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1.  Seroepidemiological Study of Interepidemic Rift Valley Fever Virus Infection among Persons with Intense Ruminant Exposure in Madagascar and Kenya 
In this cross-sectional seroepidemiological study we sought to examine the evidence for circulation of Rift Valley fever virus (RVFV) among herders in Madagascar and Kenya. From July 2010 to June 2012, we enrolled 459 herders and 98 controls (without ruminant exposures) and studied their sera (immunoglobulin G [IgG] and IgM through enzyme-linked immunosorbent assay [ELISA] and plaque reduction neutralization test [PRNT] assays) for evidence of previous RVFV infection. Overall, 59 (12.9%) of 459 herders and 7 (7.1%) of the 98 controls were positive by the IgG ELISA assay. Of the 59 ELISA-positive herders, 23 (38.9%) were confirmed by the PRNT assay (21 from eastern Kenya). Two of the 21 PRNT-positive study subjects also had elevated IgM antibodies against RVFV suggesting recent infection. Multivariate modeling in this study revealed that being seminomadic (odds ratio [OR] = 6.4, 95% confidence interval [CI] = 2.1–15.4) was most strongly associated with antibodies against RVFV. Although we cannot know when these infections occurred, it seems likely that some interepidemic RVFV infections are occurring among herders. As there are disincentives regarding reporting RVFV outbreaks in livestock or wildlife, it may be prudent to conduct periodic, limited, active seroepidemiological surveillance for RVFV infections in herders, especially in eastern Kenya.
doi:10.4269/ajtmh.15-0383
PMCID: PMC4674260  PMID: 26458775
2.  Influenza seasonality in Madagascar: the mysterious African free-runner 
Background
The seasonal drivers of influenza activity remain debated in tropical settings where epidemics are not clearly phased. Antananarivo is a particularly interesting case study because it is in Madagascar, an island situated in the tropics and with quantifiable connectivity levels to other countries.
Objectives
We aimed at disentangling the role of environmental forcing and population fluxes on influenza seasonality in Madagascar.
Methods
We compiled weekly counts of laboratory-confirmed influenza-positive specimens for the period 2002 to 2012 collected in Antananarivo, with data available from sub-Saharan countries and countries contributing most foreign travelers to Madagascar. Daily climate indicators were compiled for the study period.
Results
Overall, influenza activity detected in Antananarivo predated that identified in temperate Northern Hemisphere locations. This activity presented poor temporal matching with viral activity in other countries from the African continent or countries highly connected to Madagascar excepted for A(H1N1)pdm09. Influenza detection in Antananarivo was not associated with travel activity and, although it was positively correlated with all climatic variables studied, such association was weak.
Conclusions
The timing of influenza activity in Antananarivo is irregular, is not driven by climate, and does not align with that of countries in geographic proximity or highly connected to Madagascar. This work opens fresh questions regarding the drivers of influenza seasonality globally particularly in mid-latitude and less-connected regions to tailor vaccine strategies locally.
doi:10.1111/irv.12308
PMCID: PMC4415694  PMID: 25711873
Influenza; Madagascar; population connectivity; seasonality; time series; viral migration
3.  Severe Acute Respiratory Illness Deaths in Sub-Saharan Africa and the Role of Influenza: A Case Series From 8 Countries 
The Journal of infectious diseases  2015;212(6):853-860.
Background
Data on causes of death due to respiratory illness in Africa are limited.
Methods
From January to April 2013, 28 African countries were invited to participate in a review of severe acute respiratory illness (SARI)–associated deaths identified from influenza surveillance during 2009–2012.
Results
Twenty-three countries (82%) responded, 11 (48%) collect mortality data, and 8 provided data. Data were collected from 37 714 SARI cases, and 3091 (8.2%; range by country, 5.1%–25.9%) tested positive for influenza virus. There were 1073 deaths (2.8%; range by country, 0.1%–5.3%) reported, among which influenza virus was detected in 57 (5.3%). Case-fatality proportion (CFP) was higher among countries with systematic death reporting than among those with sporadic reporting. The influenza-associated CFP was 1.8% (57 of 3091), compared with 2.9% (1016 of 34 623) for influenza virus–negative cases (P < .001). Among 834 deaths (77.7%) tested for other respiratory pathogens, rhinovirus (107 [12.8%]), adenovirus (64 [6.0%]), respiratory syncytial virus (60 [5.6%]), and Streptococcus pneumoniae (57 [5.3%]) were most commonly identified. Among 1073 deaths, 402 (37.5%) involved people aged 0–4 years, 462 (43.1%) involved people aged 5–49 years, and 209 (19.5%) involved people aged ≥50 years.
Conclusions
Few African countries systematically collect data on outcomes of people hospitalized with respiratory illness. Stronger surveillance for deaths due to respiratory illness may identify risk groups for targeted vaccine use and other prevention strategies.
doi:10.1093/infdis/jiv100
PMCID: PMC4826902  PMID: 25712970
influenza; human; mortality; Africa South of the Sahara
5.  Integrated Analysis of Environment, Cattle and Human Serological Data: Risks and Mechanisms of Transmission of Rift Valley Fever in Madagascar 
PLoS Neglected Tropical Diseases  2016;10(7):e0004827.
Background
Rift Valley fever (RVF) is a vector-borne disease affecting ruminants and humans. Madagascar was heavily affected by RVF in 2008–2009, with evidence of a large and heterogeneous spread of the disease. The identification of at-risk environments is essential to optimize the available resources by targeting RVF surveillance in Madagascar. Herein, the objectives of our study were: (i) to identify the environmental factors and areas favorable to RVF transmission to both cattle and human and (ii) to identify human behaviors favoring human infections in Malagasy contexts.
