Incidence and seasonality of Kawasaki disease in children in the Philippines, and its association with ambient air temperature.

Background: Despite an unknown cause, Kawasaki disease (KD) is currently the primary leading cause of acquired heart disease in developed countries in children and has been increasing in recent years. Research efforts have explored environmental factors related to KD, but they are still unclear especially in the tropics. We aimed to describe the incidence of KD in children, assess its seasonality, and determine its association with ambient air temperature in the National Capital Region (NCR), Philippines from January 2009 to December 2019. Methods: Monthly number of KD cases from the Philippine Pediatric Society (PPS) disease registry was collected to determine the incidence of KD. A generalized linear model (GLM) with quasi-Poisson regression was utilized to assess the seasonality of KD and determine its association with ambient air temperature after adjusting for the relevant confounders. Results: The majority of KD cases (68.52%) occurred in children less than five years old, with incidence rates ranging from 14.98 to 23.20 cases per 100,000 population, and a male-to-female ratio of 1.43:1. Seasonal variation followed a unimodal shape with a rate ratio of 1.13 from the average, peaking in March and reaching the lowest in September. After adjusting for seasonality and long-term trend, every one-degree Celsius increase in the monthly mean temperature significantly increased the risk of developing KD by 8.28% (95% CI: 2.12%, 14.80%). Season-specific analysis revealed a positive association during the dry season (RR: 1.06, 95% CI: 1.01, 1.11), whereas no evidence of association was found during the wet season (RR: 1.10, 95% CI: 0.95, 1.27). Conclusion: We have presented the incidence of KD in the Philippines which is relatively varied from its neighboring countries. The unimodal seasonality of KD and its linear association with temperature, independent of season and secular trend, especially during dry season, may provide insights into its etiology and may support enhanced KD detection efforts in the country.

Possible vertical transmission of Chikungunya virus infection detected in the cord blood samples from a birth cohort in Vietnam.

BACKGROUND: Chikungunya virus (CHIKV) is an alphavirus (genus Alphavirus, family Togaviridae) that is primarily transmitted to humans by Aedes mosquitoes, and can be transmitted from mother to child. Little is known about CHIKV transmission in Vietnam, where dengue is endemic and Aedes mosquitoes are abundant. This study aimed to determine the prevalence and characteristics of vertical CHIKV infection in a birth cohort, and seroprevalence of anti-CHIKV antibodies with or without confirmation by neutralization tests among women bearing children in Vietnam. METHODS: We collected umbilical cord blood plasma samples from each newly delivered baby in Nha Trang, Central Vietnam, between July 2017 and September 2018. Samples were subjected to molecular assay (quantitative real-time RT-PCR) and serological tests (anti-CHIKV IgM capture and IgG indirect enzyme-linked immunosorbent assay, and neutralization tests). RESULTS: Of the 2012 tested cord blood samples from newly delivered babies, the CHIKV viral genome was detected in 6 (0.3%) samples by RT-PCR, whereas, 15 samples (0.7%) were anti-CHIKV-IgM positive. Overall, 18 (0.9%, 95% CI: 0.6-1.5) samples, including three positives for both CHIKV IgM and viral genome on RT-PCR, were regarded as vertical transmission of CHIKV infection. Of the 2012 cord blood samples, 10 (0.5%, 95% CI: 0.2-0.9) were positive for both anti-CHIKV IgM and IgG. Twenty-nine (1.4%, 95% CI: 1.0-2.1) were seropositive for anti-CHIKV IgG while 26 (1.3%, 95% CI: 0.8-1.9) of them were also positive for neutralizing antibodies, and regarded as seropositive with neutralization against CHIKV infection. CONCLUSION: This is the first report of a possible CHIKV maternal-neonatal infection in a birth cohort in Vietnam. The findings indicate that follow-up and a differential diagnosis of CHIKV infection in pregnant women are needed to clarify the potential for CHIKV vertical transmission and its impact in the newborn.

Sero and Carriage Epidemiology of Pertussis in Urban and Rural Regions in Vietnam.

