Prevalence of pulmonary tuberculosis and HIV infections and risk factors associated to tuberculosis in detained persons in Antananarivo, Madagascar.

The incidence rate of tuberculosis in prisons is estimated to be 8 times greater than that in the general population in Madagascar. Our objectives were to estimate the prevalence of pulmonary tuberculosis and HIV infection among prisoners and to identify risk factors associated with tuberculosis. We conducted a cross-sectional study at the central prison of Antananarivo from March to July 2021. Individual male and female inmates aged ≥ 13 years who had lived in the prison for at least three months prior to the study period were included as participants. Acid-fast bacilli detection by microscopy and/or culture, an intradermal tuberculin test, a chest X-ray, and a rapid diagnostic orientation test for HIV were performed. Among 748 participants, 4 (0.5%) were confirmed to have pulmonary tuberculosis. Overall, 14 (1.9%) patients had "confirmed" or "probable" tuberculosis [0.90-2.84, 95% CI]. The proportion of participants with latent tuberculosis infection was 69.6% (517/743) based on a positive tuberculin test without clinical symptoms or radiography images indicating tuberculosis. Out of 745 HIV screening tests, three showed reactive results (0.4%). Age (OR = 4.4, 95% CI [1.4-14.0]) and prior tuberculosis treatment (or episodes) were found to be associated with confirmed and probable tuberculosis.

Mixed methods to evaluate knowledge, attitudes and practices (KAP) towards rabies in central and remote communities of Moramanga district, Madagascar.

Control of dog-mediated rabies relies on raising awareness, access to post-exposure prophylaxis (PEP) and mass dog vaccination. To assess rabies awareness in Moramanga district, Madagascar, where rabies is endemic, two complementary quantitative and qualitative approaches were carried out in 2018. In the quantitative approach, a standardized questionnaire was administered to 334 randomized participants living in 170 households located less than 5 km from the anti-rabies treatment center (ARTC) located in Moramanga city (thereafter called the central area), and in 164 households located more than 15 km away from the ARTC in two rural communes (thereafter called the remote area). Logistic regression models were fitted to identify factors influencing knowledge and practice scores. The qualitative approach consisted in semi-structured interviews conducted with 28 bite victims who had consulted the ARTC, three owners of biting dogs, three ARTC staff and two local authorities. Overall, 15.6% (52/334) of households owned at least one dog. The dog-to-human ratio was 1:17.6. The central area had a significantly higher dog bite incidence (0.53 per 100 person-years, 95% CI: 0.31-0.85) compared to the remote area (0.22 per 100 person-years, 95% CI: 0.09-0.43) (p = 0.03). The care pathway following a bite depended on wound severity, how the dog was perceived and its owner's willingness to cover costs. Rabies vaccination coverage in dogs in the remote area was extremely low (2.4%). Respondents knew that vaccination prevented animal rabies but owners considered that their own dogs were harmless and cited access and cost of vaccine as main barriers. Most respondents were not aware of the existence of the ARTC (85.3%), did not know the importance of timely access to PEP (92.2%) or that biting dogs should be isolated (89.5%) and monitored. Good knowledge scores were significantly associated with having a higher socio-economic status (OR = 2.08, CI = 1.33-3.26) and living in central area (OR = 1.91, CI = 1.22-3.00). Good practice scores were significantly associated with living in central area (OR = 4.78, CI = 2.98-7.77) and being aware of the ARTC's existence (OR = 2.29, CI = 1.14-4.80). In Madagascar, knowledge on rabies was disparate with important gaps on PEP and animal management. Awareness campaigns should inform communities (i) on the importance of seeking PEP as soon as possible after an exposure, whatever the severity of the wound and the type of biting dog who caused it, and (ii) on the existence and location of ARTCs where free-of-charge PEP is available. They should also encourage owners to isolate and monitor the health of biting dogs. Above all, awareness and dog vaccination campaigns should be designed so as to reach the more vulnerable remote rural populations as knowledge, good practices and vaccination coverage were lower in these areas. They should also target households with a lower socio-economic status. If awareness campaigns are likely to succeed in improving access to ARTCs in Madagascar, their impact on prompting dog owners to vaccinate their own dogs seems more uncertain given the financial and access barriers. Therefore, to reach the 70% dog vaccination coverage goal targeted in rabies elimination programs, awareness campaigns must be combined with free-of-charge mass dog vaccination.

