in methicillin-resistant Staphylococcus aureus. Most participants had no information about local antibiotic resistance for Salmonella Typhi (211/385, 54.8%) and hospital-acquired pneumonia (253/384, 65.9%). Unnecessary antibiotic prescriptions were considered as harmless by 115 participants and 148 considered locally-available generic antibiotics to be of poor quality. Nearly three-quarters (280/386) of participants agreed that it was difficult to select the correct antibiotics. Most participants (373/386) welcomed educational programmes on antibiotic prescribing and 65.0% (249/383) preferred local over international antibiotic guidelines. CONCLUSION: Doctors in the Lao People's Democratic Republic seem to favour antibiotic prescribing interventions. Health authorities should consider a capacity building programme that incorporates antibiotic prescribing and hospital infection control.

Diphtheria in Lao PDR: Insufficient Coverage or Ineffective Vaccine?

BACKGROUND: During late 2012 and early 2013 several outbreaks of diphtheria were notified in the North of the Lao People's Democratic Republic. The aim of this study was to determine whether the re-emergence of this vaccine-preventable disease was due to insufficient vaccination coverage or reduction of vaccine effectiveness within the affected regions. METHODS: A serosurvey was conducted in the Huaphan Province on a cluster sampling of 132 children aged 12-59 months. Serum samples, socio-demographic data, nutritional status and vaccination history were collected when available. Anti-diphtheria and anti-tetanus IgG antibody levels were measured by ELISA. RESULTS: Overall, 63.6% of participants had detectable diphtheria antibodies and 71.2% tetanus antibodies. Factors independently associated with non-vaccination against diphtheria were the distance from the health centre (OR: 6.35 [95% CI: 1.4-28.8], p = 0.01), the Lao Theung ethnicity (OR: 12.2 [95% CI:1,74-85, 4], p = 0.01) and the lack of advice on vaccination given at birth (OR: 9.8 [95% CI: 1.5-63.8], (p = 0.01) while the level of maternal edu-cation was a protective factor (OR: 0.08 [95% CI: 0.008-0.81], p = 0.03). Most respondents claimed financial difficulties as the main reason for non-vaccination. Out of 55 children whose vaccination certificates stated that they were given all 3 doses of diphtheria-containing vaccine, 83.6% had diphtheria antibodies and 92.7% had tetanus antibodies. Furthermore, despite a high prevalence of stunted and underweight children (53% and 25.8%, respectively), the low levels of anti-diphtheria antibodies were not correlated to the nutritional status. CONCLUSIONS: Our data highlight a significant deficit in both the vaccination coverage and diphtheria vaccine effectiveness within the Huaphan Province. Technical deficiencies in the methods of storage and distribution of vaccines as well as unreliability of vaccination cards are discussed. Several hypotheses are advanced to explain such a decline in immunity against diphtheria and recommendations are provided to prevent future outbreaks.

Colonization with Enterobacteriaceae producing ESBLs in children attending pre-school childcare facilities in the Lao People's Democratic Republic.

OBJECTIVES: Intestinal carriage constitutes an important reservoir of antimicrobial-resistant bacteria, with some of the highest rates reported from Asia. Antibiotic resistance has been little studied in Laos, where some antibiotics are available without restriction, but others such as carbapenems are not available. PATIENTS AND METHODS: We collected stools from 397 healthy children in 12 randomly selected pre-school childcare facilities in and around Vientiane. Colonization with ESBL-producing Enterobacteriaceae (ESBLE) and carbapenemase-producing Enterobacteriaceae (CPE) was detected using a disc diffusion screening test and ESBLE were characterized using WGS. Risk factor data were collected by questionnaire. RESULTS: Ninety-two children (23%) were colonized with ESBLE, mainly Escherichia coli carrying blaCTX-M and Klebsiella pneumoniae carrying blaSHV or blaCTX-M, which were frequently resistant to multiple antibiotic classes. Although residence in Vientiane Capital, foreign travel, higher maternal level of education, antibiotic use in the preceding 3 months and attending a childcare facility with a 'good' level of hygiene were all associated with ESBLE colonization on univariable analysis, a significant association remained only for antibiotic use when a stepwise approach was used with a multivariate random-effects model. WGS analysis suggested transmission in both childcare facilities and community settings. CONCLUSIONS: The high prevalence of paediatric colonization with ESBLE in Laos, one of the highest reported in Asia, is probably the result of inappropriate antibiotic use. Paediatric colonization with CPE was not identified in this study, but it is important to continue to monitor the spread of antibiotic-resistant Enterobacteriaceae in Laos.