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Following a rubella outbreak in 2011, Vietnam implemented a mass measles-rubella vaccination campaign for children aged 1–14 years in 2014–2015, further expanding the target age to 16–17 years in 2016; routine vaccination was introduced in 2014. However, there was concern that a substantial proportion of women of child-bearing age were still susceptible to rubella, with the fear of congenital rubella emergence. Thus, we conducted a prospective cohort study in Nha Trang, Vietnam, from 2017–2018 to investigate pregnant women’s susceptibility to rubella infection, the incidence of congenital rubella infection, and factors associated with susceptibility. Cord blood was tested for rubella-specific immunoglobulin M (IgM) and IgG; neonatal saliva and cord blood specimens were examined for rubella-RNA. We analyzed 2013 mother-baby pairs. No baby was rubella-IgM or rubella-RNA positive. Overall, 20.4% of mothers were seronegative (95% confidence interval, 18.6%–22.1%). The seronegativity was significantly low among mothers aged

A birth cohort study was conducted in Khan Hoa Province, central Vietnam between 2009 and 2012 to determine the seroprevalence of hepatitis B virus (HBV) in pregnant women and their children, and associated risk factors. We enrolled 1987 pregnant women with their babies at the birth phase, and 12.6% (95% confidence interval [CI]: 11.1–14.0) of mothers were hepatitis B surface antigen (HBsAg)+. At 2-year follow-up phase, 1339 (67.4%) children were enrolled of whom 76.6% completed hepatitis B vaccines (HepB) and 1.9% (95% CI: 1.2–2.7) were HBsAg+. When mothers were hepatitis B e antigen (HBeAg)+, 28.3% of children have got infected even with complete HepB. HBV infection in mothers, hepatitis B surface antibody (anti-HBs antibody) below the seroprotective level in children, and mothers with pre-pregnancy low body mass index were associated with HBV infection in children. Meanwhile, HBV infection in children, older maternal age, no or incomplete doses of HepB, and boys were associated with anti-HBs antibody below the seroprotective level in children. Our birth cohort study determined a low rate of congenital HBV infection and associated risk factors in Vietnam, however further studies are needed to advance prevention including anti-viral therapy in pregnant women at high risk., Scientific Reports, 11, art. no. 8676; 2021

To detect congenital ZIKV infection (CZI) in a birth cohort and among high-risk neonates in Vietnam, we collected umbilical cord blood plasma samples of newly delivered babies and peripheral plasma samples of high-risk neonates in Nha Trang, central Vietnam, between July 2017 and September 2018. Samples were subjected to serological and molecular tests. Of the 2013 newly delivered babies, 21 (1%) were positive for Zika virus (ZIKV) IgM and 1,599 (79%) for Flavivirus IgG. Among the 21 ZIKV IgM-positives, 11 were confirmed to have CZI because their plasma samples had anti-ZIKV neutralization titers 3 4 times higher than those against dengue virus (DENV)-1 to 4 and Japanese encephalitis virus (JEV) and were tested for the ZIKV RNA positive by real-time reverse transcription-PCR. Therefore,the incidence of CZI in our birth cohort was approximately 0.5%. Of the 150 high-risk neonates, three (2%) and 95 (63%) were positive for ZIKV IgM and Flavivirus IgG antibodies, respectively. None of the three ZIKV IgM-positives had 3 4 times higher anti-ZIKV neutralization titers than those against DENV-1 to 4 and JEV, and were therefore considered as probable CZI. Our results indicate that CZI is not rare in Vietnam. Although those with confirmed CZI did not show apparent symptoms suspected of congenital Zika syndrome at birth, detailed examinations and follow-up studies are needed to clarify the CZI impact in Vietnam. This is the first report of CZI cases in a birth cohort in Asia., American Journal of Tropical Medicine and Hygiene, 103(5), pp.2059-2064; 2020

Background In dengue-endemic countries, targeting limited control interventions to populations at risk of severe disease could enable increased efficiency. Individuals who have had their first (primary) dengue infection are at risk of developing more severe secondary disease, thus could be targeted for disease prevention. Currently, there is no reliable algorithm for determining primary and post-primary (infection with more than one flavivirus) status from a single serum sample. In this study, we developed and validated an immune status algorithm using single acute serum samples from reporting patients and investigated dengue immuno-epidemiological patterns across the Philippines. Methods During 2015/2016, a cross-sectional sample of 10,137 dengue case reports provided serum for molecular (anti-DENV PCR) and serological (anti-DENV IgM/G capture ELISA) assay. Using mixture modelling, we re-assessed IgM/G seroprevalence and estimated functional, disease day-specific, IgG:IgM ratios that categorised the reporting population as negative, historical, primary and post-primary for dengue. We validated our algorithm against WHO gold standard criteria and investigated cross-reactivity with Zika by assaying a random subset for anti-ZIKV IgM and IgG. Lastly, using our algorithm, we explored immuno-epidemiological patterns of dengue across the Philippines. Results Our modelled IgM and IgG seroprevalence thresholds were lower than kit-provided thresholds. Individuals anti-DENV PCR+ or IgM+ were classified as active dengue infections (83.1%, 6998/8425). IgG− and IgG+ active dengue infections on disease days 1 and 2 were categorised as primary and post-primary, respectively, while those on disease days 3 to 5 with IgG:IgM ratios below and above 0.45 were classified as primary and post-primary, respectively. A significant proportion of post-primary dengue infections had elevated anti-ZIKV IgG inferring previous Zika exposure. Our algorithm achieved 90.5% serological agreement with WHO standard practice. Post-primary dengue infections were more likely to be older and present with severe symptoms. Finally, we identified a spatio-temporal cluster of primary dengue case reporting in northern Luzon during 2016. Conclusions Our dengue immune status algorithm can equip surveillance operations with the means to target dengue control efforts. The algorithm accurately identified primary dengue infections who are at risk of future severe disease.

Background Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years. Methods We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus–associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths. Findings In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries. Interpretation Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries. Funding Bill & Melinda Gates Foundation.

During 2015-2018, seven schools in rural Vietnam experienced diphtheria outbreaks. Multilocus sequence types were the same within schools but differed between schools. Low vaccine coverage and crowded dormitories might have contributed to the outbreaks. Authorities should consider administering routine vaccinations and booster doses for students entering the school system.

Background: Influenza B is one of the major etiologies for acute respiratory infections (ARI) among children worldwide; however, its clinical-epidemiological information is limited. We aimed to investigate the hospitalization incidence and clinical-epidemiological characteristics of influenza B-associated paediatric ARIs in central Vietnam. Methods: We collected clinical-epidemiological information and nasopharyngeal swabs from ARI children hospitalized at Khanh Hoa General Hospital, Nha Trang, Vietnam from February 2007 through June 2013. Nasopharyngeal samples were screened for 13 respiratory viruses using Multiplex-PCRs. Influenza B-confirmed cases were genotyped by Haemagglutinin gene sequencing. We analyzed the clinical-epidemiological characteristics of influenza B Lineages (Victoria/Yamagata) and WHO Groups. Results: In the pre-A/H1N1pdm09 period, influenza B-associated ARI hospitalization incidence among children under five was low, ranging between 14.7 and 80.7 per 100 000 population. The incidence increased to between 51.4 and 330 in the post-A/H1N1pdm09. Influenza B ARI cases were slightly older with milder symptoms. Both Victoria and Yamagata lineages were detected before the A/H1N1pdm09 outbreak; however, Victoria lineage became predominant in 2010-2013 (84% Victoria vs 16% Yamagata).Victoria and Yamagata lineages did not differ in demographic and clinical characteristics. In Victoria lineage, Group1 ARI cases were clinically more severe compared to Group5, presenting a greater proportion of wheeze, tachypnea, and lower respiratory tract infection. Conclusions: The current results highlight the increased incidence of influenza B-related ARI hospitalization among children in central Vietnam in the post-A/H1N1pdm09 era. Furthermore,the difference in clinical severity between Victoria lineage Group1 and 5 implies the importance of influenza B genetic variation on clinical presentation., Influenza and other Respiratory Viruses, 13(3), pp. 248-261; 2018

Background: Respiratory viruses cause acute respiratory illness (ARI) in early childhood, but their effect on subsequent ARI admissions is not fully understood. This study aimed to determine the association between initial ARI admission because of viruses including human rhinovirus (HRV), respiratory syncytial virus (RSV), human adenovirus (HAdV) and human metapneumovirus (hMPV) and the risk of ARI readmission in children.Methods: Clinical information and nasopharyngeal swab samples were collected from children, The Pediatric infectious disease journal, 37(12), pp.1217-1222; 2018