Multiple Introductions of Yersinia pestis during Urban Pneumonic Plague Epidemic, Madagascar, 2017.

Pneumonic plague (PP) is characterized by high infection rate, person-to-person transmission, and rapid progression to severe disease. In 2017, a PP epidemic occurred in 2 Madagascar urban areas, Antananarivo and Toamasina. We used epidemiologic data and Yersinia pestis genomic characterization to determine the sources of this epidemic. Human plague emerged independently from environmental reservoirs in rural endemic foci >20 times during August-November 2017. Confirmed cases from 5 emergences, including 4 PP cases, were documented in urban areas. Epidemiologic and genetic analyses of cases associated with the first emergence event to reach urban areas confirmed that transmission started in August; spread to Antananarivo, Toamasina, and other locations; and persisted in Antananarivo until at least mid-November. Two other Y. pestis lineages may have caused persistent PP transmission chains in Antananarivo. Multiple Y. pestis lineages were independently introduced to urban areas from several rural foci via travel of infected persons during the epidemic.

Investigation of Dengue Infection in Asymptomatic Individuals during a Recent Outbreak in La Réunion.

The number of dengue cases has increased dramatically over the past 20 years and is an important concern, particularly as the trends toward urbanization continue. While the majority of dengue cases are thought to be asymptomatic, it is unknown to what extent these contribute to transmission. A better understanding of their importance would help to guide control efforts. In 2019, a dengue outbreak in La Reunion resulted in more than 18,000 confirmed cases. Between October 2019 and August 2020, 19 clusters were investigated in the south, west, and east of the island, enabling the recruitment of 605 participants from 368 households within a 200 m radius of the home of the index cases (ICs). No active asymptomatic infections confirmed by RT-PCR were detected. Only 15% were possible asymptomatic dengue infections detected by the presence of anti-dengue IgM antibodies. Only 5.3% of the participants had a recent dengue infection confirmed by RT-PCR. Although the resurgence of dengue in La Réunion is very recent (2016), the rate of anti-dengue IgG positivity, a marker of past infections, was already high at 43% in this study. Dengue transmission was focal in time and space, as most cases were detected within a 100-m radius of the ICs, and within a time interval of less than 7 days between infections detected in a same cluster. No particular demographic or socio-cultural characteristics were associated with dengue infections. On the other hand, environmental risk factors such as type of housing or presence of rubbish in the streets were associated with dengue infections.

Genomic epidemiology of SARS-CoV-2 in Cambodia, January 2020 to February 2021.

The first case of coronavirus disease 2019 (COVID-19) in Cambodia was confirmed on 27 January 2020 in a traveller from Wuhan. Cambodia subsequently implemented strict travel restrictions, and although intermittent cases were reported during the first year of the COVID-19 pandemic, no apparent widespread community transmission was detected. Investigating the routes of severe acute respiratory coronavirus 2 (SARS-CoV-2) introduction into the country was critical for evaluating the implementation of public health interventions and assessing the effectiveness of social control measures. Genomic sequencing technologies have enabled rapid detection and monitoring of emerging variants of SARS-CoV-2. Here, we detected 478 confirmed COVID-19 cases in Cambodia between 27 January 2020 and 14 February 2021, 81.3 per cent in imported cases. Among them, fifty-four SARS-CoV-2 genomes were sequenced and analysed along with representative global lineages. Despite the low number of confirmed cases, we found a high diversity of Cambodian viruses that belonged to at least seventeen distinct PANGO lineages. Phylogenetic inference of SARS-CoV-2 revealed that the genetic diversity of Cambodian viruses resulted from multiple independent introductions from diverse regions, predominantly, Eastern Asia, Europe, and Southeast Asia. Most cases were quickly isolated, limiting community spread, although there was an A.23.1 variant cluster in Phnom Penh in November 2020 that resulted in a small-scale local transmission. The overall low incidence of COVID-19 infections suggests that Cambodia's early containment strategies, including travel restrictions, aggressive testing and strict quarantine measures, were effective in preventing large community outbreaks of COVID-19.