Methodology/Principal Findings
First, we characterized the environments of Malagasy communes using a Multiple Factor Analysis (MFA). Then, we analyzed cattle and human serological data collected at national level using Generalized Linear Mixed Models, with the individual serological status (cattle or human) as the response, and MFA factors, as well as other potential risk factors (cattle density, human behavior) as explanatory variables. Cattle and human seroprevalence rates were positively associated to humid environments (p<0.001). Areas with high cattle density were at risk (p<0.01; OR = 2.6). Furthermore, our analysis showed that frequent contact with raw milk contributed to explain human infection (OR = 1.6). Finally, our study highlighted the eastern-coast, western and north-western parts as high-risk areas for RVF transmission in cattle.
Conclusions/Significance
Our integrated approach analyzing environmental, cattle and human datasets allow us to bring new insight on RVF transmission patterns in Madagascar. The association between cattle seroprevalence, humid environments and high cattle density suggests that concomitant vectorial and direct transmissions are critical to maintain RVF enzootic transmission. Additionally, in the at-risk humid environment of the western, north-western and the eastern-coast areas, suitable to Culex and Anopheles mosquitoes, vectorial transmission probably occurs in both cattle and human. The relative contribution of vectorial or direct transmissions could be further assessed by mathematic modelling.
Author Summary
Rift Valley fever virus (RVFV) is a pathogen that causes a vector-borne tropical disease. The disease affects ruminants and humans and severely impacts the health and economy of affected countries. Madagascar was heavily affected by Rift Valley fever (RVF) in 2008–2009, with evidence of a large and heterogeneous spread of the disease. Our study aims at identifying environmental and human-related risk factors for RVFV transmission. First, we characterized Malagasy environments according to their putative influence on RVFV mosquito density and population dynamics. Then we statistically analyzed cattle and human serological data collected at a national level with the individual serological status as response, and Malagasy environments previously characterized by climatic and landscape variables as well as other potential risk factors as explanatory variables. Our results identified humid environments of the western, north-western and eastern parts of the island as risky areas. The identification of at-risk environments is essential to focus veterinary surveillance and control of RVFV.
doi:10.1371/journal.pntd.0004827
PMCID: PMC4945045  PMID: 27415438
6.  Fatal Pancreatitis in Simian Immunodeficiency Virus SIVmac251-Infected Macaques Treated with 2′,3′-Dideoxyinosine and Stavudine following Cytotoxic-T-Lymphocyte-Associated Antigen 4 and Indoleamine 2,3-Dioxygenase Blockade 
Journal of Virology  2012;86(1):108-113.
Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4+-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIVmac251 and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-d-tryptophan (d-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.
doi:10.1128/JVI.05609-11
PMCID: PMC3255892  PMID: 22013040
7.  Introduction of rubella-containing-vaccine to Madagascar: implications for roll-out and local elimination 
Journal of the Royal Society Interface  2016;13(117):20151101.
Few countries in Africa currently include rubella-containing vaccination (RCV) in their immunization schedule. The Global Alliance for Vaccines Initiative (GAVI) recently opened a funding window that has motivated more widespread roll-out of RCV. As countries plan RCV introductions, an understanding of the existing burden, spatial patterns of vaccine coverage, and the impact of patterns of local extinction and reintroduction for rubella will be critical to developing effective programmes. As one of the first countries proposing RCV introduction in part with GAVI funding, Madagascar provides a powerful and timely case study. We analyse serological data from measles surveillance systems to characterize the epidemiology of rubella in Madagascar. Combining these results with data on measles vaccination delivery, we develop an age-structured model to simulate rubella vaccination scenarios and evaluate the dynamics of rubella and the burden of congenital rubella syndrome (CRS) across Madagascar. We additionally evaluate the drivers of spatial heterogeneity in age of infection to identify focal locations where vaccine surveillance should be strengthened and where challenges to successful vaccination introduction are expected. Our analyses indicate that characteristics of rubella in Madagascar are in line with global observations, with an average age of infection near 7 years, and an impact of frequent local extinction with reintroductions causing localized epidemics. Modelling results indicate that introduction of RCV into the routine programme alone may initially decrease rubella incidence but then result in cumulative increases in the burden of CRS in some regions (and transient increases in this burden in many regions). Deployment of RCV with regular supplementary campaigns will mitigate these outcomes. Results suggest that introduction of RCV offers a potential for elimination of rubella in Madagascar, but also emphasize both that targeted vaccination is likely to be a lynchpin of this success, and the public health vigilance that this introduction will require.
doi:10.1098/rsif.2015.1101
PMCID: PMC4874430  PMID: 27122178
rubella; vaccination; Madagascar; congenital rubella syndrome; evaluation of vaccination programmes; Africa
8.  Temporal Patterns of Influenza A and B in Tropical and Temperate Countries: What Are the Lessons for Influenza Vaccination? 
PLoS ONE  2016;11(3):e0152310.
Introduction
Determining the optimal time to vaccinate is important for influenza vaccination programmes. Here, we assessed the temporal characteristics of influenza epidemics in the Northern and Southern hemispheres and in the tropics, and discuss their implications for vaccination programmes.
Methods
This was a retrospective analysis of surveillance data between 2000 and 2014 from the Global Influenza B Study database. The seasonal peak of influenza was defined as the week with the most reported cases (overall, A, and B) in the season. The duration of seasonal activity was assessed using the maximum proportion of influenza cases during three consecutive months and the minimum number of months with ≥80% of cases in the season. We also assessed whether co-circulation of A and B virus types affected the duration of influenza epidemics.
Results
212 influenza seasons and 571,907 cases were included from 30 countries. In tropical countries, the seasonal influenza activity lasted longer and the peaks of influenza A and B coincided less frequently than in temperate countries. Temporal characteristics of influenza epidemics were heterogeneous in the tropics, with distinct seasonal epidemics observed only in some countries. Seasons with co-circulation of influenza A and B were longer than influenza A seasons, especially in the tropics.