Conjunctival pneumococcal serotypes among members of a community have not been investigated well. We determined the prevalence and association of Streptococcus pneumoniae in the nasopharynx and conjunctiva among children in a community before pneumococcal conjugate vaccine introduction. In October 2016, conjunctival and nasopharyngeal swabs were collected from children (< 24 months old) and nasopharyngeal swabs from mothers in Nha Trang, Vietnam. Quantitative lytA PCR and DNA microarray were performed to detect and serotype S. pneumoniae. The association between S.pneumoniae in the nasopharynx and conjunctiva was evaluated using multivariable logistic regression model. Among 698 children,62 (8.9%, 95% CI 6.9–11.2%) were positive for S. pneumoniae in the conjunctiva. Non-encapsulated S. pneumoniae were most commonly identified,followed by serotypes 6A, 6B, and 14. Nasopharyngeal and conjunctival detection were positively associated (aOR 47.30, 95% CI 24.07–92.97). Low birth-weight, day-care attendance, and recent eye symptoms were independently associated with S. pneumoniae detection in the conjunctiva (aOR 11.14, 95% CI 3.76–32.98, aOR 2.19, 95% CI 1.45–3.31, and aOR 3.59, 95% CI 2.21–5.84, respectively). Serotypes and genotypes in the conjunctiva and nasopharynx matched in 87% of the children. Three mothers’ nasopharyngeal pneumococcal samples had matched serotype and genotype with their child’s in the conjunctiva and nasopharynx. S. pneumoniae presence in nasopharynx and conjunctiva were strongly associated. The high concordance of serotypes suggests nasopharyngeal carriage may be a source of transmission to the conjunctiva., Scientific Reports, 11(1), art.no.337; 2021

Background Eosinophilic meningitis (EM) is a rare clinical syndrome caused by both infectious and noninfectious diseases. In tropical pacific countries, Angiostrongylus cantonensis is the most common cause. However, the EM definition varies in the literature, and its relation to parasitic meningitis (PM) remains unclear. Methodology/Principal findings Adult and adolescent patients of 13 years old or above with suspected central nervous system (CNS) infections with abnormal CSF findings were prospectively enrolled at a tertiary referral hospital in Hanoi, Vietnam from June 2012 to May 2014. Patients with EM or suspected PM (EM/PM) were defined by the presence of either ≥10% eosinophils or an absolute eosinophil cell counts of ≥10/mm3 in the CSF or blood eosinophilia (>16% of WBCs) without CSF eosinophils. In total 679 patients were enrolled: 7 (1.03%) had ≥10% CSF eosinophilia, 20 (2.95%) had ≥10/mm3 CSF eosinophilia, and 7 (1.03%) had >16% blood eosinophilia. The patients with ≥10% CSF eosinophilia were significantly younger (p = 0.017), had a lower body temperature (p = 0.036) than patients with ≥10/mm3 CSF eosinophilia among whom bacterial pathogens were detected in 72.2% (13/18) of those who were tested by culture and/or PCR. In contrast, the characteristics of the patients with >16% blood eosinophilia resembled those of patients with ≥10% CSF eosinophilia. We further conducted serological tests and real-time PCR to identify A. cantonensis. Serology or real-time PCR was positive in 3 (42.8%) patients with ≥10% CSF eosinophilia and 6 (85.7%) patients with >16% blood eosinophilia without CSF eosinophils but none of patients with ≥10/mm3 CSF eosinophilia. Conclusions The etiology of PM in northern Vietnam is A. cantonensis. The eosinophil percentage is a more reliable predictor of parasitic EM than absolute eosinophil count in the CSF. Patients with PM may present with a high percentage of eosinophils in the peripheral blood but not in the CSF., Author summary Eosinophilic meningitis (EM) is a rare meningitis accompanied by eosinophils in the CSF and caused by multiple etiologies. Angiostrongylus cantonensis, which is a rat lungworm parasite, is the most common cause in tropical Asia. Previous papers have defined EM as CSF eosinophils ≥10% or CSF eosinophils ≥10/mm3. However, the relationship of EM to parasitic meningitis (PM) remains unclear. This prospective study enrolled 679 patients with suspected CNS infection who were admitted to a tertiary referral hospital in Hanoi, Vietnam from June 2012 to May 2014. The characteristics of patients with ≥10% CSF eosinophilia resembled those of patients with >16% blood eosinophilia without CSF eosinophils, whereas those of patients with ≥10/mm3 CSF eosinophilia were comparable with those of patients with typical bacterial meningitis. Serology or real-time PCR for A. cantonensis was positive in 3 out of 7 patients with ≥10% CSF eosinophilia and 6 out of 7 patients with > 16% blood eosinophilia without CSF eosinophils but none of patients with ≥10/mm3 CSF eosinophilia. The percentage, in contrast to the absolute eosinophil count in CSF, is reliable for predicting parasitic EM. Patients with PM may present with eosinophilia in the peripheral blood but not in the CSF.

Background Acute lower respiratory tract infections (ALRIs) are the most common disease for hospitalized children in Japan. The aim of this study was to identify viruses in children hospitalized for ALRIs and to demonstrate epidemiologic and clinical characteristics in Japan. Methods During a 2-year period from February 2013 to January 2015, we collected nasopharyngeal swab specimens from almost all hospitalized children with ALRIs in Nagasaki, a regional city of Japan, and its environs. Viruses were detected by multiplex polymerase chain reaction from these samples. Results We detected one or more viruses from 259 (69%) of 374 patients, 227 of whom were infected with a single virus, 30 with 2, and 2 with 3 viruses. Detected viruses in this study were rhinovirus (46.4%), respiratory syncytial virus (29.7%), human metapneumovirus (6.8%), parainfluenza virus (5.5%), enterovirus D68 (3.4%), influenza virus (2.7%), adenovirus (2.4%), bocavirus (2.0%) and Coxsackie virus (1.0%). We detected a seasonal shift in respiratory syncytial virus outbreaks from the 2013-2014 to the 2014-2015 seasons. There was no significant difference in clinical course and severity among those viruses. Patients with a history of asthma or underlying diseases were older and more frequently required oxygen therapy than previously healthy patients. Conclusions Viral etiology in hospitalized children with ALRIs in Nagasaki, Japan, was similar to that in many other countries. Enterovirus D68, which was recently recognized as a causative agent of severe ALRIs, was also identified in this study area. Severity of ALRIs may depend on underlying disease rather than type of etiological virus.

Influenza virus B belongs to the family Orthomyxoviridae with segmented negative-sense RNA genomes. Since 1970s, influenza B has diverged intoVictoria and Yamagata, which differs in antigenic and evolutionary characteristics. Yet, molecular-epidemiological information of influenza B from developing nations is limited. In central Vietnam, influenza A subtype-specific circulation pattern and clinical characteristics were previously described. However, molecular evolutionary characteristics of influenza B has not been discussed to date. We utilized the influenza B positives obtained from paediatric ARI surveillance during 2007?2013. Influenza B HA and NA genes were amplified, sequenced, and phylogenetic/molecular evolutionary analysis was performed using Maximum Likelihood and Bayesian MCMC. Phylodynamics analysis was performed with Bayesian Skyline Plot (BSP). Furthermore, we performed selection pressure analysis and estimated N-glycosylation sites. In the current study, overall positive rate for influenza B was 3.0%, and Victoria lineage immediately became predominant in post-A/H1N1pdm09 period. The noticeable shift in Victoria lineage WHO Group occurred. With respect to the evolutionary rate (substitutions/site/year), Victoria lineage HA gene was evolving faster than Yamagata lineage (2.43 × 10?3 vs 2.00 × 10?3). Furthermore, the evolutionary rate of Victoria Group 5 was greater than Group 1. BSP presented the rapid growth in Effective Population Size (EPS) of Victoria lineage occurred soon after the 1st A/H1N1pdm09 case was detected whereas the EPS of Yamagata lineage was stable for both genes. N-glycosylation pattern between lineages and among WHO Groups were slightly different, and HA gene had a total of 6 amino acid substitutions under positive section pressure (4 for Victoria and 2 for Yamagata). The current results highlight the importance of Victoria lineage in post-A/H1N1pdm09 period. Difference in evolutionary characteristics and phylodynamics may indicate lineage and WHO Group-specific evolutionary dynamics. It is necessary to further continue the molecular-epidemiological surveillance in local setting to gain a better understanding of local evolutionary characteristics of influenza B strains., Infection, Genetics and Evolution, 81, art.no.104264; 2020