Proactive community case management decreased malaria prevalence in rural Madagascar: results from a cluster randomized trial.

BACKGROUND: Malaria remains a leading cause of morbidity and mortality worldwide, with progress in malaria control stalling in recent years. Proactive community case management (pro-CCM) has been shown to increase access to diagnosis and treatment and reduce malaria burden. However, lack of experimental evidence may hinder the wider adoption of this intervention. We conducted a cluster randomized community intervention trial to assess the efficacy of pro-CCM at decreasing malaria prevalence in rural endemic areas of Madagascar. METHODS: Twenty-two fokontany (smallest administrative unit) of the Mananjary district in southeast Madagascar were selected and randomized 1:1 to pro-CCM (intervention) or conventional integrated community case management (iCCM). Residents of all ages in the intervention arm were visited by a community health worker every 2 weeks from March to October 2017 and screened for fever; those with fever were tested by a rapid diagnostic test (RDT) and treated if positive. Malaria prevalence was assessed using RDTs on all consenting study area residents prior to and following the intervention. Hemoglobin was measured among women of reproductive age. Intervention impact was assessed via difference-in-differences analyses using logistic regressions in generalized estimating equations. RESULTS: A total of 27,087 and 20,475 individuals participated at baseline and endline, respectively. Malaria prevalence decreased from 8.0 to 5.4% in the intervention arm for individuals of all ages and from 6.8 to 5.7% in the control arm. Pro-CCM was associated with a significant reduction in the odds of malaria positivity in children less than 15 years (OR = 0.59; 95% CI [0.38-0.91]), but not in older age groups. There was no impact on anemia among women of reproductive age. CONCLUSION: This trial suggests that pro-CCM approaches could help reduce malaria burden in rural endemic areas of low- and middle-income countries, but their impact may be limited to younger age groups with the highest malaria burden. TRIAL REGISTRATION: NCT05223933. Registered on February 4, 2022.

Analytical framework to evaluate and optimize the use of imperfect diagnostics to inform outbreak response: Application to the 2017 plague epidemic in Madagascar.

During outbreaks, the lack of diagnostic "gold standard" can mask the true burden of infection in the population and hamper the allocation of resources required for control. Here, we present an analytical framework to evaluate and optimize the use of diagnostics when multiple yet imperfect diagnostic tests are available. We apply it to laboratory results of 2,136 samples, analyzed with 3 diagnostic tests (based on up to 7 diagnostic outcomes), collected during the 2017 pneumonic (PP) and bubonic plague (BP) outbreak in Madagascar, which was unprecedented both in the number of notified cases, clinical presentation, and spatial distribution. The extent of these outbreaks has however remained unclear due to nonoptimal assays. Using latent class methods, we estimate that 7% to 15% of notified cases were Yersinia pestis-infected. Overreporting was highest during the peak of the outbreak and lowest in the rural settings endemic to Y. pestis. Molecular biology methods offered the best compromise between sensitivity and specificity. The specificity of the rapid diagnostic test was relatively low (PP: 82%, BP: 85%), particularly for use in contexts with large quantities of misclassified cases. Comparison with data from a subsequent seasonal Y. pestis outbreak in 2018 reveal better test performance (BP: specificity 99%, sensitivity: 91%), indicating that factors related to the response to a large, explosive outbreak may well have affected test performance. We used our framework to optimize the case classification and derive consolidated epidemic trends. Our approach may help reduce uncertainties in other outbreaks where diagnostics are imperfect.

Adaptation of time-driven activity-based costing to the evaluation of the efficiency of ambulatory care provided in the emergency department.