The underestimation of the pertussis burden prompted our study to investigate the prevalence of recent pertussis infection, its associated factors, and antibody titer changes in the same individuals in Vietnam. Two cross-sectional surveys were conducted in Nha Trang in 2017 and Quang Ngai in 2019, representing high- and low-vaccine-coverage areas, respectively. Serum anti-pertussis toxin immunoglobulin-G (anti-PT IgG) ≥ 62.5 IU/mL by ELISA indicated infection in the previous 12 months. In Nha Trang, the participants of the 2017 survey were followed up in 2019. Logistic regression was used to determine the odds ratios for the characteristics associated with anti-PT IgG ≥ 62.5. The age-stratified prevalence in patients aged >2 years ranged from 2.1% (age 26-35) to 9.6% (3-5) in Nha Trang (2017) and from 7.2% (age 26-35) to 11.4% (6-15) in Quang Ngai. The prevalence tended to be higher in Quang Ngai across all age groups. Cough, recent antibiotic use, and smoking in Nha Trang were positively associated with an anti-PT IgG of ≥62.5, and having been diagnosed with pertussis and persistent cough with paroxysms/whoop in Quang Ngai were positively associated with an anti-PT IgG of ≥62.5. No nasopharyngeal swabs were positive for Bordetella pertussis using real-time PCR. The geometric mean of the IgG titer ratio from 2019 to 2017 was 1.45 in the paired samples. This study emphasizes Bordetella pertussis circulation across all age groups in both low- and high-vaccine-coverage settings in Vietnam, underscoring the need for continuous and standardized surveillance for a comprehensive understanding of its epidemiology.

Evaluation of the effect of reduced-dose pneumococcal conjugate vaccine schedules on vaccine serotype carriage in children and their caretakers in a naïve population in Vietnam: Protocol for a cluster randomized non-inferiority trial.

Introduction: The WHO currently recommends giving pneumococcal conjugate vaccines (PCVs) as three doses - either three doses in infancy with Pentavalent vaccine (3p+0), or two doses in infancy followed by a booster around 12 months (2p+1). However, their high price is a barrier to introduction and sustainability in low and middle-income countries. We hypothesize that a schedule with a single priming and a booster dose (1p+1) may maintain similar levels of protection for the community by sustaining herd immunity, once circulation of vaccine types has been controlled. Methods and analysis: We will conduct a cluster randomized trial with four intervention arms (1p+1, 0p+1, 2p+1, 3p+0) and three unvaccinated clusters in the 27 communes of Nha Trang, central Vietnam. A PCV catch-up vaccination campaign to all children under three years of age will be performed at the start of the trial. The primary endpoint is non-inferiority of the1p+1 schedule if compared to the WHO standard 2p+1 and 3p+0 schedules in reducing vaccine serotype carriage prevalence in infants. We will also explore impact of 0p+1 schedule. A baseline and annual pneumococcal carriage surveys of 6480 participants per survey covering infants, toddlers and their mothers will be conducted. Ethics and dissemination: Ethical approvals were obtained from the ethical review committees of Institute of Tropical Medicine, Nagasaki University (151203149-2) and the Ministry of Health, Vietnam (1915/QD-BYT). The results, interpretation and conclusions will be presented at national and international conferences, and published in peer-reviewed open access journals. Trial registration number: NCT02961231.

A Birth Cohort Follow-Up Study on Congenital Zika Virus Infection in Vietnam.

We assessed the development, sensory status, and brain structure of children with congenital Zika virus (ZIKV) infection (CZI) at two years and preschool age. CZI was defined as either ZIKV RNA detection or positive ZIKV IgM and neutralization test in the cord or neonatal blood. Twelve children with CZI born in 2017-2018 in Vietnam, including one with Down syndrome, were assessed at 23-25.5 months of age, using Ages and Stages Questionnaire (ASQ-3), ASQ:Social-Emotional (ASQ:SE-2), Modified Checklist for Autism in Toddlers, automated auditory brainstem response (AABR), and Spot Vision Screener (SVS). They underwent brain CT and MRI. They had detailed ophthalmological examinations, ASQ-3, and ASQ:SE-2 at 51-62 months of age. None had birthweight or head circumference z-score < -3 except for the one with Down syndrome. All tests passed AABR (n = 10). No ophthalmological problems were detected by SVS (n = 10) and detailed examinations (n = 6), except for a girl's astigmatism. Communication and problem-solving domains in a boy at 24 months, gross-motor area in a boy, and gross-motor and fine-motor areas in another boy at 59-61 months were in the referral zone. Brain CT (n = 8) and MRI (n = 6) revealed no abnormalities in the cerebrum, cerebellum, or brainstem other than cerebellar hypoplasia with Down syndrome. The CZI children were almost age-appropriately developed with no brain or eye abnormalities. Careful and longer follow-up is necessary for children with CZI.