We performed molecular evolutionary analyses of the G gene C-terminal 3rd hypervariable region of RSV-A genotypes NA1 and ON1 strains from the paediatric acute respiratory infection patients in central Vietnam during the 2010?2012 study period. Time-scaled phylogenetic analyses were performed using Bayesian Markov Chain Monte Carlo (MCMC) method, and pairwise distances (p-distances) were calculated. Bayesian Skyline Plot (BSP) was constructed to analyze the time-trend relative genetic diversity of central Vietnam RSV-A strains. We also estimated the N-glycosylation sites within G gene hypervariable region. Amino acid substitutions under positive and negative selection pressure were examined using Conservative Single Likelihood Ancestor Counting (SLAC), Fixed Effects Likelihood (FEL), Internal Fixed Effects Likelihood (IFEL) and Mixed Effects Model for Episodic Diversifying Selection (MEME) models. The majority of central Vietnam ON1 strains detected in 2012 were classified into lineage 1 with few positively selected substitutions. As for the Vietnamese NA1 strains, four lineages were circulating during the study period with a few positive selection sites. Shifting patterns of the predominantly circulating NA1 lineage were observed in each year during the investigation period. Median p-distance of central Vietnam NA1 strains was wider (p-distance = 0.028) than that of ON1 (p-distance = 0.012). The molecular evolutionary rate of central Vietnam ON1 strains was estimated to be 2.55 × 10? 2 (substitutions/site/year) and was faster than NA1 (7.12 × 10? 3 (substitutions/site/year)). Interestingly, the evolutionary rates of both genotypes ON1 and NA1 strains from central Vietnam were faster than the global strains respectively. Furthermore, the shifts of N-glycosylation pattern within the G gene 3rd hypervariable region of Vietnamese NA1 strains were observed in each year. BSP analysis indicated the rapid growth of RSV-A effective population size in early 2012. These results suggested that the molecular evolution of RSV-A G gene detected in central Vietnam was fast with unique evolutionary dynamics., Infection, Genetics and Evolution, 45, pp.437-446; 2016

Impaired efferocytosis is a key mechanism of inflammatory lung diseases, including chronic obstructive pulmonary disease and cystic fibrosis.Cigarette smoking activates RhoA and impairs efferocytosis in alveolar macrophages, but the mechanism has not been fully elucidated. We investigated the role of endoplasmic reticulum (ER) stress induced by cigarette smoking in the disruption of efferocytosis.Both tunicamycin (10 μg/ml) and thapsigargin (0.1 and 1 μM), which are ER stress inducers, suppressed efferocytosis in J774 cells,and a Rho-associated coiled-coil-forming kinase (ROCK) inhibitor (Y27632) reversed this effect.We validated the effect of tunicamycin on efferocytosis in experiments using RAW264.7 cells. Then, we investigated the role of the unfolded protein response (UPR) in efferocytosis impaired by ER stress. A PERK inhibitor (GSK2606414) restored the efferocytosis that had been impaired by TM, and an eIF2α dephosphorylation inhibitor (salubrinal) suppressed efferocytosis. Cigarette smoke extract (CSE) induced ER stress in J774 macrophages and RhoA activation in J774 cells, and the CSE-induced ROCK activity was successfully reversed by GSK2606414 and tauroursodeoxycholic acid. Finally, we confirmed that ER stress suppresses efferocytosis in murine alveolar macrophages and that GSK2606414 could rescue this process. These data suggest that cigarette smoke-induced ER stress and the UPR play crucial roles in RhoA activation and suppression of efferocytosis in the lung., Scientific Reports, 10(1), art.no.12620; 2020

BACKGROUND: Scrub typhus (ST) is a leading cause of non-malarial febrile illness in Southeast Asia, but evidence of its true disease burden is limited because of difficulties of making the clinical diagnosis and lack of adequate diagnostic tests. To describe the epidemiology and clinical characteristics of ST, we conducted an observational study using multiple diagnostic assays at a national tertiary hospital in Hanoi, Vietnam. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled 1,127 patients hospitalized with documented fever between June 2012 and May 2013. Overall, 33 (2.9%) patients were diagnosed with ST by PCR and/or screening of ELISA for immunoglobulin M (IgM) with confirmatory tests: 14 (42.4%) were confirmed by indirect immunoperoxidase assay (IIP), and 19 (57.6%) were by IIP and PCR. Living by farming, conjunctival injection, eschar, aspartate aminotransferase elevation, and alanine aminotransferase elevation were significantly associated with ST cases (adjusted odds ratios (aORs): 2.8, 3.07, 48.8, 3.51, and 4.13, respectively), and having a comorbidity and neutrophilia were significantly less common in ST cases (aORs: 0.29 and 0.27, respectively). The majority of the ST cases were not clinically diagnosed with rickettsiosis (72.7%). Dominant IIP reactions against a single antigen were identified in 15 ST cases, whereas indistinguishably high reactions against multiple antigens were seen in 11 ST cases. The most frequently observed dominant IIP reaction was against Karp antigen (eight cases) followed by Gilliam (four cases). The highest diagnostic accuracy of IgM ELISA in acute samples was 78%. In a phylogenetic analysis of the 56-kDa type-specific antigen gene, the majority (14 cases) were located in the Karp-related branch followed by the Gilliam-related (two cases), Kato-related (two cases), and TA763-related clades (one case). CONCLUSIONS/SIGNIFICANCE: Both the clinical and laboratory diagnoses of ST remain challenging at a tertiary hospital. Implementation of both serological and nucleic acid amplification assays covering endemic O. tsutsugamushi strains is essential., PLoS neglected tropical diseases, 13(12), e0007928; 2019

Highlights • Hospitalizations for respiratory viruses are seasonal in Vietnam • Respiratory syncytial virus peaks in the late summer months, and inuenza A in April to June • No clear seasonality is seen for human rhinovirus • Human parainuenza 3 and human rhinovirus are positively associated with dew point • This work can inform the timing of inuenza and RSV vaccination and the judicious use of antibiotics in Vietnam, Background Acute respiratory infections (ARIs) are the most common causes of death in children under 5 years of age. While the etiology of most pneumonia and ARI episodes is undiagnosed, a broad range of ARI-causing viruses circulate widely in South East Asia. However, the patterns and drivers of the seasonal transmission dynamics are largely unknown. Here we identify the seasonal patterns of multiple circulating viruses associated with hospitalizations for ARIs in Nha Trang, Vietnam. Methods Hospital based enhanced surveillance of childhood ARI is ongoing at Khanh Hoa General Hospital in Nha Trang. RT-PCR was performed to detect 13 respiratory viruses in nasopharyngeal samples from enrolled patients. Seasonal patterns of childhood ARI hospital admissions of various viruses were assessed, as well as their association with rainfall, temperature, and dew point. Results Respiratory syncytial virus peaks in the late summer months, and influenza A in April to June. We find significant associations between detection of human parainfluenza 3 and human rhinovirus with the month's mean dew point. Using a cross-wavelet transform we find a significant out-of-phase relationship between human parainfluenza 3 and temperature and dew point. Conclusions Our results are important for understanding the temporal risk associated with circulating pathogens in Southern Central Vietnam. Specifically, our results can inform timing of routing seasonal influenza vaccination and for when observed respiratory illness is likely viral, leading to judicious use of antibiotics in the region.