Objectives: The aim of this study was: (1) to adapt the time-driven activity-based costing (TDABC) method to emergency department (ED) ambulatory care; (2) to estimate the cost of care associated with frequently encountered ambulatory conditions; and (3) to compare costs calculated using estimated time and objectively measured time. Methods: TDABC was applied to a retrospective cohort of patients with upper respiratory tract infections, urinary tract infections, unspecified abdominal pain, lower back pain and limb lacerations who visited an ED in Québec City (Canada) during fiscal year 2015-2016. The calculated cost of care was the product of the time required to complete each care procedure and the cost per minute of each human resource or equipment involved. Costing based on durations estimated by care professionals were compared to those based on objective measurements in the field. Results: Overall, 220 care episodes were included and 3080 time measurements of 75 different processes were collected. Differences between costs calculated using estimated and measured times were statistically significant for all conditions except lower back pain and ranged from $4.30 to $55.20 (US) per episode. Differences were larger for conditions requiring more advanced procedures, such as imaging or the attention of ED professionals. Conclusions: The greater the use of advanced procedures or the involvement of ED professionals in the care, the greater is the discrepancy between estimated-time-based and measured-time-based costing. TDABC should be applied using objective measurement of the time per procedure.

Assessing the safety, impact and effectiveness of RTS,S/AS01E malaria vaccine following its introduction in three sub-Saharan African countries: methodological approaches and study set-up.

BACKGROUND: Following a 30-year development process, RTS,S/AS01E (GSK, Belgium) is the first malaria vaccine to reach Phase IV assessments. The World Health Organization-commissioned Malaria Vaccine Implementation Programme (MVIP) is coordinating the delivery of RTS,S/AS01E through routine national immunization programmes in areas of 3 countries in sub-Saharan Africa. The first doses were given in the participating MVIP areas in Malawi on 23 April, Ghana on 30 April, and Kenya on 13 September 2019. The countries participating in the MVIP have little or no baseline incidence data on rare diseases, some of which may be associated with immunization, a deficit that could compromise the interpretation of possible adverse events reported following the introduction of a new vaccine in the paediatric population. Further, effects of vaccination on malaria transmission, existing malaria control strategies, and possible vaccine-mediated selective pressure on Plasmodium falciparum variants, could also impact long-term malaria control. To address this data gap and as part of its post-approval commitments, GSK has developed a post-approval plan comprising of 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S/AS01E through active participant follow-up in the context of its real-life implementation. METHODS: EPI-MAL-002 (NCT02374450) is a pre-implementation safety surveillance study that is establishing the background incidence rates of protocol-defined adverse events of special interest. EPI-MAL-003 (NCT03855995) is an identically designed post-implementation safety and vaccine impact study. EPI-MAL-005 (NCT02251704) is a cross-sectional pre- and post-implementation study to measure malaria transmission intensity and monitor the use of other malaria control interventions in the study areas, and EPI-MAL-010 (EUPAS42948) will evaluate the P. falciparum genetic diversity in the periods before and after vaccine implementation. CONCLUSION: GSK's post-approval plan has been designed to address important knowledge gaps in RTS,S/AS01E vaccine safety, effectiveness and impact. The studies are currently being conducted in the MVIP areas. Their implementation has provided opportunities and posed challenges linked to conducting large studies in regions where healthcare infrastructure is limited. The results from these studies will support ongoing evaluation of RTS,S/AS01E's benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa.

Pain induced by investigations and procedures commonly administered to older adults in the emergency department: a prospective cohort study.

BACKGROUND: This study aimed to assess the level of pain induced by common interventions performed in older adults consulting to the ED. METHODS: We conducted a prospective multicentre observational cohort study in two academic EDs (Quebec City, Canada) between June 2018 and December 2019. A convenience sample of well-oriented and haemodynamically stable older adults (≥65 years old) who underwent at least two interventions during their ED stay was recruited. The level of pain was assessed using an 11-point Numerous Rating Scale (NRS) and is presented using median and IQR or categorised as no pain (0), mild (1-3), moderate (4-6) or severe pain (7-10). RESULTS: A total of 318 patients were included. The mean age was 77.8±8.0 years old and 54.4% were female . The number of pain assessments per intervention ranged between 22 (urinary catheterisation) and 240 (intravenous catheter). All imaging investigations (X-rays, CT and bedside ultrasound) were associated with a median level of pain of 0. The median level of pain for other interventions was as follows: blood samplings (n=231, NRS 1 (IQR 0-3)), intravenous catheters (n=240, NRS 2 (IQR 0-4)), urinary catheterisations (n=22, NRS 4.5 (IQR 2-6)), cervical collars (n=50, NRS 5 (IQR 0-8)) and immobilisation mattresses (n=34, NRS 5 (IQR 0-8)). Urinary catheterisations (63.8%), cervical collars (56.0%) and immobilisation mattresses (52.9%) frequently induced moderate or severe pain. CONCLUSIONS: Most interventions administered to older adults in the ED are associated with no or low pain intensity. However, urinary catheterisation and spinal motion restriction devices are frequently associated with moderate or severe pain.