Discussion
Our findings show that influenza seasonality is less well defined in the tropics than in temperate regions. This has important implications for vaccination programmes in these countries. High-quality influenza surveillance systems are needed in the tropics to enable decisions about when to vaccinate.
doi:10.1371/journal.pone.0152310
PMCID: PMC4816507  PMID: 27031105
9.  Global Role and Burden of Influenza in Pediatric Respiratory Hospitalizations, 1982–2012: A Systematic Analysis 
PLoS Medicine  2016;13(3):e1001977.
Background
The global burden of pediatric severe respiratory illness is substantial, and influenza viruses contribute to this burden. Systematic surveillance and testing for influenza among hospitalized children has expanded globally over the past decade. However, only a fraction of the data has been used to estimate influenza burden. In this analysis, we use surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide.
Methods and Findings
We aggregated data from a systematic review (n = 108) and surveillance platforms (n = 37) to calculate a pooled estimate of the proportion of samples collected from children hospitalized with respiratory illnesses and positive for influenza by age group (<6 mo, <1 y, <2 y, <5 y, 5–17 y, and <18 y). We applied this proportion to global estimates of acute lower respiratory infection hospitalizations among children aged <1 y and <5 y, to obtain the number and per capita rate of influenza-associated hospitalizations by geographic region and socio-economic status.
Influenza was associated with 10% (95% CI 8%–11%) of respiratory hospitalizations in children <18 y worldwide, ranging from 5% (95% CI 3%–7%) among children <6 mo to 16% (95% CI 14%–20%) among children 5–17 y. On average, we estimated that influenza results in approximately 374,000 (95% CI 264,000 to 539,000) hospitalizations in children <1 y—of which 228,000 (95% CI 150,000 to 344,000) occur in children <6 mo—and 870,000 (95% CI 610,000 to 1,237,000) hospitalizations in children <5 y annually. Influenza-associated hospitalization rates were more than three times higher in developing countries than in industrialized countries (150/100,000 children/year versus 48/100,000). However, differences in hospitalization practices between settings are an important limitation in interpreting these findings.
Conclusions
Influenza is an important contributor to respiratory hospitalizations among young children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could reduce this burden and protect infants <6 mo.
The substantial global burden of influenza infections in children is revealed by Lafond and colleagues. Children in developing countries are 3 times more likely to be hospitalised and treatments vary. This study highlights the need for vaccination programs in the young.
Editors' Summary
Background
Acute lower respiratory infections—bacterial and viral infections of the lungs and airways (the tubes that take oxygen-rich air to the lungs)—are major causes of illness and death in children worldwide. Pneumonia (infection of the lungs) alone is responsible for 15% of deaths among children under five years old and kills nearly one million young children every year. Globally, infections with respiratory syncytial virus and with Streptococcus pneumoniae are associated with about 25% and 18.3%, respectively, of all episodes of severe respiratory infection in young children. Another infectious organism that contributes to the global burden of respiratory disease among children is the influenza virus. Every year, millions of people become infected with this virus, which infects the airways and causes symptoms that include a high temperature, tiredness and weakness, general aches and pains, and a dry chesty cough. Most infected individuals recover quickly, but seasonal influenza outbreaks (epidemics) nevertheless kill about half a million people annually, with the highest burden of severe disease being experienced by elderly people and by children under five years old.
Why Was This Study Done?
Annual immunization (vaccination) can reduce an individual’s risk of catching influenza, but before a country implements this preventative measure, policymakers need reliable estimates of the burden of influenza in their country. Although such estimates have been calculated for resource-rich countries with temperate climates, where influenza largely occurs in the winter, few estimates of influenza burden are available for resource-limited countries, which has hampered informed consideration of vaccination for influenza prevention in many settings. Recently, however, there has been a global expansion of systematic surveillance and testing for influenza virus among patients admitted to hospital for severe respiratory infection. Here, the researchers use this expanded surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide between 1982 and 2012. Specifically, they undertake a systematic review to identify published research articles on influenza-associated respiratory disease in hospitalized children, and, by aggregating the data from these articles with data collected by hospital-based influenza surveillance, they calculate a pooled estimate of the proportion of children hospitalized with respiratory disease who are positive for influenza.
What Did the Researchers Do and Find?
Using predefined search criteria, the researchers identified 108 published research articles that provided information on influenza-associated respiratory illness among hospitalized children. In addition, the Global Respiratory Hospitalizations–Influenza Proportion Positive (GRIPP) working group provided 37 hospital-based influenza surveillance datasets. By aggregating the data from these sources using a statistical approach called meta-analysis, the researchers calculated that, overall, influenza was associated with 9.5% of hospitalizations for severe respiratory infection among children under 18 years old worldwide, ranging from 4.8% among children under six months old to 16.4% among children aged 5–17 years. The researchers also calculated that, on average over the study period, influenza resulted in about 374,000 hospitalizations annually among children under one year old (including 228,000 hospitalizations among children less than six months old) and nearly one million hospitalizations annually among children under five years old. Finally, the researchers calculated that influenza-associated hospitalization rates among children under five years old over the study period were more than three times higher in resource-limited countries than in industrialized countries (150 and 48 hospitalizations, respectively, per 100,000 children per year).
What Do These Findings Mean?
Differences in hospitalization practices, in applications of case definitions, and in influenza testing protocols between settings may affect the accuracy of these findings. Specifically, the approach taken by the researchers may mean that their estimate of the total burden of severe respiratory disease due to influenza is an underestimate of the true situation. Even so, these findings suggest that influenza is an important contributor to hospitalizations for severe respiratory illness among children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could, therefore, reduce the contribution that influenza makes to hospitalizations for respiratory infections among children. Importantly, the estimates of the burden of influenza provided by these findings can now be used by countries considering influenza vaccination programs for children and/or pregnant women to help them investigate the possible health and cost implications of such programs and should also stimulate further research into the development of effective influenza vaccines for young children.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001977.