A decade of human metapneumovirus in hospitalized children with acute respiratory infection: molecular epidemiology in central Vietnam, 2007-2017.

Human metapneumovirus (hMPV) can cause severe acute respiratory infection (ARI). We aimed to clarify the clinical and molecular epidemiological features of hMPV. We conducted an ARI surveillance targeting hospitalized children aged 1 month to 14 years in Nha Trang, Vietnam. Nasopharyngeal swabs were tested for respiratory viruses with PCR. We described the clinical characteristics of hMPV patients in comparison with those with respiratory syncytial virus (RSV) and those with neither RSV nor hMPV, and among different hMPV genotypes. Among 8822 patients, 278 (3.2%) were hMPV positive, with a median age of 21.0 months (interquartile range: 12.7-32.5). Among single virus-positive patients, hMPV cases were older than patients with RSV (p < 0.001) and without RSV (p = 0.003). The proportions of clinical pneumonia and wheezing in hMPV patients resembled those in RSV patients but were higher than in non-RSV non-hMPV patients. Seventy percent (n = 195) were genotyped (A2b: n = 40, 20.5%; A2c: n = 99, 50.8%; B1: n = 37, 19%; and B2: n = 19, 9.7%). The wheezing frequency was higher in A2b patients (76.7%) than in those with other genotypes (p = 0.033). In conclusion, we found a moderate variation in clinical features among hMPV patients with various genotypes. No seasonality was observed, and the multiple genotype co-circulation was evident.

Molecular Epidemiology of Streptococcus pneumoniae Detected in Hospitalized Pediatric Acute Respiratory Infection Cases in Central Vietnam.

Streptococcus pneumoniae is the major bacterial pathogen causing high pneumonia morbidity and mortality in children <5 years of age. This study aimed to determine the molecular epidemiology of S. pneumoniae detected among hospitalized pediatric ARI cases at Khanh Hoa General Hospital, Nha Trang, Vietnam, from October 2015 to September 2016 (pre-PCV). We performed semi-quantitative culture to isolate S. pneumoniae. Serotyping, antimicrobial susceptibility testing, resistance gene detection and multi-locus sequence typing were also performed. During the study period, 1300 cases were enrolled and 413 (31.8%) S. pneumoniae were isolated. School attendance, age <3 years old and prior antibiotic use before admission were positively associated with S. pneumoniae isolation. Major serotypes were 6A/B (35.9%), 19F (23.7%) and 23F (12.7%), which accounted for 80.3% of vaccine-type pneumococci. High resistance to Clarithromycin, Erythromycin and Clindamycin (86.7%, 85%, 78.2%) and the mutant drug-resistant genes pbp1A (98.1%), pbp2b (98.8%), pbp2x (99.6%) ermB (96.6%) and mefA (30.3%) were detected. MLST data showed high genetic diversity among the isolates with dominant ST 320 (21.2%) and ST 13223 (19.3%), which were mainly found in Vietnam. Non-typeables accounted for most of the new STs found in the study. Vaccine-type pneumococcus and macrolide resistance were commonly detected among hospitalized pediatric ARI cases.

Evaluation and validation of a commercial ELISA versus the in vitro toxin neutralization assay for determination of diphtheria anti-toxin in human serum.