Few studies have investigated possible causative and protective factors associated with allergic diseases in resource-limited countries, Southeast Asia. We estimated the current prevalence of asthma, rhinoconjunctivitis, and eczema among 6-year-old children,and identified anthropometric factors associated with asthma, rhinoconjunctivitis and eczema, in South-Central Vietnam. A birth cohort study recruited 1,999 children born at a provincial hospital in Nha Trang, Vietnam between May 2009 and May 2010.A 6-year follow-up survey was conducted where clinical, familial, and environmental information was collected by interviewing caregivers using a standardized form based on the International Study of Asthma and Allergies in Childhood,Phase Three Core and Environmental Questionnaire for 6?7-year-old children. The odds ratios of asthma, rhinoconjunctivitis, and eczema for anthropometric factors were estimated using logistic regression analysis. In total, 1202 children participated in the follow-up survey. The proportions of children who had current asthma, rhinoconjunctivitis, and eczema were 5.1% (95% confidence interval [CI] 3.9?6.5%), 11.5% (9.7?13.4%), and 6.7% (5.3?8.2%),respectively. Low birthweight (adjusted odds ratio 5.12, 95% CI 1.92?13.64) was independently associated with increased risk of eczema.Further studies are necessary to understand the involved mechanism., Scientific Reports, 9(1), art.no.2655; 2019

Background Various viruses are known to be associated with pneumonia. However, the impact of viral infections on adult pneumonia mortality remains unclear. This study aimed to clarify the effect of virus infection on pneumonia mortality among adults stratified by virus type and patient comorbidities. Methods This multicentre prospective study enrolled pneumonia patients aged ≥15 years from September 2011 to August 2014. Sputum samples were tested by in-house multiplex polymerase chain reaction assays to identify 13 respiratory viruses. Viral infection status and its effect on in-hospital mortality were examined by age group and comorbidity status. Results A total of 2617 patients were enrolled in the study and 77.8% was aged ≥65 years. 574 (21.9%) did not have comorbidities, 790 (30.2%) had chronic respiratory disease, and 1253 (47.9%) had other comorbidities. Viruses were detected in 605 (23.1%) patients. Human rhinovirus (9.8%) was the most frequently identified virus, followed by influenza A (3.9%) and respiratory syncytial virus (3.9%). Respiratory syncytial virus was more frequently identified in patients with chronic respiratory disease (4.7%) than those with other comorbidities (4.2%) and without comorbidities (2.1%) (p = 0.037). The frequencies of other viruses were almost identical between the three groups. Virus detection overall was not associated with increased mortality (adjusted risk ratio (ARR) 0.76, 95% CI 0.53–1.09). However, influenza virus A and B were associated with three-fold higher mortality in patients with chronic respiratory disease but not with other comorbidities (ARR 3.38, 95% CI 1.54–7.42). Intriguingly, paramyxoviruses were associated with dramatically lower mortality in patients with other comorbidities (ARR 0.10, 95% CI 0.01–0.70) but not with chronic respiratory disease. These effects were not affected by age group. Conclusions The impact of virus infections on pneumonia mortality varies by virus type and comorbidity status in adults. Electronic supplementary material The online version of this article (10.1186/s12879-017-2858-y) contains supplementary material, which is available to authorized users.

Supported by GAVI Alliance, measles-rubella vaccination was introduced in Vietnam in 2014, involving a mass campaign among 1-14 year olds and routine immunization of children aged 9 months. We explore the impact on the incidence of Congenital Rubella Syndrome (CRS) during 2013-2050 of this strategy and variants involving women aged 15-35 years. We use an age and sex-structured dynamic transmission model, set up using recently-collected seroprevalence data from Central Vietnam, and also consider different levels of transmission and contact patterns. If the serological profile resembles that in Central Vietnam, the planned vaccination strategy could potentially prevent 125,000 CRS cases by 2050 in Vietnam, despite outbreaks predicted in the meantime. Targeting the initial campaign at 15-35 year old women with or without children aged 9 months-14 years led to sustained reductions in incidence, unless levels of ongoing transmission were medium-high before vaccination started. Assumptions about contact greatly influenced predictions if the initial campaign just targeted 15-35 year old women and/or levels of ongoing transmission were medium-high. Given increased interest in rubella vaccination, resulting from GAVI Alliance funding, the findings are relevant for many countries.

Highlights • The burden of Hib pneumonia in Southeast Asia has been quantified in few studies. • We estimate the impact of routine vaccination against Hib in Nha Trang. • Population-based surveillance allowed statistical adjustment for confounding viral pneumonia. • Hib vaccination has substantially reduced the burden of childhood pneumonia., Introduction Despite the global success of Hib vaccination in reducing disease and mortality, uncertainty about the disease burden and the potential impact of Hib vaccination in Southeast Asia has delayed the introduction of vaccination in some countries in the region. Hib vaccination was introduced throughout Vietnam in July 2010 without catch-up. In an observational, population based surveillance study we estimated the impact of routine Hib vaccination on all cause radiologically confirmed childhood pneumonia in Nha Trang, Vietnam. Materials and methods In 2007 active hospital based surveillance was established in Khanh Hoa General Hospital, the only hospital in Nha Trang, Khanh Hoa province. Nasopharyngeal samples and chest radiographs are taken routinely from all children diagnosed with acute respiratory illness on admission. For admissions between 02/2007 and 03/2012 chest radiographs were interpreted for the presence of WHO primary endpoint pneumonia and nasopharyngeal swabs were analysed by PCR for the presence of Influenza A or B, RSV and rhinovirus. We employed Poisson regression to estimate the impact of Hib vaccination on radiologically confirmed pneumonia (RCP) while statistically accounting for potential differences in viral circulation in the post vaccination era which could have biased the estimate. Results Of 3151 cases admitted during the study period, 166 had RCP and major viruses were detected in 1601. The adjusted annual incidence of RCP in children younger than 5 years declined by 39% (12–58%) after introduction of Hib vaccination. This decline was most pronounced in children less than 2 years old, adjusted IRR: 0.52 (0.33–0.81), and no significant impact was observed in the 2–4 years old who were not eligible for vaccination, adjusted IRR: 0.96 (0.52–1.72). Discussion We present early evidence that the burden of Hib associated RCP in Nha Trang before vaccination was substantial and that shortly after introduction to the routine childhood immunisation scheme vaccination has substantially reduced that burden.

We studied the prevalence of HIV drug resistance among high-risk groups such as injecting drug users (IDUs), female sex workers (FSWs), and men having sex with men (MSM) in central Vietnam. We used HIV-positive blood samples from 2012?2013 sentinel surveillance surveys. Study subjects were screened for HIV infection by standardized screening assays, and the HIV-positive samples were further tested for HIV viral load and drug-resistance mutations (DRMs) by in-house assays. DRMs were identified using the Stanford University online sequence analysis tool. Their risk behaviors were also investigated. During the study period, 6,016 (high-risk) subjects were screened, and 97 tested positive for HIV infection (IDUs: n = 63, 3.0%; FSWs: n = 24, 0.9%; and MSM: n = 10, 1.0%). Ninety-two of the 97 samples (45 from 2012 and 47 from 2013) were available for further testing. HIV RNA was detected in 56 (60.9%) of the 92 samples, and drug resistance genotyping was successfully performed on 40 (71.4%) samples. All these isolates were subtype CRF01_AE, except for 1 (2.5%) IDU whose HIV belongs to subtype B. Thirteen individuals (32.5%) were carrying HIV with at least 1 DRM: 9 IDUs, 1 FSW, and 3 MSM. Thus, HIV seroprevalence among high-risk individuals in central Vietnam is low, but a high proportion of drug resistant HIV-1 isolates is observed in the high-risk group., Japanese Journal of Infectious Diseases, 70(6), pp.621-627; 2017

To investigate susceptibility to and factors associated with rubella infection among pregnant mothers and to estimate the burden of congenital rubella infection (CRI) in Vietnam where rubella-containing vaccine (RCV) is not included in the routine immunization program, we conducted a prospective cohort study in Nha Trang, Vietnam between 2009 and 2010. Rubella-specific immunoglobulin-M and immunoglobulin-G were investigated in cord blood samples by enzyme immunoassay. Corresponding clinical-epidemiological data were analyzed and the national congenital rubella syndrome (CRS) incidence was estimated using modeling. We enrolled 1988 pairs of mothers aged 17-45 years and their newborn babies. No mothers had received RCV. Multivariate analysis revealed that mothers aged 17-24 (aOR 2.5, 95% CI: 1.7-3.8) or 25-34 (1.4, 1.0-2.1) years were more likely to be susceptible than those aged 35-45 years. Overall 28.9% (574/1988, 95% CI: 26.9-30.9%) of mothers were seronegative. The CRI rate was 151 (95% CI: 0-322) per 100,000 live births. Modeling estimated that 3788 babies (95% CI: 3283-4143) were born with CRS annually in Vietnam with an overall CRS incidence of 234 (95% CI: 207-262) cases per 100,000 live births. A substantial proportion of women of childbearing age (WCBA) are at risk of rubella infection during pregnancy and this can result in a high frequency of miscarriage or burden of CRS across Vietnam. Prompt introduction of RCV into national immunization program with catch-up vaccination to children and WCBA will reduce CRI in Vietnam., Vaccine, 32(10), pp.1192-1198; 2014