The UK National Health Service Choices website provides information about respiratory infections, seasonal influenza, influenza vaccination, and influenza vaccination in children
The World Health Organization provides information on seasonal influenza (in several languages) and on influenza vaccines
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects seasonal influenza, including information about vaccination, and about children, influenza, and vaccination; its website contains a short video about personal experiences of influenza
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)
doi:10.1371/journal.pmed.1001977
PMCID: PMC4807087  PMID: 27011229
10.  High Prevalence of West Nile Virus in Domestic Birds and Detection in 2 New Mosquito Species in Madagascar 
PLoS ONE  2016;11(1):e0147589.
West Nile virus is an arthropod-borne zoonosis transmitted by a large number of mosquito species, and birds play a key role as reservoir of the virus. Its distribution is largely widespread over Africa, Asia, the Americas and Europe. Since 1978, it has frequently been reported in Madagascar. Studies described a high seroprevalence level of the virus in humans in different areas of the island and a human fatal case of WNV infection was reported in 2011. Despite these reports, the epidemiology of WNV in Madagascar, in particular, viral circulation remains unclear. To explore the transmission of WNV in two rural human populations of Madagascar, we investigated local mosquitoes and poultry for evidence of current infections, and determined seroprevalence of candidate sentinel species among the local poultry. These 2 areas are close to lakes where domestic birds, migratory wild birds and humans coexist. Serological analysis revealed WNV antibodies in domestic birds (duck, chicken, goose, turkey and guinea fowl) sampled in both districts (Antsalova 29.4% and Mitsinjo 16.7%). West Nile virus nucleic acid was detected in one chicken and in 8 pools of mosquitoes including 2 mosquito species (Aedeomyia madagascarica and Anopheles pauliani) that have not been previously described as candidate vectors for WNV. Molecular analysis of WNV isolates showed that all viruses detected were part of the lineage 2 that is mainly distributed in Africa, and were most closely matched by the previous Malagasy strains isolated in 1988. Our study showed that WNV circulates in Madagascar amongst domestic birds and mosquitoes, and highlights the utility of poultry as a surveillance tool to detect WNV transmission in a peri-domestic setting.
doi:10.1371/journal.pone.0147589
PMCID: PMC4725773  PMID: 26807720
11.  Epidemiological and virological characteristics of influenza B: results of the Global Influenza B Study 
Introduction
Literature on influenza focuses on influenza A, despite influenza B having a large public health impact. The Global Influenza B Study aims to collect information on global epidemiology and burden of disease of influenza B since 2000.
Methods
Twenty-six countries in the Southern (n = 5) and Northern (n = 7) hemispheres and intertropical belt (n = 14) provided virological and epidemiological data. We calculated the proportion of influenza cases due to type B and Victoria and Yamagata lineages in each country and season; tested the correlation between proportion of influenza B and maximum weekly influenza-like illness (ILI) rate during the same season; determined the frequency of vaccine mismatches; and described the age distribution of cases by virus type.
Results
The database included 935 673 influenza cases (2000–2013). Overall median proportion of influenza B was 22·6%, with no statistically significant differences across seasons. During seasons where influenza B was dominant or co-circulated (>20% of total detections), Victoria and Yamagata lineages predominated during 64% and 36% of seasons, respectively, and a vaccine mismatch was observed in ≈25% of seasons. Proportion of influenza B was inversely correlated with maximum ILI rate in the same season in the Northern and (with borderline significance) Southern hemispheres. Patients infected with influenza B were usually younger (5–17 years) than patients infected with influenza A.
Conclusion
Influenza B is a common disease with some epidemiological differences from influenza A. This should be considered when optimizing control/prevention strategies in different regions and reducing the global burden of disease due to influenza.
doi:10.1111/irv.12319
PMCID: PMC4549097  PMID: 26256290
Burden of disease; epidemiology; Global Influenza B Study (GIBS); influenza; vaccination; vaccine mismatch
12.  Detection of new genetic variants of Betacoronaviruses in Endemic Frugivorous Bats of Madagascar 
Virology Journal  2015;12:42.
Background
Bats are amongst the natural reservoirs of many coronaviruses (CoVs) of which some can lead to severe infection in human. African bats are known to harbor a range of pathogens (e.g., Ebola and Marburg viruses) that can infect humans and cause disease outbreaks. A recent study in South Africa isolated a genetic variant closely related to MERS-CoV from an insectivorous bat. Though Madagascar is home to 44 bat species (41 insectivorous and 3 frugivorous) of which 34 are endemic, no data exists concerning the circulation of CoVs in the island’s chiropteran fauna. Certain Malagasy bats can be frequently found in close contact with humans and frugivorous bats feed in the same trees where people collect and consume fruits and are hunted and consumed as bush meat. The purpose of our study is to detect and identify CoVs from frugivorous bats in Madagascar to evaluate the risk of human infection from infected bats.
Methods
Frugivorous bats belonging to three species were captured in four different regions of Madagascar. We analyzed fecal and throat swabs to detect the presence of virus through amplification of the RNA-dependent RNA polymerase (RdRp) gene, which is highly conserved in all known coronaviruses. Phylogenetic analyses were performed from positive specimens.
Results
From 351 frugivorous bats, we detected 14 coronaviruses from two endemic bats species, of which 13 viruses were identified from Pteropus rufus and one from Eidolon dupreanum, giving an overall prevalence of 4.5%. Phylogenetic analysis revealed that the Malagasy strains belong to the genus Betacoronavirus but form three distinct clusters, which seem to represent previously undescribed genetic lineages.