Introduction. Diphtheria is a potentially life-threatening infection and remains endemic in many low- and middle-income countries (LMICs). A reliable, low-cost method for serosurveys in LMICs is warranted to estimate the accurate population immunity to control diphtheria.Hypothesis/Gap Statement. The correlation between the ELISA results against diphtheria toxoid and the gold standard diphtheria toxin neutralization test (TNT) values is poor when ELISA values are <0.1 IU ml-1, which results in inaccurate estimates of susceptibility in populations when ELISA is used for measuring antibody levels.Aim. To explore methods to accurately predict population immunity and TNT-derived anti-toxin titres from ELISA anti-toxoid results.Methodology. A total of 96 paired serum and dried blood spot (DBS) samples collected in Vietnam were used for comparison of TNT and ELISA. The diagnostic accuracy of ELISA measurement with reference to TNT was assessed by area under the receiver operating characteristic (ROC) curve (AUC) and other parameters. Optimal ELISA cut-off values corresponding to TNT cut-off values of 0.01 and 0.1 IU ml-1 were identified by ROC analysis. A method based on the multiple imputation approach was also applied to estimate TNT measurements in a dataset that only included ELISA results. These two approaches were then applied to ELISA results previously generated from 510 subjects in a serosurvey in Vietnam.Results. The ELISA results on DBS samples showed a good diagnostic performance compared to TNT. The cut-off values for ELISA measurement corresponding to the TNT cut-off values of 0.01 IU ml-1 were 0.060 IU ml-1 in serum samples, and 0.044 IU ml-1 in DBS samples. When a cut-off value of 0.06 IU ml-1 was applied to the 510 subject serosurvey data, 54 % of the population were considered susceptible (<0.01 IU ml-1). The multiple imputation-based approach estimated that 35 % of the population were susceptible. These proportions were much larger than the susceptible proportion estimated by the original ELISA measurements.Conclusion. Testing a subset of sera by TNT combined with ROC analysis or a multiple imputation approach helps to adjust ELISA thresholds or values to assess population susceptibility more accurately. DBS is an effective low-cost alternative to serum for future serological studies for diphtheria.

The fecal carriage rate of extended-spectrum ß-lactamase-producing or carbapenem-resistant Enterobacterales among Japanese infants in the community at the 4-month health examination in a rural city.

Background: Extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) is a great public health concern globally not only in hospitals but also in the community. To our knowledge, there have been few studies on the prevalence of ESBL-E and much less about carbapenem-resistant Enterobacterales (CRE) among children in the community, and there is no such study in Japan despite such situations. This study aimed to clarify their carriage status among Japanese infants in the community by taking the opportunity of the 4-month health checkup. Methods: This prospective analysis was conducted from April 2020 to March 2021 in Shimabara City, Nagasaki Prefecture, Japan. The research-related items were mailed to all subjects with official documents for the checkup. The fecal samples were obtained from the diaper by guardians beforehand and were collected with the questionnaire and then screened for ESBL-E and CRE by a clinical laboratory company with selective agars followed by identification and confirmation. Only the positive samples were analyzed about resistant genotypes. Results: One hundred fifty infants aged 4-5 months, over half of the subjects, participated in this study. The overall ESBL-E carriage rate was 19.3% (n = 29), and no CRE carrier was detected among them. All identified ESBL-E were E. coli except for one K. pneumoniae. A significantly higher carriage rate was recorded among the infants born at "Hospital A" (25.0%) than the others (11.3%). Enterobacterales producing CTX-M-9 ± TEM were broadly distributed among the positive samples (65.5%), whereas the CTX-M-1 group was exclusively detected among those from "Hospital A". Recursive partitioning analysis suggested that delivery facilities might be an important factor for ESBL-E colonization, although the effect could be decreased as they grow. In contrast, no significant effect was observed for other factors such as parent(s) as healthcare worker(s), having a sibling(s), and the mode of delivery. Conclusion: This study revealed the ESBL-E and CRE carriage status of Japanese infants in the community for the first time, although the setting is somewhat limited. Our findings indicated that environmental factors, especially delivery facilities, influenced ESBL-E colonization among infants aged 4-5 months, implying the need for strengthening countermeasures against antimicrobial resistance at delivery facilities and communities outside the hospitals.

Antibiotic-Resistant Vibrio cholerae O1 and Its SXT Elements Associated with Two Cholera Epidemics in Kenya in 2007 to 2010 and 2015 to 2016.