This study investigated the characteristics of congenital rubella syndrome (CRS)-associated cardiac complications, particularly patent ductus arteriosus (PDA). We reviewed the medical records of patients with CRS who were admitted to the Children’s Hospital 1 in Vietnam between December 2010 and December 2012, and patients with CRS who underwent PDA transcatheter occlusion therapy at the cardiology department between December 2009 and December 2015. We compared the characteristics of PDA treated with transcatheter closure between children with CRS (CRS-PDA) and those without CRS (non-CRS-PDA) who underwent PDA transcatheter closure between July 2014 and December 2015. One-hundred-and-eight children with CRS were enrolled. Cardiac defects (99%), cataracts (72%), and hearing impairment (7%) were detected. Fifty CRS-PDA and 290 non-CRS-PDA patients were examined. CRS-PDA patients had smaller median birthweight (p < 0.001), more frequent pulmonary (p < 0.001) and aortic stenosis (p < 0.001), higher main pulmonary artery pressure, and higher aortic pressure in systole/diastole (p < 0.001 for each) than did non-CRS-PDA patients. The proportion of tubular-type PDA was higher in CRS-PDA patients (16%) than in non-CRS-PDA patients (3%) (p = 0.020). Tubular-type PDA was frequently seen in patients with CRS and accompanied by pulmonary/systemic hypertension and pulmonary/aortic stenosis; in these patients, more cautious device selection is needed for transcatheter PDA closure., Scientific Reports, 9(1), art.no.17105; 2019

Background: Understanding the relationship between serotype epidemiology and antimicrobial susceptibility of Streptococcus pneumoniae is essential for the effective introduction of pneumococcal conjugate vaccines (PCVs) and control of antimicrobial-resistant pneumococci. Methods: We conducted a community-based study in Nha Trang,central Vietnam, to clarify the serotype distribution and pattern of S. pneumoniae antimicrobial susceptibility in children under 5 years of age and to identify risk factors for carrying antimicrobial-resistant strains. Nasopharyngeal swabs collected from children with acute respiratory infections (ARIs) hospitalized between April 7,2008, and March 30, 2009, and from healthy children randomly selected in July 2008 were subjected to bacterial culture. Minimum inhibitory concentrations (MICs) against S. pneumoniae were determined, and multiplex-polymerase chain reaction (PCR) serotyping assays were performed. Logistic regression was applied to identify risk factors. Results: We collected 883 samples from 331 healthy children and 552 ARI cases; S. pneumoniae was isolated from 95 (28.7%) healthy children and 202 (36.6%) ARI cases. Age and daycare attendance were significantly associated with pneumococcal carriage. In total, 18.0, 25.8 and 75.6% of the isolates had high MICs for penicillin (?4 μg/ml), cefotaxime (?2 μg/ml) and meropenem (?0.5 μg/ml), respectively. The presence of pneumococci non-susceptible to multiple beta-lactams was significantly associated with serotype 19F(Odds Ratio: 4.23) and daycare attendance (Odds Ratio: 2.56) but not ARIs, age or prior antimicrobial use. The majority of isolates non-susceptible to multiple beta-lactams (90%) were PCV13 vaccine serotypes. Conclusions: S. pneumoniae serotype 19F isolates non-susceptible to multiple beta-lactams are widely prevalent among Vietnamese children. Vaccine introduction is expected to significantly increase drug susceptibility., BMC Infectious Diseases, 19(1), art.no.241; 2019

Several mutations in the surfactant protein C (SP-C) gene (SFTPC) have been reported as causing familial pulmonary fibrosis (FPF). However, the genetic background and clinical features of FPF are still not fully understood. We identified one Japanese kindred, in which at least six individuals over three generations were diagnosed with pulmonary fibrosis. We examined the patients radiologically and histopathologically and sequenced their SFTPC and ABCA3 genes. We also established a cell line stably expressing the mutant gene. All the patients had similar radiological and histopathological characteristics. Their histopathological pattern was that of usual interstitial pneumonia, showing numerous fibroblastic foci even in areas without abnormal radiological findings on chest high-resolution computed tomography. No child had respiratory symptoms in the kindred. Sequencing of SFTPC showed a novel heterozygous mutation, c.298G>A (G100S), in the BRICHOS domain of proSP-C, which co-segregated with the disease. However, in the ABCA3 gene, no mutation was found. In vitro expression of the mutant gene revealed that several endoplasmic reticulum stress-related proteins were strongly expressed. The mutation increases endoplasmic reticulum stress and induces apoptotic cell death compared with wild-type SP-C in alveolar type II cells, supporting the significance of this mutation in the pathogenesis of pulmonary fibrosis.

The interplay between nasopharyngeal bacterial carriage, viral coinfection, and lower respiratory tract infections (LRTIs) is poorly understood. We explored this association in Vietnamese children aged less than 5 years.A hospital-based case-control study of pediatric LRTIs was conducted in Nha Trang, Vietnam. A total of 550 hospitalized children (274 radiologically confirmed pneumonia [RCP] and 276 other LRTIs) were enrolled and 350 healthy controls were randomly selected from the community. Polymerase chain reaction-based methods were used to measure bacterial loads of Streptococcus pneumoniae (SP), Haemophilus influenzae, and Moraxella catarrhalis and to detect 13 respiratory viruses and bacterial serotypes in nasopharyngeal samples of study participants.The median nasopharyngeal bacterial load of SP was substantially higher in children with RCP compared with healthy controls or children with other LRTIs (P0.001). SP load was 15-fold higher in pneumonia children with viral coinfection compared with those children without viral coinfection (1.4 x 10⁷/mL vs. 9.1 x 10⁵/mL; P 0.0001). SP load was over 200-fold higher in serotypeable SP compared with nontypeable SP (2.5 x 10⁶/mL vs. 1 x 10⁴/mL; P0.0001). These associations were independent of potential confounders in multiple regression models. No clear association was found between nasopharyngeal load of Haemophilus influenzae or Moraxella catarrhalis and viral coinfection in either RCP or other LRTIs groups.An increased load of SP in the nasopharynx was associated with RCP, viral coinfection, and presence of pneumococcal capsule.

BACKGROUND: The association between environmental tobacco smoking (ETS) and childhood pneumonia has not been established in developed or developing countries. A study was conducted to assess the effect and impact of ETS exposure on pneumonia among children in central Vietnam. METHODS: A population-based large-scale cross-sectional survey was conducted covering all residents of 33 communes in Khanh Hoa Province, the central part of Vietnam. Information on demographics, socioeconomic status and house environment, including smoking status of each household member, was collected from householders. Hospital admissions for pneumonia among children aged, Thorax, 64(6), pp.484-489; 2009

A prospective case-control study was conducted in urban districts in Hanoi, northern Vietnam to evaluate the effect of migration on the risk of hospitalisation for dengue in a Vietnamese urban population. We enrolled laboratory-confirmed dengue patients aged ≥ 18 years who were hospitalised in local hospitals in November and December 2010. Four neighbourhood-matched controls for each case were recruited within a week of hospitalisation. Sociodemographic data were collected by interviews, and the number of immature and adult mosquitoes within household premises was counted by entomological survey. Matched-pair analyses were conducted using conditional logistic regression models. Among 43 cases and 168 controls, 84% and 83% were migrants from rural areas, respectively. Although statistical significance was marginal, recent migration (residing in study area for ≤ 5 years) independently increased the risk of hospitalisation for dengue compared with inhabitants after controlling for potential confounders (adjusted odds ratio [aOR] = 3.78; 95% confidence interval [CI] = 0.99-14.27), whereas longer-term migration (residing in study area for ≥ 6 years) did not change the risk (aOR = 1.1; 95% CI = 0.30-4.05). Younger age (18-34 years) (aOR = 7.26; 95% CI = 2.39-22.06) and higher adult Aedes aegypti infestation level within household premises (aOR = 9.25; 95% CI = 1.68-51.09) were also independently associated with hospitalisation for dengue. Recent migration from rural areas seems to increase the risk of hospitalisation for dengue in urban populations in endemic areas. Further research including cohort study should be done to confirm the impact of migration on the risk of dengue in urban areas.

BackgroundThe burden of Congenital Rubella Syndrome (CRS) is typically underestimated in routine surveillance. Updated estimates are needed following the recent WHO position paper on rubella and recent GAVI initiatives, funding rubella vaccination in eligible countries. Previous estimates considered the year 1996 and only 78 (developing) countries.MethodsWe reviewed the literature to identify rubella seroprevalence studies conducted before countries introduced rubella-containing vaccination (RCV). These data and the estimated vaccination coverage in the routine schedule and mass campaigns were incorporated in mathematical models to estimate the CRS incidence in 1996 and 2000–2010 for each country, region and globally.ResultsThe estimated CRS decreased in the three regions (Americas, Europe and Eastern Mediterranean) which had introduced widespread RCV by 2010, reaching ConclusionsWhilst falling dramatically in the Americas, Europe and the Eastern Mediterranean after vaccination, the estimated CRS incidence remains high elsewhere. Well-conducted seroprevalence studies can help to improve the reliability of these estimates and monitor the impact of rubella vaccination.