Conclusions
Our findings suggest that CoVs circulate in frugivorous bats of Madagascar, demonstrating the needs to evaluate spillover risk to human populations especially for individuals that hunt and consume infected bats. Possible dispersal mechanisms as to how coronaviruses arrived on Madagascar are discussed.
doi:10.1186/s12985-015-0271-y
PMCID: PMC4404003  PMID: 25888853
Coronavirus; Chiroptera; Pteropodidae; Madagascar
13.  Anjozorobe Hantavirus, a New Genetic Variant of Thailand Virus Detected in Rodents from Madagascar 
Abstract
Until now, there was only serological evidence that hantaviruses were circulating in rodents and infecting humans from Madagascar. To assess the presence of a hantavirus on the island, between October, 2008, and March, 2010, we sampled 585 rodents belonging to seven species in the Anjozorobe-Angavo forest corridor, 70 km north from the capital city Antananarivo. A hantavirus was detected from organs of the ubiquist roof rat (Rattus rattus) and of the endemic Major's tufted-tailed rat (Eliurus majori). Amazingly, sequence analysis of the S (small), M (medium), and L (large) coding DNA sequence of this virus showed that the Anjozorobe strain (proposed name) was a new genetic variant of Thailand virus (THAIV) that comprises other variants found in Southeast Asia. Because THAIV is suspected of causing hemorrhagic fever with renal syndrome in humans, ongoing studies are addressing the risk of infection by this new variant in the Malagasy population.
doi:10.1089/vbz.2013.1359
PMCID: PMC3952587  PMID: 24575755
Hantavirus; Madagascar; Rattus rattus; Eliurus majori
14.  Highly Diverse Morbillivirus-Related Paramyxoviruses in Wild Fauna of the Southwestern Indian Ocean Islands: Evidence of Exchange between Introduced and Endemic Small Mammals 
Journal of Virology  2014;88(15):8268-8277.
ABSTRACT
The Paramyxoviridae form an increasingly diverse viral family, infecting a wide variety of different hosts. In recent years, they have been linked to disease emergence in many different animal populations and in humans. Bats and rodents have been identified as major animal populations capable of harboring paramyxoviruses, and host shifting between these animals is likely to be an important driving factor in the underlying evolutionary processes that eventually lead to disease emergence. Here, we have studied paramyxovirus circulation within populations of endemic and introduced wild small mammals of the southwestern Indian Ocean region and belonging to four taxonomic orders: Rodentia, Afrosoricida, Soricomorpha, and Chiroptera. We report elevated infection levels as well as widespread paramyxovirus dispersal and frequent host exchange of a newly emerging genus of the Paramyxoviridae, currently referred to as the unclassified morbillivirus-related viruses (UMRVs). In contrast to other genera of the Paramyxoviridae, where bats have been shown to be a key host species, we show that rodents (and, in particular, Rattus rattus) are significant spreaders of UMRVs. We predict that the ecological particularities of the southwestern Indian Ocean, where small mammal species often live in densely packed, multispecies communities, in combination with the increasing invasion of R. rattus and perturbations of endemic animal communities by active anthropological development, will have a major influence on the dynamics of UMRV infection.
IMPORTANCE Identification of the infectious agents that circulate within wild animal reservoirs is essential for several reasons: (i) infectious disease outbreaks often originate from wild fauna; (ii) anthropological expansion increases the risk of contact between human and animal populations and, as a result, the risk of disease emergence; (iii) evaluation of pathogen reservoirs helps in elaborating preventive measures to limit the risk of disease emergence. Many paramyxoviruses for which bats and rodents serve as major reservoirs have demonstrated their potential to cause disease in humans and animals. In the context of the biodiversity hot spot of southwestern Indian Ocean islands and their rich endemic fauna, we show that highly diverse UMRVs exchange between various endemic animal species, and their dissemination likely is facilitated by the introduced Rattus rattus. Hence, many members of the Paramyxoviridae appear well adapted for the study of the viral phylodynamics that may be associated with disease emergence.
doi:10.1128/JVI.01211-14
PMCID: PMC4135957  PMID: 24829336
15.  First Full Genome Sequence of a Human Enterovirus A120, Isolated in Madagascar 
Genome Announcements  2014;2(3):e00568-14.
We report the first complete genome sequence of an enterovirus isolate belonging to the human enterovirus A species of the Picornaviridae family and to type A120 (EV-A120). The EV-A120 isolate MAD-2741-11 was obtained from the stool of a healthy child living on Madagascar Island. The isolate genome was amplified by a reverse transcription-PCR method, and the consensus sequence was determined.
doi:10.1128/genomeA.00568-14
PMCID: PMC4064025  PMID: 24948760
16.  Outcome Risk Factors during Respiratory Infections in a Paediatric Ward in Antananarivo, Madagascar 2010–2012 
PLoS ONE  2013;8(9):e72839.
Background
Acute respiratory infections are a leading cause of infectious disease-related morbidity, hospitalisation and mortality among children worldwide, and particularly in developing countries. In these low-income countries, most patients with acute respiratory infection (ARI), whether it is mild or severe, are still treated empirically.
The aim of the study was to evaluate the risk factors associated with the evolution and outcome of respiratory illnesses in patients aged under 5 years old.
Materials and Methods
We conducted a prospective study in a paediatric ward in Antananarivo from November 2010 to July 2012 including patients under 5 years old suffering from respiratory infections. We collected demographic, socio-economic, clinical and epidemiological data, and samples for laboratory analysis. Deaths, rapid progression to respiratory distress during hospitalisation, and hospitalisation for more than 10 days were considered as severe outcomes. We used multivariate analysis to study the effects of co-infections.