How geographic access to care shapes disease burden: The current impact of post-exposure prophylaxis and potential for expanded access to prevent human rabies deaths in Madagascar.

BACKGROUND: Post-exposure prophylaxis (PEP) is highly effective at preventing human rabies deaths, however access to PEP is limited in many rabies endemic countries. The 2018 decision by Gavi to add human rabies vaccine to its investment portfolio should expand PEP availability and reduce rabies deaths. We explore how geographic access to PEP impacts the rabies burden in Madagascar and the potential benefits of improved provisioning. METHODOLOGY & PRINCIPAL FINDINGS: We use spatially resolved data on numbers of bite patients seeking PEP across Madagascar and estimates of travel times to the closest clinic providing PEP (N = 31) in a Bayesian regression framework to estimate how geographic access predicts reported bite incidence. We find that travel times strongly predict reported bite incidence across the country. Using resulting estimates in an adapted decision tree, we extrapolate rabies deaths and reporting and find that geographic access to PEP shapes burden sub-nationally. We estimate 960 human rabies deaths annually (95% Prediction Intervals (PI): 790-1120), with PEP averting an additional 800 deaths (95% PI: 640-970) each year. Under these assumptions, we find that expanding PEP to one clinic per district (83 additional clinics) could reduce deaths by 19%, but even with all major primary clinics provisioning PEP (1733 additional clinics), we still expect substantial rabies mortality. Our quantitative estimates are most sensitive to assumptions of underlying rabies exposure incidence, but qualitative patterns of the impacts of travel times and expanded PEP access are robust. CONCLUSIONS & SIGNIFICANCE: PEP is effective at preventing rabies deaths, and in the absence of strong surveillance, targeting underserved populations may be the most equitable way to provision PEP. Given the potential for countries to use Gavi funding to expand access to PEP in the coming years, this framework could be used as a first step to guide expansion and improve targeting of interventions in similar endemic settings where PEP access is geographically restricted and baseline data on rabies risk is lacking. While better PEP access should save many lives, improved outreach, surveillance, and dog vaccination will be necessary, and if rolled out with Gavi investment, could catalyze progress towards achieving zero rabies deaths.

Is Madagascar at the edge of a generalised HIV epidemic? Situational analysis.

OBJECTIVES: To describe the epidemiological situation of the HIV/AIDS epidemic and to identify the main drivers for vulnerability in Madagascar. DESIGN: Literature review, qualitative research and situational analysis. DATA SOURCES: Search of electronic bibliographic databases, national repositories of documentation from 1998 to 2018. Search keywords included Madagascar, HIV, sexually transmitted infections, men who have sex with men (MSM), sex workers (SWs), transactional sex (TS), injecting drug users (IDUs), vulnerability and sexual behaviour. Qualitative sources were interviews and focus group discussions. REVIEW METHODS: Studies focused on HIV and/or vulnerability of HIV in Madagascar in general, and key populations (KPs) and HIV/AIDS response were taken into account. National reports from key HIV response actors were included. RESULTS: Madagascar is characterised by a low HIV/AIDS epidemic profile in the general population (GP) (0.3%) combined with a high prevalence of HIV among KPs (SWs, MSM and IDUs).An increase in HIV prevalence among KP has been observed during recent years. Hospital-based data suggest an increase in HIV prevalence among the GP. The vulnerability traits are inconsistent use of condoms, multipartner relationships and other contextual factors like widespread TS and gender inequality. A high prevalence/incidence of sexually transmitted infections could indicate a high vulnerability to HIV/AIDS. However, there are no reports of HIV prevalence of >1% in antenatal consultation. CONCLUSION: There is not enough evidence to make a conclusion about the HIV epidemiological situation in Madagascar due to the scarcity of the epidemiological data. However, Madagascar may be closer to a turning point towards a high-prevalence epidemic with severe consequences, particularly when taking into account its socioeconomical fragility and underlying vulnerabilities. More precise epidemiological data and improved HIV/AIDS diagnosis and case management should be a public health priority.