Introduction: Little is known about the state of HIV transmission among married couples in Vietnam. This study aims to clarify HIV serostatus in this group and elucidate risk factors for intra-marital HIV transmission. Methods: In 2012, we enrolled a group of HIV-positive married men registered at the HIV outpatient clinic of a referral hospital in northern Vietnam, along with their wives. Sociodemographic, behavioural and clinical data were collected from men and wives. HIV serodiscordant couples were followed until March 2014 to determine seroconversion rate. A phylogenetic analysis was performed based on env V3 sequence to detail cluster formation among men. Results: Of the 163 HIV-positive men enrolled in the study, 101 (62.0%) had wives testing HIV-negative. Half ofmen reported injecting drug use (IDU) as a likely transmission route. Couples reported a high incidence of unprotected sexual intercourse prior to diagnosis; the median (inter quartile range) was 4 (4-8) times per month. Only 17 couples (10.4%) reported using condoms during at least half these instances. Multivariable analysis revealed IDU history among men was independently associated with HIV-negative wives (adjusted OR 0.31; 95%CI 0.10-0.95, p=0.041). Phylogenetic analysis of 80 samples indicated CRF01-AE. Of these, 69 (86.3%) clustered with IDU-associated viruses from Vietnam. No HIV seroconversion was identified during a follow-up of 61 serodiscordant couples, with 126.5 person-years of observation during which HIV-infectedmen were on antiretroviral drug therapy (ART). Conclusion: High HIV serodiscordance was observed among HIV-affected married couples in northern Vietnam. A large number of at-risk wives therefore remain HIV-negative and can be protected with measures including proper use of ART if couples are made aware of the serodiscordance through screening., PLOS ONE, 10(4), e0125299; 2015

A descriptive study on rickettsiosis was conducted at the largest referral hospital in Hanoi, Vietnam, to identify epidemiological and clinical characteristics of specific rickettsiosis. Between March 2001 and February 2003, we enrolled 579 patients with acute undifferentiated fever (AUF), excluding patients with malaria, dengue fever, and typhoid fever, and serologically tested for Orientia tsutsugamushi and Rickettsia typhi. Of the patients, 237 (40.9%) and 193 (33.3%) had scrub and murine typhus, respectively, and 149 (25.7%) had neither of them (non-scrub and murine typhus [non-ST/MT]). The proportion of murine typhus was highest among patients living in Hanoi whereas that of scrub typhus was highest in national or regional border areas. The presence of an eschar, dyspnea, hypotension, and lymphadenopathy was significantly associated with a diagnosis of scrub typhus (OR = 46.56, 10.90, 9.01, and 7.92, respectively). Patients with murine typhus were less likely to have these findings but more likely to have myalgia, rash, and relative bradycardia (OR = 1.60, 1.56, and 1.45, respectively). Scrub typhus and murine typhus were shown to be common causes of AUF in northern Vietnam although the occurrence of spotted fever group rickettsiae was not determined. Clinical and epidemiological information may help local clinicians make clinical diagnosis of specific rickettsioses in a resource-limited setting.

This study investigated the features of developmental difficulties combined with sensory defects in children with congenital rubella syndrome (CRS). Following a large rubella outbreak in Khanh Hoa Province, Vietnam, in 2011, we enrolled 41 children with CRS from September 2011 through May 2013. Fourteen participants died and six became untraceable by October 2013; the remaining 21 children were followed up from 2013 to 2015. Thirteen and seven participants had hearing and functional ophthalmological impairment, respectively. Developmental difficulties were suspected in 19 (95%) children who failed in at least one area of the Ages and Stages Questionnaire (ASQ) and/or Denver II in 2013 and/or 2015. Developmental difficulties were frequently identified in the ASQ communication domain (n = 14 in 2013) and Denver II language area (n = 13 in 2013). Seven (41%) participants were suspected of having autism spectrum disorder (ASD) in 2013 by the Modified Checklist for Autism in Toddlers. In 2015, proportions of children failing the problem-solving (62%) and personal-social (62%) domains had increased and two of 13 were diagnosed with ASD by the Childhood Autism Rating Scale, Second Edition. Developmental difficulties were suspected in most children with CRS, including autism largely combined with sensory dysfunction., Scientific Reports, 7, 46483; 2017

The age-group-specific incidence and etiological patterns of community-acquired pneumonia (CAP) have not been fully established in Japan. A 2-year prospective surveillance was conducted in Kochi city, Western Japan. All CAP patients aged ?15 years who visited a community-based hospital were enrolled in the study. Clinical samples were examined by conventional bacterial culture and urinary antigen tests, and 6 bacterial pathogens and 16 respiratory viruses were identified from sputum samples by multiplex polymerase chain reaction assays. The age-group-specific incidence of CAP was estimated using a population-based data set of the total number of outpatients in the whole city. Ninety of the 131 enrolled patients, 68.7zwere positive for respiratory pathogens. Streptococcus pneumoniae was the leading bacterial pathogen identified (28.2z). Respiratory viruses were identified in 36 patients (27.5z), and human entero-rhinovirus was the most common (13.3z) among them. The estimated overall incidence of adult CAP in Kochi was 9.6 per 1,000 person-years (PY); the estimated age group-specific incidence was 3.4, 10.7, and 42.9 per 1,000 PY for those aged 15-64, 65-74, and ?75 years, respectively. The high incidence of CAP in these rural city of Japan, probably reflects the substantial aged population. S. pneumoniae and respiratory viruses play important roles in CAP in all age groups., Japanese Journal of Infectious Diseases, 67(4), pp.269-275; 2014

OBJECTIVE: Outbreaks of rubella and congenital rubella syndrome (CRS) continue to arise in various countries where a rubella-containing vaccine is not included in the national immunization program. After a large-scale rubella outbreak in 2011, CRS cases emerged in Vietnam. The aim of this study was to clarify the clinical features of these cases with an emphasis on cardiovascular complications and outcomes. METHODS: From October 2011 to September 2012, we conducted a prospective surveillance study of infants RESULTS: We enrolled 38 cases of CRS characterized by a low birth weight (71%), cardiovascular defects (72%), cataracts (13%), hearing impairment (93%), purpura (84%), hepatosplenomegaly (68%), and thrombocytopenia (76%). Patent ductus arteriosus, the most common cardiovascular complication, was often associated with progressive pulmonary hypertension (PH). As of January 2013, 13 infants (34%) had died, and PH was significantly more frequent among the fatalities (P = .004); however, therapeutic closure of the ductus reversed the PH in several cases. CONCLUSIONS: PH-associated mortality is high among infants who have CRS in Vietnam. Providing proper assessments, continuous follow-up, and timely intervention for cardiovascular defects is critical for the management of CRS patients. Echocardiography is of diagnostic and prognostic value and can support better clinical management of CRS, even in a developing country setting.