Results
From November 2010 to July 2012, a total of 290 patients were enrolled. Co-infection was found in 192 patients (70%). Co-infections were more frequent in children under 36 months, with a significant difference for the 19–24 month-old group (OR: 8.0).
Sixty-nine percent (230/290) of the patients recovered fully and without any severe outcome during hospitalisation; the outcome was scored as severe for 60 children and nine patients (3%) died.
Risk factors significantly associated with worsening evolution during hospitalisation (severe outcome) were admission at age under 6 months (OR = 5.3), comorbidity (OR = 4.6) and low household income (OR = 4.1).
Conclusion
Co-mordidity, low-income and age under 6 months increase the risk of severe outcome for children infected by numerous respiratory pathogens. These results highlight the need for implementation of targeted public health policy to reduce the contribution of respiratory diseases to childhood morbidity and mortality in low income countries.
doi:10.1371/journal.pone.0072839
PMCID: PMC3771918  PMID: 24069161
17.  Dried-Blood Spots: A Cost-Effective Field Method for the Detection of Chikungunya Virus Circulation in Remote Areas 
Background
In 2005, there were outbreaks of febrile polyarthritis due to Chikungunya virus (CHIKV) in the Comoros Islands. CHIKV then spread to other islands in the Indian Ocean: La Réunion, Mauritius, Seychelles and Madagascar. These outbreaks revealed the lack of surveillance and preparedness of Madagascar and other countries. Thus, it was decided in 2007 to establish a syndrome-based surveillance network to monitor dengue-like illness.
Objective
This study aims to evaluate the use of capillary blood samples blotted on filter papers for molecular diagnosis of CHIKV infection. Venous blood samples can be difficult to obtain and the shipment of serum in appropriate temperature conditions is too costly for most developing countries.
Methodology and principal findings
Venous blood and dried-blood blotted on filter paper (DBFP) were collected during the last CHIKV outbreak in Madagascar (2010) and as part of our routine surveillance of dengue-like illness. All samples were tested by real-time RT-PCR and results with serum and DBFP samples were compared for each patient. The sensitivity and specificity of tests performed with DBFP, relative to those with venous samples (defined as 100%) were 93.1% (95% CI:[84.7–97.7]) and 94.4% (95% CI:[88.3–97.7]), respectively. The Kappa coefficient 0.87 (95% CI:[0.80–0.94]) was excellent.
Conclusion
This study shows that DBFP specimens can be used as a cost-effective alternative sampling method for the surveillance and monitoring of CHIKV circulation and emergence in developing countries, and probably also for other arboviruses. The loss of sensitivity is insignificant and involved a very small number of patients, all with low viral loads. Whether viruses can be isolated from dried blood spots remains to be determined.
Author Summary
Chikungunya is a mosquito-transmitted viral disease. No treatment is currently available. The only way to prevent infection is to avoid mosquito bites. Surveillance of circulation by early diagnosis is useful to prevent or limit outbreak. CHIKV, like all RNA viruses, is heat-labile. Consequently, confirmatory diagnosis classically requires blood samples that are transported in appropriate conditions (i.e. at 4°C within 48 hours, in liquid nitrogen, or frozen at −80°C and transported on dry ice) to prevent false negative results. This is not always possible in field conditions in low income countries. Dried blood spots are already used to diagnose parasitic, bacterial and viral infection. We compared venous sample to dried blood sample to make diagnosis of Chikungunya infection. We demonstrate the usefulness of this sampling method for the molecular diagnosis of Chikungunya infection. In particular, dried blood spots were very nearly as suitable as frozen serum specimens for the diagnosis of recent infection by CHIKV.
doi:10.1371/journal.pntd.0002339
PMCID: PMC3723542  PMID: 23936570
18.  Absence of Rift Valley Fever Virus in Wild Small Mammals, Madagascar 
Emerging Infectious Diseases  2013;19(6):1025-1027.
doi:10.3201/eid1906.121074
PMCID: PMC3713820  PMID: 23735220
Rift Valley fever; wild terrestrial mammals; Madagascar; viruses
19.  Reemergence of Recombinant Vaccine–derived Polioviruses in Healthy Children, Madagascar 
Emerging Infectious Diseases  2013;19(6):1008-1010.
doi:10.3201/eid1906.130080
PMCID: PMC3713839  PMID: 23735779
poliovirus; vaccine-derived polioviruses; recombinant; Madagascar; viruses; reemergence; vaccine coverage
20.  Vaccine Induced Antibodies to the First Variable Loop of Human Immunodeficiency Virus Type 1 gp120, Mediate Antibody-Dependent Virus Inhibition in Macaques 
Vaccine  2011;30(1):78-94.
The role of antibodies directed against the hyper variable envelope region V1 of human immunodeficiency virus type 1 (HIV-1), has not been thoroughly studied. We show that a vaccine able to elicit strain-specific non-neutralizing antibodies to this region of gp120 is associated with control of highly pathogenic chimeric SHIV89.6P replication in rhesus macaques. The vaccinated animal that had the highest titers of antibodies to the amino terminus portion of V1, prior to challenge, had secondary antibody responses that mediated cell killing by antibody-dependent cellular cytotoxicity (ADCC), as early as two weeks after infection and inhibited viral replication by antibody-dependent cell-mediated virus inhibition (ADCVI), by four weeks after infection. There was a significant inverse correlation between virus level and binding antibody titers to the envelope protein, (R = -0.83, p 0.015), and ADCVI (R = -0.84 p=0.044). Genotyping of plasma virus demonstrated in vivo selection of three SHIV89.6P variants with changes in potential N-linked glycosylation sites in V1. We found a significant inverse correlation between virus levels and titers of antibodies that mediated ADCVI against all the identified V1 virus variants. A significant inverse correlation was also found between neutralizing antibody titers to SHIV89.6 and virus levels (R = -0.72 p =0.0050). However, passive inoculation of purified immunoglobulin from animal M316, the macaque that best controlled virus, to a naïve macaque, resulted in a low serum neutralizing antibodies and low ADCVI activity that failed to protect from SHIV89.6P challenge. Collectively, while our data suggest that anti-envelope antibodies with neutralizing and non-neutralizing FcγR-dependent activities may be important in the control of SHIV replication, they also demonstrate that low levels of these antibodies alone are not sufficient to protect from infection.
doi:10.1016/j.vaccine.2011.10.040
PMCID: PMC3246802  PMID: 22037204
21.  The Spread of Influenza A(H1N1)pdm09 Virus in Madagascar Described by a Sentinel Surveillance Network 
PLoS ONE  2012;7(5):e37067.