Multidrug-resistant Vibrio cholerae O1 strains have long been observed in Africa, and strains exhibiting new resistance phenotypes have emerged during recent epidemics in Kenya. This study aimed to determine the epidemiological aspects, drug resistance patterns, and genetic elements of V. cholerae O1 strains isolated from two cholera epidemics in Kenya between 2007 and 2010 and between 2015 and 2016. A total of 228 V. cholerae O1 strains, including 226 clinical strains isolated from 13 counties in Kenya during the 2007-2010 and 2015-2016 cholera epidemics and two environmental isolates (from shallow well water and spring water isolates) isolated from Pokot and Kwale Counties, respectively, in 2010 were subjected to biotyping, serotyping, and antimicrobial susceptibility testing, including the detection of antibiotic resistance genes and mobile genetic elements. All V. cholerae isolates were identified as El Tor biotypes and susceptible to ceftriaxone, gentamicin, and ciprofloxacin. The majority of isolates were resistant to trimethoprim-sulfamethoxazole (94.6%), streptomycin (92.8%), and nalidixic acid (64.5%), while lower resistance was observed against ampicillin (3.6%), amoxicillin (4.2%), chloramphenicol (3.0%), and doxycycline (1.8%). Concurrently, the integrating conjugative (SXT) element was found in 95.5% of the V. cholerae isolates; conversely, class 1, 2, and 3 integrons were absent. Additionally, 64.5% of the isolates exhibited multidrug resistance patterns. Antibiotic-resistant gene clusters suggest that environmental bacteria may act as cassette reservoirs that favor resistant pathogens. On the other hand, the 2015-2016 epidemic strains were found susceptible to most antibiotics except nalidixic acid. This revealed the replacement of multidrug-resistant strains exhibiting new resistance phenotypes that emerged after Kenya's 2007-2010 epidemic. IMPORTANCE Kenya is a country where cholera is endemic; it has experienced three substantial epidemics over the past few decades, but there are limited data on the drug resistance patterns of V. cholerae at the national level. To the best of our knowledge, this is the first study to investigate the antimicrobial susceptibility profiles of V. cholerae O1 strains isolated from two consecutive epidemics and to examine their associated antimicrobial genetic determinants. Our study results revealed two distinct antibiotic resistance trends in two separate epidemics, particularly trends for multidrug-associated mobile genetic elements and chromosomal mutation-oriented resistant strains from the 2007-2010 epidemic. In contrast, only nalidixic acid-associated chromosomal mutated strains were isolated from the 2015-2016 epidemic. This study also found similar patterns of antibiotic resistance in environmental and clinical strains. Continuous monitoring is needed to control emerging multidrug-resistant isolates in the future.

A phylogenetic study of dengue virus in urban Vietnam shows long-term persistence of endemic strains.

Dengue virus (DENV) causes repeated outbreaks of disease in endemic areas, with patterns of local transmission strongly influenced by seasonality, importation via human movement, immunity, and vector control efforts. An understanding of how each of these interacts to enable endemic transmission (continual circulation of local virus strains) is largely unknown. There are times of the year when no cases are reported, often for extended periods of time, perhaps wrongly implying the successful eradication of a local strain from that area. Individuals who presented at a clinic or hospital in four communes in Nha Trang, Vietnam, were initially tested for DENV antigen presence. Enrolled positive individuals then had their corresponding household members invited to participate, and those who enrolled were tested for DENV. The presence of viral nucleic acid in all samples was confirmed using quantitative polymerase chain reaction, and positive samples were then whole-genome sequenced using an amplicon and target enrichment library preparation techniques and Illumina MiSeq sequencing technology. Generated consensus genome sequences were then analysed using phylogenetic tree reconstruction to categorise sequences into clades with a common ancestor, enabling investigations of both viral clade persistence and introductions. Hypothetical introduction dates were additionally assessed using a molecular clock model that calculated the time to the most recent common ancestor (TMRCA). We obtained 511 DENV whole-genome sequences covering four serotypes and more than ten distinct viral clades. For five of these clades, we had sufficient data to show that the same viral lineage persisted for at least several months. We noted that some clades persisted longer than others during the sampling time, and by comparison with other published sequences from elsewhere in Vietnam and around the world, we saw that at least two different viral lineages were introduced into the population during the study period (April 2017-2019). Next, by inferring the TMRCA from the construction of molecular clock phylogenies, we predicted that two of the viral lineages had been present in the study population for over a decade. We observed five viral lineages co-circulating in Nha Trang from three DENV serotypes, with two likely to have remained as uninterrupted transmission chains for a decade. This suggests clade cryptic persistence in the area, even during periods of low reported incidence.