The objective of this study was to estimate influenza vaccine effectiveness (VE) against medically attended, laboratoryconfirmed influenza during the 2011-2012 season in Japan using a test-negative case-control study design. The effect of cocirculating non-influenza respiratory viruses (NIRVs) on VE estimates was also explored. Nasopharyngeal swab samples were collected from outpatients with influenza-like illnesses (ILIs) in a community hospital in Nagasaki, Japan. Thirteen respiratory viruses (RVs), including influenza A and B, were identified from the samples using a multiplex polymerase chain reaction. The difference in VE point estimates was assessed using three different controls: ILI patients that tested negative for influenza, those that tested negative for all RVs, and those that tested positive for NIRVs. The adjusted VE against medically attended, laboratory-confirmed influenza using all influenza-negative controls was 5.3% (95% confidence interval [CI], -60.5 to 44.1). The adjusted VEs using RV-negative and NIRV-positive controls were -1.5% (95% CI, -74.7 to 41) and 50% (95% CI, -43.2 to 82.5), respectively. Influenza VE was limited in Japan during the 2011-2012 season. Although the evidence is not conclusive, co-circulating NIRVs may affect influenza VE estimates in test-negative case-control studies., PLoS ONE, 9(2), e88813; 2014

Background: Among pneumococcal serotypes, some serotypes are more prevalent in the nasopharynx than others; determining factors for higher prevalence remain to be fully explored. As non-vaccine serotypes have emerged after the introduction of 7-valent conjugate vaccines, study of serotype specific epidemiology is in need. When two or more serotypes co-colonize, they evolve rapidly to defend host's immune responses; however, a clear association of cocolonization with a clinical outcome is lacking. Methods: Children less than 5 years old who were admitted to hospital due to acute respiratory infections (ARI) (n = 595) and healthy children (n = 350) were recruited. Carriage of pneumococcus was determined by culture and lytA PCR in the nasopharyngeal samples. Serotype/serogroup detection and its quantification were done by the nanofluidic real time PCR system. Spearman's correlation and logistic regression were used to examine a correlation of serotype/serogroup specific bacterial load with its prevalence and an association of co-colonization with ARI respectively. Results: Serotype/serogroup specific bacterial load was correlated with its prevalence, both in ARI cases (Spearman's rho = 0.44, n = 186; P, PLoS ONE, 9(10), e110777; 2014

The purpose of this study was to investigate the prevalence of bed net use and elucidate the effect of daytime bed net use on preventing dengue hemorrhagic fever (DHF) among children in Vietnam. We conducted a population-based cross-sectional survey and a matched case-control study in Khanh Hoa Province where not only some pre-schoolchildren but also some school children, who take a nap during lunch break prior to returning to school, used bed nets during the day. Among 36,901 children 2-10 years of age, most used untreated bed nets during the night (98.3%) compared with 8.4% during the day. The results of the case-control study, which defined 151 cases who were hospitalized with DHF in the provincial hospitals and 604 age-matched neighborhood controls, did not support our hypothesis that children using untreated bed nets during the day are less likely to be hospitalized with DHF (adjusted odds ratio = 0.56, 95% confidence interval = 0.23-1.39)., The American journal of tropical medicine and hygiene, 82(6), pp.1157-1159; 2010

Hospitalized Vietnamese children with acute respiratory infection were investigated for 13 viral pathogens using multiplex-polymerase chain reaction. We enrolled 958 children of whom 659 (69%) had documented viral infection: rhinovirus (28%), respiratory syncytial virus (23%), influenza virus (15%), adenovirus (5%), human metapneumo virus (4.5%), parainfluenza virus (5%), and bocavirus (2%). These Vietnamese children had a range of respiratory viruses which underscores the need for enhanced acute respiratory infection surveillance in tropical developing countries., The Pediatric infectious disease journal, 29(1), pp.75-77; 2010

Background Lower respiratory tract infection (LRTI) including Community-acquired pneumonia (CAP) is a common infectious disease that is associated with significant morbidity and mortality. The patterns of aetiological pathogens differ by region and country. Special attention must be paid to CAP in Southeast Asia (SEA), a region facing rapid demographic transition. Estimates burden and aetiological patterns of CAP are essential for the clinical and public health management. The purposes of the study are to determine the incidence, aetiological pathogens, clinical pictures and risk factors of community-acquired pneumonia (CAP) in the Vietnamese adult population. Methods A prospective surveillance for hospitalised adult CAP was conducted in Khanh Hoa Province, Central Vietnam. All adults aged ≥15 years with lower respiratory tract infections (LRTI) admitted to a provincial hospital from September 2009 to August 2010 were enrolled in the study. Patients were classified into CAP and non-pneumonic LRTI (NPLRTI) according to the radiological findings. Bacterial pathogens were identified from sputum samples by the conventional culture and polymerase chain reaction (PCR) for Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis; 13 respiratory viruses were identified from nasopharyngeal specimens by PCR. Results Of all 367 LRTI episodes examined, 174 (47%) were CAP. Older age, the presence of underlying respiratory conditions, and higher index score of smoking were associated with CAP. The one-year estimated incidence of hospitalised adult CAP in our study population was 0.81 per 1,000 person years. The incidence increased considerably with age and was highest among the elderly. The case fatality proportion of hospitalised CAP patients was 9.8%. Among 286 sputum samples tested for bacterial PCR, 79 (28%) were positive for H. influenzae, and 65 (23%) were positive for S. pneumoniae. Among 357 samples tested for viral PCR, 73 (21%) were positive for respiratory viruses; influenza A (n = 32, 9%) was the most common. Conclusions The current adult CAP incidence in Vietnam was relatively low; this result was mainly attributed to the young age of our study population.

Comprehensive population-based data on the role of respiratory viruses in the development of lower respiratory tract infections (LRTIs) remain unclear. We investigated the incidence and effect of single and multiple infections with respiratory viruses on the risk of LRTIs in Vietnam. Population-based prospective surveillance and a case-control study of hospitalised paediatric patients with acute respiratory infection (ARI) were conducted from April 2007 through to March 2010. Healthy controls were randomly recruited from the same community. Nasopharyngeal samples were collected and tested for 13 respiratory viruses using multiplex PCRs. 1992 hospitalised ARI episodes, including 397 (19.9%) with LRTIs, were enrolled. Incidence of hospitalised LRTIs among children aged

To investigate the association between environmental exposure to livestock and incidence of diarrhoea among Vietnamese children.A population-based cohort of 353,525 individuals, living in 75,828 households in Khanh Hoa Province, Vietnam, with baseline data covering geo-referenced information on demography, socio-economic status and household animals was investigated. Geographic information system was applied to calculate the density of livestock. The data were linked to hospitalized diarrhoea cases of children under 5 years recorded at two hospitals treating patients from the area as inpatients in the study area.Overall, 3116 children with diarrhoea were hospitalized during the study period. The incidence of diarrhoea hospitalization was 60.8/1000 child-years. Male gender, age2 years, higher number of household members and lack of tap water were significantly associated with an increased risk of diarrhoea. There was no evidence that ownership of livestock increased the risk of diarrhoea. In spatial analysis, we found no evidence that a high density of any animals was associated with an increased risk of diarrhoea.Exposure to animals near or in households does not seem to constitute a major risk for diarrhoea in children under the age of 5 in Vietnam. Public health interventions to reduce childhood diarrhoea burden should focus on well-recognized causes such as sanitation, personal hygiene, access to adequate clean water supply and vaccination.

In many countries, girls have been reported to be less often admitted to hospital than boys. We studied the influence of socio-economic factors, education and access to health care on girls' and boys' admission rates for pneumonia, diarrhoea and dengue fever in south-central Vietnam. We explored whether the user fee exemption for children under 6 years introduced in 2005 had an impact on girls' admission rates. In a cohort analysis, we used data from a large census in Khanh Hoa Province conducted in 2006, linked to hospital admission records at individual level. We further analysed a cross-sectional health care utilization survey in a sample of children reported ill at the census. There were 38 731 children under 6 years among a total census population of 353 891. Overall, girls under the age of 6 years were 29% less likely to be admitted to hospital than boys. The gender differences in admission rates in children under 6 years were similar for diarrhoea, pneumonia and dengue. None of the socio-economic and educational factors appeared to affect the gender difference. The user fee exemption starting from October 2005 had no impact on the girls/boys rate ratio of admission. In conclusion, the higher hospital admission rates of boys compared with girls in Vietnam are independent of socio-economic factors and user fees. Higher susceptibility of boys to severe disease could explain part of the gender gap, but profound cultural norms and beliefs may also have contributed to the findings.