Background
The influenza A(H1N1)pdm09 virus has been a challenge for public health surveillance systems in all countries. In Antananarivo, the first imported case was reported on August 12, 2009. This work describes the spread of A(H1N1)pdm09 in Madagascar.
Methods
The diffusion of influenza A(H1N1)pdm09 in Madagascar was explored using notification data from a sentinel network. Clinical data were charted to identify peaks at each sentinel site and virological data was used to confirm viral circulation.
Results
From August 1, 2009 to February 28, 2010, 7,427 patients with influenza-like illness were reported. Most patients were aged 7 to 14 years. Laboratory tests confirmed infection with A(H1N1)pdm09 in 237 (33.2%) of 750 specimens. The incidence of patients differed between regions. By determining the epidemic peaks we traced the diffusion of the epidemic through locations and time in Madagascar. The first peak was detected during the epidemiological week 47-2009 in Antananarivo and the last one occurred in week 07-2010 in Tsiroanomandidy.
Conclusion
Sentinel surveillance data can be used for describing epidemic trends, facilitating the development of interventions at the local level to mitigate disease spread and impact.
doi:10.1371/journal.pone.0037067
PMCID: PMC3353907  PMID: 22615893
22.  Smallpox Vaccine Safety Is Dependent on T Cells and Not B Cells 
The Journal of Infectious Diseases  2011;203(8):1043-1053.
(See the editorial commentary by Bray, on pages 1037–9.)
The licensed smallpox vaccine, ACAM2000, is a cell culture derivative of Dryvax. Both ACAM2000 and Dryvax are administered by skin scarification and can cause progressive vaccinia, with skin lesions that disseminate to distal sites. We have investigated the immunologic basis of the containment of vaccinia in the skin with the goal to identify safer vaccines for smallpox. Macaques were depleted systemically of T or B cells and vaccinated with either Dryvax or an attenuated vaccinia vaccine, LC16m8. B cell depletion did not affect the size of skin lesions induced by either vaccine. However, while depletion of both CD4+ and CD8+ T cells had no adverse effects on LC16m8-vaccinated animals, it caused progressive vaccinia in macaques immunized with Dryvax. As both Dryvax and LC16m8 vaccines protect healthy macaques from a lethal monkeypox intravenous challenge, our data identify LC16m8 as a safer and effective alternative to ACAM2000 and Dryvax vaccines for immunocompromised individuals.
doi:10.1093/infdis/jiq162
PMCID: PMC3068024  PMID: 21450994
23.  An Unexpected Recurrent Transmission of Rift Valley Fever Virus in Cattle in a Temperate and Mountainous Area of Madagascar 
Rift Valley fever is an acute, zoonotic viral disease of domestic ruminants, caused by a phlebovirus (Bunyaviridae family). A large outbreak occurred in Madagascar in 2008–2009. The goal of the present study was to evaluate the point prevalence of antibodies against Rift Valley Fever Virus (RVFV) in cattle in the Anjozorobe district, located in the wet and temperate highland region of Madagascar and yet heavily affected by the disease, and analyse environmental and trade factors potentially linked to RVFV transmission. A serological study was performed in 2009 in 894 bovines. For each bovine, the following variables were recorded: age, location of the night pen, minimum distance from the pen to the nearest water point and the forest, nearest water point type, and herd replacement practices. The serological data were analyzed using a generalized linear mixed model. The overall anti-RVFV IgG seroprevalence rate was 28% [CI95% 25–31]. Age was statistically linked to prevalence (p = 10−4), being consistent with a recurrent RVFV circulation. Distance from the night pen to the nearest water point was a protective factor (p = 5.10−3), which would be compatible with a substantial part of the virus transmission being carried out by nocturnal mosquito vectors. However, water point type did not influence the risk of infection: several mosquito species are probably involved. Cattle belonging to owners who purchase animals to renew the herd were significantly more likely to have seroconverted than others (p = 0.04): cattle trade may contribute to the introduction of the virus in this area. The minimum distance of the night pen to the forest was not linked to the prevalence. This is the first evidence of a recurrent transmission of RVFV in such an ecosystem that associates a wet, temperate climate, high altitude, paddy fields, and vicinity to a dense rain forest. Persistence mechanisms need to be further investigated.