Seroepidemiology and Carriage of Diphtheria in Epidemic-Prone Area and Implications for Vaccination Policy, Vietnam.

In 2019, a community-based, cross-sectional carriage survey and a seroprevalence survey of 1,216 persons 1-55 years of age were conducted in rural Vietnam to investigate the mechanism of diphtheria outbreaks. Seroprevalence was further compared with that of an urban area that had no cases reported for the past decade. Carriage prevalence was 1.4%. The highest prevalence, 4.5%, was observed for children 1-5 years of age. Twenty-seven asymptomatic Coerynebacterium diphtheriae carriers were identified; 9 carriers had tox gene-bearing strains, and 3 had nontoxigenic tox gene-bearing strains. Child malnutrition was associated with low levels of diphtheria toxoid IgG, which might have subsequently increased child carriage prevalence. Different immunity patterns in the 2 populations suggested that the low immunity among children caused by low vaccination coverage increased transmission, resulting in symptomatic infections at school-going age, when vaccine-induced immunity waned most. A school-entry booster dose and improved infant vaccination coverage are recommended to control transmissions.

Phylogenetic inference of pneumococcal transmission from cross-sectional data, a pilot study.

Background: Inference on pneumococcal transmission has mostly relied on longitudinal studies which are costly and resource intensive. Therefore, we conducted a pilot study to test the ability to infer who infected whom from cross-sectional pneumococcal sequences using phylogenetic inference. Methods: Five suspected transmission pairs, for which there was epidemiological evidence of who infected whom, were selected from a household study. For each pair, Streptococcus pneumoniae full genomes were sequenced from nasopharyngeal swabs collected on the same day. The within-host genetic diversity of the pneumococcal population was used to infer the transmission direction and then cross-validated with the direction suggested by the epidemiological records. Results: The pneumococcal genomes clustered into the five households from which the samples were taken. The proportion of concordantly inferred transmission direction generally increased with increasing minimum genome fragment size and single nucleotide polymorphisms. We observed a larger proportion of unique polymorphic sites in the source bacterial population compared to that of the recipient in four of the five pairs, as expected in the case of a transmission bottleneck. The only pair that did not exhibit this effect was also the pair that had consistent discordant transmission direction compared to the epidemiological records suggesting potential misdirection as a result of false-negative sampling. Conclusions: This pilot provided support for further studies to test if the direction of pneumococcal transmission can be reliably inferred from cross-sectional samples if sequenced with sufficient depth and fragment length.

Effect of pneumococcal conjugate vaccine on prevalence of otitis media with effusion among children in Vietnam.

PURPOSE: Otitis media with effusion (OME) is common in young children and is associated with Streptococcus pneumoniae infection. We aimed to determine the impact of pneumococcal conjugate vaccine (PCV) introduction on the prevalence of OME and OME associated with vaccine-type (VT) or non-VT. METHODS: Population-based cross-sectional surveys were conducted in pre- (2016) and post-PCV periods (2017, 2018, and 2019) at selected communes in Nha Trang, Vietnam. For each survey, we randomly selected 60 children aged 4-11 months and 60 aged 14-23 months from each commune. Nasopharyngeal sample collection and tympanic membrane examination by digital otoscope were performed. S. pneumoniae was detected and serotyped by lytA qPCR and microarray. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated using Firth's logistic regression, stratified by age group. RESULTS: Over the four surveys, 2089 children had a bilateral ear examination. Compared to pre-PCV, the prevalence of OME reduced in 2018 (OR 0.51, 95 %CI 0.28-0.93) and in 2019 (OR 0.53, 95 %CI 0.29-0.97) among the <12-month-olds, but no significant reduction among the 12-23-month-olds. The prevalence of OME associated with VT pneumococcus decreased in 2018 and 2019 (2018: OR 0.14, 95 %CI 0.03-0.55; 2019: OR 0.20, 95 %CI 0.05-0.69 in the <12-months-olds, 2018: OR 0.05, 95 %CI 0.00-0.44, 2019: OR 0.41, 95 %CI 0.10-1.61 in the 12-23-months-olds). The prevalence of OME associated with non-VT pneumococcus increased in the 12-23-month-olds in 2017 (OR 3.09, 95 %CI 1.47-7.45) and returned to the pre-PCV level of prevalence in 2018 and 2019 (OR 0.94, 95 %CI 0.40-2.43 and 1.40, 95 %CI 0.63-3.49). CONCLUSION: PCV10 introduction was associated with a reduction of OME prevalence in infants but not in older children.