Perception of Drug Vendors and Pig and Poultry Farmers of Imerintsiatosika, in Madagascar, Toward Risks Related to Antibiotic Usage: A Q-Method Approach.

Antimicrobial resistance is a One Health issue that must be tackled worldwide. In order to implement effective communication strategies in Madagascar, a better understanding must be gained of practices and perceptions related to antimicrobial use at the smallholder farm level. Our study used a semi-qualitative approach, called Q methodology, to identify patterns of opinion on antimicrobial use, or its alternatives, among pig and poultry smallholders and drug vendors in the commune of Imerintsiatosika, in Madagascar. Twenty-nine breeders and 23 drug vendors were asked to rank, respectively, 38 and 45 statements, produced from semi-structured interviews and secondary data, through a 7 grade scale from -3 (totally disagree) to +3 (totally agree) about antimicrobial use, related risks and alternatives. The interview ended with a discussion around extreme statements. The Q-sortings were analyzed by factor analysis and Principal Component Analysis. Regarding antimicrobial use, antimicrobial resistance and alternatives, the breeders and drug vendors were divided according to three discourses: "A: confidence in antibiotics" (respectively, 13 and 6 individuals), "B: belief in alternatives" (7 and 7 individuals), and "C: moderate approach to antibiotic use" (6 and 6 individuals), explaining, respectively, 57 and 60% of total variance. Group A was associated with the use of antibiotics as a preventive measure, poor knowledge of resistance and low trust in alternatives. Group B considered the preventive use of antibiotics to be a major problem for antimicrobial resistance and believed that alternatives, such as vaccines, were useful preventive methods. Group C seemed to have a hazy opinion. The presence of three main points of view offers the possibility to adapt awareness messages. Group B might also be used as a showcase to reduce the amounts of antibiotics used by the two other groups. This study revealed different practices and risk perceptions related to antimicrobial use that must be better characterized and accurately quantified.

Human plague: An old scourge that needs new answers.

Yersinia pestis, the bacterial causative agent of plague, remains an important threat to human health. Plague is a rodent-borne disease that has historically shown an outstanding ability to colonize and persist across different species, habitats, and environments while provoking sporadic cases, outbreaks, and deadly global epidemics among humans. Between September and November 2017, an outbreak of urban pneumonic plague was declared in Madagascar, which refocused the attention of the scientific community on this ancient human scourge. Given recent trends and plague's resilience to control in the wild, its high fatality rate in humans without early treatment, and its capacity to disrupt social and healthcare systems, human plague should be considered as a neglected threat. A workshop was held in Paris in July 2018 to review current knowledge about plague and to identify the scientific research priorities to eradicate plague as a human threat. It was concluded that an urgent commitment is needed to develop and fund a strong research agenda aiming to fill the current knowledge gaps structured around 4 main axes: (i) an improved understanding of the ecological interactions among the reservoir, vector, pathogen, and environment; (ii) human and societal responses; (iii) improved diagnostic tools and case management; and (iv) vaccine development. These axes should be cross-cutting, translational, and focused on delivering context-specific strategies. Results of this research should feed a global control and prevention strategy within a "One Health" approach.

An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial.

BACKGROUND: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. METHODS: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague 'seasons'. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. DISCUSSION: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. TRIAL REGISTRATION: ClinicalTrials.gov NCT04110340 . Registered on 1 October 2019.

Inequalities in cause-specific mortality in children and adolescents in the Moramanga health survey, Madagascar.

OBJECTIVES: One child or young adolescent dies every 10 min in Madagascar and large disparities in survival persist. We estimated cause-specific mortality in a cohort of children aged 0-14 in the Moramanga district and explored how causes of death shape these inequalities. METHODS: Children were followed prospectively between 2012 and 2017. Causes of death were established based on verbal autopsies. Incidence rate ratios were estimated in Poisson regression models. RESULTS: The risk of dying before age 15 was 68.1 per thousand live births. Risks of dying were highest in the first year of life (31.2‰) and lowest in children aged 10-14 (6.4‰). The male-to-female sex ratios of mortality increased with age and reached 2.3 among adolescents aged 10-14. Communicable, nutritional and neonatal causes accounted for 79.5% of deaths below age 5 and 47.0% above age 5. Mortality was positively associated with household poverty, lack of education of the household head, and rural residence. CONCLUSIONS: Interventions should be designed with an equity lens to reduce large disparities in survival and be tailored to the needs of each age-group.