Author Summary
Rift Valley fever (RVF) is a viral disease of domestic ruminants, which may affect humans. The RVF virus (RVFV) may be transmitted either by mosquitoes or through direct contact with vireamic body fluids or products. Until now, this disease had been described in arid, hot and irrigated or tropical areas. Performed in the year following the 2008–2009 RVFV outbreak in Madagascar, this study demonstrates for the first time a regular and intense transmission of this disease in a temperate and mountainous region.The area chosen as a pilot project shows that cattle are regularly and heavily affected in the highlands of Madagascar. Statistical analyses suggest that (i) a substantial part of the transmission is due to mosquito vectors; (ii) many mosquito species such as Culex and Anopheles, are probably involved in the transmission; (iii) cattle trade, by a regular introduction of the virus via herds coming from infected areas of the island, may explain the recurrence of the disease in this region. Further investigations are needed to understand the mechanisms of transmission of the disease, and design and implement appropriate surveillance and control measures in this area.
doi:10.1371/journal.pntd.0001423
PMCID: PMC3243698  PMID: 22206026
24.  Laboratory Surveillance of Rabies in Humans, Domestic Animals, and Bats in Madagascar from 2005 to 2010 
Background. Rabies virus (RABV) has circulated in Madagascar at least since the 19th century. Objectives. To assess the circulation of lyssavirus in the island from 2005 to 2010. Materials and Methods. Animal (including bats) and human samples were tested for RABV and other lyssavirus using antigen, ribonucleic acid (RNA), and antibodies detection and virus isolation. Results. Half of the 437 domestic or tame wild terrestrial mammal brains tested were found RABV antigen positive, including 54% of the 341 dogs tested. This percentage ranged from 26% to 75% across the period. Nine of the 10 suspected human cases tested were laboratory confirmed. RABV circulation was confirmed in 34 of the 38 districts sampled. No lyssavirus RNA was detected in 1983 bats specimens. Nevertheless, antibodies against Lagos bat virus were detected in the sera of 12 among 50 Eidolon dupreanum specimens sampled. Conclusion. More than a century after the introduction of the vaccine, rabies still remains endemic in Madagascar.
doi:10.4061/2011/727821
PMCID: PMC3170745  PMID: 21991442
25.  Risk Factors for Severe Outcomes following 2009 Influenza A (H1N1) Infection: A Global Pooled Analysis 
PLoS Medicine  2011;8(7):e1001053.
This study analyzes data from 19 countries (from April 2009 to Jan 2010), comprising some 70,000 hospitalized patients with severe H1N1 infection, to reveal risk factors for severe pandemic influenza, which include chronic illness, cardiac disease, chronic respiratory disease, and diabetes.
Background
Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures.
Methods and Findings
Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5–14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50–64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3).
Conclusions
Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In April 2009, a new strain of influenza A H1N1 was first identified in Mexico and the United States and subsequently spread around the world. In June 2009, the World Health Organization (WHO) declared a pandemic alert phase 6, which continued until August 2010. Throughout the pandemic, WHO and member states gathered information to characterize the patterns of risk associated with the new influenza A H1N1 virus infection and to assess the clinical picture. Although risk factors for severe disease following seasonal influenza infection have been well documented in many countries (for example, pregnancy; chronic medical conditions such as pulmonary, cardiovascular, renal, hepatic, neuromuscular, hematologic, and metabolic disorders; some cognitive conditions; and immunodeficiency), risk factors for severe disease following infection early in the 2009 H1N1 pandemic were largely unknown.
Why Was This Study Done?
Many countries have recently reported data on the association between severe H1N1 influenza and a variety of underlying risk factors, but because these data are presented in different formats, making direct comparisons across countries is difficult, with no clear consensus for some conditions. Therefore, to assess the frequency and distribution of known and new potential risk factors for severe H1N1 infection, this study was conducted to collect data (from 1 April 2009 to 1 January 2010) from surveillance programs of the Ministries of Health or National Public Health Institutes in 19 countries―Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong (special administrative region), Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom.
What Did the Researchers Do and Find?
As part of routine surveillance, countries were asked to provide risk factor data on laboratory-confirmed H1N1 in patients who were admitted to hospital, admitted to the intensive care unit (ICU), or had died because of their infection, using a standardized format. The researchers grouped potential risk conditions into four categories: age, chronic medical illnesses, pregnancy (by trimester), and other conditions that were not previously considered as risk conditions for severe influenza outcomes, such as obesity. For each risk factor (except pregnancy), the researchers calculated the percentage of each group of patients using the total number of cases reported in each severity category (hospitalization, admission to ICU, and death). To evaluate the risk associated with pregnancy, the researchers used the ratio of pregnant women to all women of childbearing age (age 15–49 years) at each level of severity to describe the differences between levels.
The researchers were able to collect data on approximately 70,000 patients requiring hospitalization, 9,700 patients admitted to the ICU, and 2,500 patients who died from H1N1 infection. The proportion of patients with H1N1 with one or more reported chronic conditions increased with severity—the median was 31.1% of hospitalized patients, 52.3% of patients admitted to the ICU, and 61.8% of patients who died. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. The proportion of patients with obesity increased with increasing disease severity—median of 6% of hospitalized patients, 11.3% of patients admitted to the ICU, and 12.0% of all deaths from H1N1.
What Do These Findings Mean?
These findings show that risk factors for severe H1N1 infection are similar to those for seasonal influenza, with some notable differences: a substantial proportion of people with severe and fatal cases of H1N1 had pre-existing chronic illness, which indicates that the presence of chronic illness increases the likelihood of death. Cardiac disease, chronic respiratory disease, and diabetes are important risk factors for severe disease that will be especially relevant for countries with high rates of these illnesses. Approximately 2/3 of hospitalized people and 40% of people who died from H1N1 infection did not have any identified pre-existing chronic illness, but this study was not able to comprehensively assess how many of these cases had other risk factors, such as pregnancy, obesity, smoking, and alcohol misuse. Because of large differences between countries, the role of risk factors such as obesity and pregnancy need further study—although there is sufficient evidence to support vaccination and early intervention for pregnant women. Overall, the findings of this study reinforce the need to identify and target high-risk groups for interventions such as immunization, early medical advice, and use of antiviral medications.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001053.
WHO provides a Global Alert and Response (GAR) with updates on a number of influenza-related topics
The US Centers for Disease Control and Prevention provides information on risk factors and H1N1
doi:10.1371/journal.pmed.1001053
PMCID: PMC3130021  PMID: 21750667

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