Waning rate of immunity and duration of protective immunity against diphtheria toxoid as a function of age and number of doses: Systematic review and quantitative data analysis.

Although the burden of diphtheria has declined greatly since the introduction of vaccines, sporadic outbreaks continue to be reported. WHO recommends booster doses after a primary series, but questions remain about the optimal interval between these doses. We conducted a systematic review and quantitative data analysis to quantify the duration of protective immunity after different numbers of doses. Fifteen cross-sectional seroprevalence studies provided data on geometric mean concentration (GMC). Single-year age-stratified GMCs were analyzed using a mixed-effect linear regression model with a random intercept incorporating the between-country variability. GMC was estimated to decline to 0.1 IU/ml in 2.5 years (95% CI: 0.9-4.0), 10.3 years (95% CI: 7.1-13.6), and 25.1 years (95% CI: 7.6-42.6) after receiving three, four and five doses, respectively. The results drawn from cross-sectional data collected in countries with different epidemiologies, vaccines, and schedules had several limitations. However, these analyses contribute to the discussion of optimal timing between booster doses of diphtheria toxoid-containing vaccine.

Association of pneumococcal carriage in infants with the risk of carriage among their contacts in Nha Trang, Vietnam: A nested cross-sectional survey.

BACKGROUND: Infants are at highest risk of pneumococcal disease. Their added protection through herd effects is a key part in the considerations on optimal pneumococcal vaccination strategies. Yet, little is currently known about the main transmission pathways to this vulnerable age group. Hence, this study investigates pneumococcal transmission routes to infants in the coastal city of Nha Trang, Vietnam. METHODS AND FINDINGS: In October 2018, we conducted a nested cross-sectional contact and pneumococcal carriage survey in randomly selected 4- to 11-month-old infants across all 27 communes of Nha Trang. Bayesian logistic regression models were used to estimate age specific carriage prevalence in the population, a proxy for the probability that a contact of a given age could lead to pneumococcal exposure for the infant. We used another Bayesian logistic regression model to estimate the correlation between infant carriage and the probability that at least one of their reported contacts carried pneumococci, controlling for age and locality. In total, 1,583 infants between 4 and 13 months old participated, with 7,428 contacts reported. Few infants (5%, or 86 infants) attended day care, and carriage prevalence was 22% (353 infants). Most infants (61%, or 966 infants) had less than a 25% probability to have had close contact with a pneumococcal carrier on the surveyed day. Pneumococcal infection risk and contact behaviour were highly correlated: If adjusted for age and locality, the odds of an infant's carriage increased by 22% (95% confidence interval (CI): 15 to 29) per 10 percentage points increase in the probability to have had close contact with at least 1 pneumococcal carrier. Moreover, 2- to 6-year-old children contributed 51% (95% CI: 39 to 63) to the total direct pneumococcal exposure risks to infants in this setting. The main limitation of this study is that exposure risk was assessed indirectly by the age-dependent propensity for carriage of a contact and not by assessing carriage of such contacts directly. CONCLUSIONS: In this study, we observed that cross-sectional contact and infection studies could help identify pneumococcal transmission routes and that preschool-age children may be the largest reservoir for pneumococcal transmission to infants in Nha Trang, Vietnam.

Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care.