To the Editor: Xu and colleagues (1) examined the nasopharyngeal bacterial colonization rates in children with acute otitis media (AOM) and in healthy children. They found that Haemophilus influenzae colonization was competitively associated with Streptococcus pneumoniae and Morexella catarrhalis colonization in children with AOM but was not associated with S. pneumoniae and M. catarrhalis colonization in healthy children. We have a serious concern regarding their analysis. The authors calculated odds ratios (ORs) by considering a bacterial colonization as an outcome variable and another bacterial colonization as an exposure variable. They considered an OR >1 as the presence of synergistic associations between bacteria (i.e., co-colonization is more likely to occur than it would by chance) and OR 1 for diseased children and 1 (“pseudo-synergistic associations”) in healthy children. This is probably what the authors have observed in the study. We cannot infer an association of multiple bacterial colonizations in a population despite an observed association in the diseased (or healthy) children, and this association is widely misunderstood (2–4). The authors’ discussion regarding a potential emergence of H. influenzae, associated with AOM, after the introduction of pneumococcal conjugate vaccine is thus unjustifiable. Technical Appendix: Number of children by bacterial colonization status in a stationary population and case-patients enrolled during a specified period. Click here to view.(61K, pdf)

Background. To understand the epidemiology of childhood bacterial diseases, including invasive pneumococcal disease, prospective surveillance was conducted among hospitalized children in Nha Trang, Vietnam. Methods. From April 2005 through August 2006, pediatricians at the Khanh Hoa General Hospital used standardized screening criteria to identify children aged

Background A strategy to combat infectious diseases, including neglected tropical diseases (NTDs), will depend on the development of reliable epidemiological surveillance methods. To establish a simple and practical seroprevalence detection system, we developed a microsphere-based multiplex immunoassay system and evaluated utility using samples obtained in Kenya. Methods We developed a microsphere-based immuno-assay system to simultaneously measure the individual levels of plasma antibody (IgG) against 8 antigens derived from 6 pathogens: Entamoeba histolytica (C-IgL), Leishmania donovani (KRP42), Toxoplasma gondii (SAG1), Wuchereria bancrofti (SXP1), HIV (gag, gp120 and gp41), and Vibrio cholerae (cholera toxin). The assay system was validated using appropriate control samples. The assay system was applied for 3411 blood samples collected from the general population randomly selected from two health and demographic surveillance system (HDSS) cohorts in the coastal and western regions of Kenya. The immunoassay values distribution for each antigen was mathematically defined by a finite mixture model, and cut-off values were optimized. Findings Sensitivities and specificities for each antigen ranged between 71 and 100%. Seroprevalences for each pathogen from the Kwale and Mbita HDSS sites (respectively) were as follows: HIV, 3.0% and 20.1%; L. donovani, 12.6% and 17.3%; E. histolytica, 12.8% and 16.6%; and T. gondii, 30.9% and 28.2%. Seroprevalences of W. bancrofti and V. cholerae showed relatively high figures, especially among children. The results might be affected by immunological cross reactions between W. bancrofti-SXP1 and other parasitic infections; and cholera toxin and the enterotoxigenic E. coli (ETEC), respectively. Interpretation A microsphere-based multi-serological assay system can provide an opportunity to comprehensively grasp epidemiological features for NTDs. By adding pathogens and antigens of interest, optimized made-to-order high-quality programs can be established to utilize limited resources to effectively control NTDs in Africa., Author Summary Monitoring the distribution of neglected tropical diseases (NTDs) is a key to controlling their spread in Africa. Currently, such surveillance is conducted independently for each NTD. To tackle this problem, we developed a microsphere-based system to permit simultaneous measurement of IgG antibody levels for antigens from six infectious diseases: Entamoeba histolytica, Leishmania donovani, Toxoplasma gondii, Wuchereria bancrofti, HIV, and Vibrio cholerae. Using this system, we conducted a serological survey using two health and demographic surveillance system (HDSS) areas in coastal and western Kenya. We randomly selected 4,600 individuals according to sex and age group, of whom 3411 agreed to participate in the study. Mathematical analyses of the distributions of the participants' reactivity to each antigen and the reactivity of the sero-positive and -negative controls indicated that this system could be used to monitor infections, especially, those associated with HIV, filariasis, toxoplasmosis, leishmaniasis, and amebiasis. For the practical development and eventual implementation of actual programs in Africa, pathogens and antigens of interest can be added to optimize made-to-order monitoring programs.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode., Tobacco control, 19(4), pp.344-345; 2010

Respiratory syncytial virus (RSV) is a major cause of acute respiratory infections (ARIs) in children worldwide and can cause high mortality, especially in developing countries. However, information on the clinical and molecular characteristics of RSV infection in developing countries is limited. From April 2010 to May 2011, 1,082 nasopharyngeal swabs were collected from children with ARI admitted to the Children's Hospital 2, Ho Chi Minh City, Vietnam. Samples were screened for RSV and genotyped by reverse transcription-PCR and sequencing. Demographic and clinical data was also recorded. RSV was found in 23.8% (257/1,082) of samples. RSV A was the dominant subgroup, accounting for 91.4% (235/257), followed by RSV B, 5.1% (13/257), and 9 cases (3.5%) were mixed infection of these subgroups. The phylogenetic analysis revealed that all group A strains belonged to the GA2 genotype. All group B strains belonged to the recently identified BA genotype, and further clustered into 2 recently described subgenotypes BA9 and BA10. One GA2 genotype strain had a premature stop codon which shortened the G protein length. RSV infection was significantly associated with younger age and higher severity score than those without. Co-infection with other viruses did not affect disease severity. RSV A caused more severe disease than RSV B. The results from this study will not only contribute to the growing database on the molecular diversity of RSV circulating worldwide but may be also useful in clinical management and vaccine development., PLoS ONE, 8(1), e45436; 2013

Results from 75,000 geo-referenced households in Vietnam during two dengue epidemics reveal that human population densities typical of villages are most prone to dengue outbreaks; rural areas may contribute as much to dissemination of dengue fever as do cities., Background Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas. We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk. Methods and Findings We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013). We applied space-time scan statistics and mathematical models to confirm the findings. We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km2 prone to dengue outbreaks. In the study area, this population density was typical of villages and some peri-urban areas. Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks. The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range. Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks. Conclusions Rural areas may contribute at least as much to the dissemination of dengue fever as cities. Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts. Please see later in the article for the Editors' Summary, Editors' Summary Background Dengue fever is a viral infection common in tropical and subtropical regions that is characterized by sudden high fever, severe headache, muscle and joint pains, and a rash. The virus is transmitted by the bite of female Aedes aegypti mosquitoes. Although dengue is not usually fatal, infection rates can be as high as 90% among those who have not been previously exposed to the virus, and in a small proportion of cases the disease can develop into dengue hemorrhagic fever, which is life threatening. It is estimated that 500,000 people are hospitalized every year with dengue hemorrhagic fever. Incidence of dengue fever is increasing, and two-fifths of the world's population, approximately 2.5 billion people, are now at risk from the disease in over 100 endemic countries. Why Was This Study Done? There is no specific treatment for dengue fever, other than managing symptoms and ensuring hydration, and no vaccine available. The best way to counter the spread of dengue fever is to target the mosquito vector, with one of the more effective methods being the disruption of mosquito habitats, in particular eliminating standing water such as in unused tires, open water storage containers, or even flower vases, where mosquitoes lay their eggs and larvae develop. Because the geographic range of the mosquitoes that transmit dengue has increased, there has been a rapid rise in global dengue epidemics over the last 30 years with Southeast Asia and the Western Pacific being most severely affected. In this study researchers aimed to define areas in Vietnam that were most at risk of dengue fever by looking at population density and water supply. What Did the Researchers Do and Find? The researchers studied a population in Kanh-Hoa Province in south-central Vietnam (∼350,000 people) that was affected by two dengue epidemics between January 2005 and June 2008. They included all patients admitted to two public hospitals that could be linked to census data from 2006 (3,013 patients). These data enabled the researchers to calculate both the population density and the proportion of households with access to tap water within 100 meters of each patient's household. The researchers found that low population densities, typical of rural villages (around 110 people residing within a 100-meter radius), had the highest rate of dengue fever. They also found that in those neighborhoods where less than 20% of households had tap water there was a peak in dengue fever rates at a population density of 190 people residing within 100 meters. On an individual household level they found that absence of tap water was associated with an increased risk of dengue fever. In the absence of data on larvae and mosquito abundance the researchers used a mathematical model to show that when mosquito numbers were limited the highest risk of dengue occurred at very low population densities. However, if mosquito numbers were limited only at high human population densities, dengue fever risk peaked at low-to-moderate human population densities. The model suggests that the provision of tap water changes the risk of dengue because mosquito numbers are limited. What Do These Findings Mean? People living in low-to-moderate population densities, such as rural villages, without access to tap water have the highest risk of contracting dengue fever. The use of water storage vessels provides breeding sites for mosquitoes and leads to a high mosquito-to-human ratio and an increased individual dengue risk. In more populated urban areas with tap water, mosquito breeding sites are limited so the relative risk of dengue for an individual is less because the mosquito-to-human ratio is smaller. Populated areas still contribute substantially to dengue epidemics, however, because the absolute number of people who can contract dengue is high. The authors point out some limitations in their study, such as only looking at the most severe cases of dengue in patients who were admitted to hospital and assuming that all taps were functional. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001082. WHO provides information on dengue fever including a dengue fact sheet The CDC provides information on the Aedes aegypti mosquito and a global health map that reports areas at risk of dengue