Rapid metagenomic characterization of a case of imported COVID-19 in Cambodia.

Rapid production and publication of pathogen genome sequences during emerging disease outbreaks provide crucial public health information. In resource-limited settings, especially near an outbreak epicenter, conventional deep sequencing or bioinformatics are often challenging. Here we successfully used metagenomic next generation sequencing on an iSeq100 Illumina platform paired with an open-source bioinformatics pipeline to quickly characterize Cambodia's first case of COVID-2019.

Factors Influencing Atypical Clinical Presentations during the 2017 Madagascar Pneumonic Plague Outbreak: A Prospective Cohort Study.

In late 2017, Madagascar experienced a large urban outbreak of pneumonic plague, the largest outbreak to date this century. During the outbreak, there were widespread reports of plague patients presenting with atypical symptoms, such as prolonged duration of illness and upper respiratory tract symptoms. Reported mortality among plague cases was also substantially lower than that reported in the literature (25% versus 50% in treated patients). A prospective multicenter observational study was carried out to investigate potential reasons for these atypical presentations. Few subjects among our cohort had confirmed or probable plague, suggesting that, in part, there was overdiagnosis of plague cases by clinicians. However, 35% subjects reported using an antibiotic with anti-plague activity before hospital admission, whereas 55% had antibiotics with anti-plague activity detected in their serum at admission. Although there may have been overdiagnosis of plague by clinicians during the outbreak, the high frequency of community antibiotic may partly explain the relatively few culture-positive sputum samples during the outbreak. Community antibiotic use may have also altered the clinical presentation of plague patients. These issues make accurate detection of patients and the development of clinical case definitions and triage algorithms in urban pneumonic plague outbreaks difficult.

Performance of plague rapid diagnostic test compared to bacteriology: a retrospective analysis of the data collected in Madagascar.

BACKGROUND: Plague is a highly fatal disease caused by Yersinia pestis. Late diagnosis hampers disease outcome and effectiveness of control measures, induces death and disease spread. Advance on its diagnosis was the use of lateral flow rapid diagnostic test (RDT). METHODS: We assessed the performance of the plague RDT based on Y. pestis F1 antigen detection more than 15 years after its deployment in Madagascar. We compared the RDT with bacteriological culture results, using data from plague notified cases collected during the periods for which both tests were performed independently and systematically. RESULTS: Used with bubonic plague (BP) patient samples, RDTs had a sensitivity of 100% (95% CI: 99.7-100%), a specificity of 67% (95% CI: 64-70%) with a good agreement between bacteriology and RDT results (86%; κ = 0.70, 95% CI 0.67-0.73). For pneumonic plague (PP), RDT had a sensitivity of 100% (95% CI: 91-100%) and a specificity of 59% (95% CI: 49-68%) and concordance between the bacteriological and plague RDT results was moderate (70%; κ = 0.43, 95% CI 0.32-0.55). Analysis focusing on the 2017-2018 plague season including the unprecedented epidemic of PP showed that RDT used on BP samples still had a sensitivity of 100% (95% CI: 85-100%) and a specificity of 82% (95% CI: 48-98%) with a very good agreement with bacteriology 94% (κ = 0.86, 95% CI 0.67-1); for PP samples, concordance between the bacteriological and plague RDT results was poor (61%; κ = - 0.03, 95% CI -0.17 - 0.10). CONCLUSIONS: RDT performance appeared to be similar for the diagnosis of BP and PP except during the 2017 PP epidemic where RDT performance was low. This RDT, with its good sensitivity on both plague clinical forms during a normal plague season, remained a potential test for alert. Particularly for BP, it may be of great value in the decision process for the initiation of therapy. However, for PP, RDT may deliver false negative results due to inconsistent sample quality. Plague diagnosis could be improved through the development of next generation of RDTs.