BACKGROUND: Characterising dengue virus (DENV) infection history at the point of care is challenging as it relies on intensive laboratory techniques. We investigated how combining different rapid diagnostic tests (RDTs) can be used to accurately determine the primary and post-primary DENV immune status of reporting patients during diagnosis. METHODS AND FINDINGS: Serum from cross-sectional surveys of acute suspected dengue patients in Indonesia (N:200) and Vietnam (N: 1,217) were assayed using dengue laboratory assays and RDTs. Using logistic regression modelling, we determined the probability of being DENV NS1, IgM and IgG RDT positive according to corresponding laboratory viremia, IgM and IgG ELISA metrics. Laboratory test thresholds for RDT positivity/negativity were calculated using Youden's J index and were utilized to estimate the RDT outcomes in patients from the Philippines, where only data for viremia, IgM and IgG were available (N:28,326). Lastly, the probabilities of being primary or post-primary according to every outcome using all RDTs, by day of fever, were calculated. Combining NS1, IgM and IgG RDTs captured 94.6% (52/55) and 95.4% (104/109) of laboratory-confirmed primary and post-primary DENV cases, respectively, during the first 5 days of fever. Laboratory test predicted, and actual, RDT outcomes had high agreement (79.5% (159/200)). Among patients from the Philippines, different combinations of estimated RDT outcomes were indicative of post-primary and primary immune status. Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1-2 of fever, yet were confirmatory of primary infections on days 3-5 of fever. CONCLUSION: We demonstrate how the primary and post-primary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM and IgG RDTs and considering the days since symptoms onset. This framework has the potential to strengthen surveillance operations and dengue prognosis, particularly in low resource settings.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Factor Structure and Measurement Invariance of the Very Short Form of Infant Behavior Questionnaire-Revised (IBQR-VSF): A Study among Vietnamese Children.

The Infant Behavior Questionnaire-Revised (IBQ-R) assesses the temperament of infants in Western and non-Western countries. Although its factor analyses revealed three factors-surgency, negative affectivity, and effortful control-in the Western culture, the degree to which these are universal or culturally specific is unclear. This study developed a Vietnamese version of the IBQ-Revised Very Short Form (R-VSF) and examined its factor structure in a Vietnamese population. The Vietnamese IBQ-R VSF was administered to 292 mothers of infants between the ages of 3 and 18 months in Nha Trang city, Vietnam, between July and September 2019. After deleting items to achieve sufficient Cronbach's alphas for each scale (surgency, negative affectivity, and orienting/regulation), the remaining 28 items were aggregated to parcels subjected to exploratory factor analyses (EFAs). EFAs revealed a 3-factor model corresponding to the original theory, and confirmatory factor analyses indicated a good fit of this structural model. The final 3-factor model with parcels indicated measurement and structural invariance between mothers of boys and girls.

Respiratory virus detection in the upper respiratory tract of asymptomatic, community-dwelling older people.

BACKGROUND: The prevalence of virus positivity in the upper respiratory tract of asymptomatic community-dwelling older people remains elusive. Our objective was to investigate the prevalence of respiratory virus PCR positivity in asymptomatic community-dwelling older people using saliva samples and nasopharyngeal and oropharyngeal swabs. METHODS: We analyzed 504 community-dwelling adults aged ≥ 65 years who were ambulatory and enrolled in a cross-sectional study conducted from February to December 2018 in Nagasaki city, Japan. Fourteen respiratory viruses were identified in saliva, nasopharyngeal and oropharyngeal samples using multiplex PCR assays. RESULTS: The prevalences of PCR positivity for rhinovirus, influenza A, enterovirus and any respiratory virus were 12.9% (95% CI: 10.1-16.1%), 7.1% (95% CI: 5.1-9.8%), 6.9% (95% CI: 4.9-9.5%) and 25.2% (95% CI: 21.5-29.2%), respectively. Rhinovirus was detected in 21.5% of subjects, influenza A in 38.9% of subjects, enterovirus in 51.4% of subjects and any virus in 32.3% of subjects using only saliva sampling. CONCLUSIONS: The prevalences of several respiratory viruses were higher than the percentages reported previously in pharyngeal samples from younger adults. Saliva sampling is a potentially useful method for respiratory virus detection in asymptomatic populations.