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To find out risk factors for disease severity and mortality of pediatric COVID-19 in the fourth wave of COVID-19 in Vietnam.This retrospective cohort study was performed at Children's Hospital 1 from July to December 2021. All children with COVID-19 confirmed by a positive Realtime RT-PCR SARS-CoV-2 result and treated at COVID-19 department for at least 72 h were included.Of the 850 cases admitting to COVID-19 department, 555 children with COVID-19 confirmed by positive RT-PCR and treated at our center for more than 72 h. Median age of confirmed cases was 22.3 (IQR: 3.2-88.6) months, 55.1% were male, and 84.5% had a history of close contact with confirmed COVID-19 patients. The rate of mild, moderate and severe/critical cases was 73,7%, 9.0% and 17.3%, respectively. One hundred ninety-two children (34.6%) had underlying diseases, in which, neurologic disease was the most common underlying disease (7.9%). Underlying disease, dyspnea, elevated CRP20 mg/L and elevated ferritin were independent factors related to severe illness. Twenty-point two percent of patients in our study needed respiratory support, including 22 invasive mechanical ventilation cases. Eighteen cases (3.2%) died because of severe comorbidities, poor response to treatment.In our study, the severe/critical and mortality rates in pediatric COVID-19 cases were relatively high. All fatal cases had severe comorbidities. Underlying disease, dyspnea, and elevated inflammatory markers were independent factors related to severity in pediatric COVID-19 cases.

Encephalitis is a major cause of morbidity and mortality worldwide. The clinical syndrome of encephalitis consists of altered mental status, seizures and neurologic signs, and is often accompanied by fever, headache, nausea, and vomiting. Encephalitis in children is more common than in adults, with the incidence rate of infants 3.9 times higher than that of people 20-44 years of age. The reported incidence of hospitalization attributed to paediatric encephalitis ranges from 3 to 13 admissions per 100,000 children per year, with overall mortality ranging from 0 to 7%. There are, however, over 100 pathogens that can cause encephalitis and accurate diagnosis is challenging. Over 50% of patients with encephalitis are left undiagnosed despite extensive laboratory investigations. Furthermore, recent studies in high-income settings have suggested autoimmune encephalitis has now surpassed infectious aetiologies, mainly due to increased awareness and diagnostic capacity, which further challenges routine diagnosis and clinical management, especially in developing countries. There are limited contemporary data on the causes of encephalitis in children in Vietnam. Improving our knowledge of the causative agents of encephalitis in this resource-constrained setting remains critical to informing case management, resource distribution and vaccination strategy. Therefore, we will conduct a prospective observational study to characterise the clinical, microbiological, and epidemiological features of encephalitis in a major children’s hospital in southern Vietnam. Admission clinical samples (cerebrospinal fluid, blood, urine, rectal and throat swabs) will be collected alongside clinical data from each study participant. A combination of classical assays (serology and PCR) and metagenomic next-generation sequencing will used to identify the causative agents. Undiagnosed patients with clinical presentations compatible with autoimmune encephalitis will then be tested for common forms of the disease. Finally, using direct- and indirect costs, we will estimate the economic burden of hospitalization and seven days post hospital discharge of paediatric encephalitis in our setting., Funding Acknowledgement: Wellcome Trust, Award: 106680 Wellcome Trust, Award: 204904 Bill and Melinda Gates Foundation, Award: OPP1211860

The evolution of influenza viruses is fundamentally shaped by within-host processes. However, the within-host evolutionary dynamics of influenza viruses remain incompletely understood, in part because most studies have focused on within-host virus diversity of infections in otherwise healthy adults based on single timepoint data. Here, we analysed the within-host evolution of 82 longitudinally-sampled individuals, mostly young children, infected with A/H3N2 or A/H1N1pdm09 viruses between 2007 and 2009. For A/H1N1pdm09 infections during the 2009 pandemic, nonsynonymous changes were common early in infection but decreased or remained constant throughout infection. For A/H3N2 viruses, early infection was dominated by purifying selection. However, as infections progressed, nonsynonymous variants increased in frequencies even though within-host virus titres decreased, leading to the maintenance of virus diversity via mutation-selection balance. Our findings suggest that this maintenance of genetic diversity in these children combined with their longer duration of infection may provide important opportunities for within-host virus evolution.

Seasonal human influenza viruses continually change antigenically to escape from neutralizing antibodies. It remains unclear how genetic variation in the intrahost virus population and selection at the level of individual hosts translates to the fast-paced evolution observed at the global level because emerging intrahost antigenic variants are rarely detected. We tracked intrahost variants in the hemagglutinin and neuraminidase surface proteins using longitudinally collected samples from 52 patients infected by A/H3N2 influenza virus, mostly young children, who received oseltamivir treatment. We identified emerging putative antigenic variants and oseltamivir-resistant variants, most of which remained detectable in samples collected at subsequent days, and identified variants that emerged intrahost immediately prior to increases in global rates. In contrast to most putative antigenic variants, oseltamivir-resistant variants rapidly increased to high frequencies in the virus population. Importantly, the majority of putative antigenic variants and oseltamivir-resistant variants were first detectable four or more days after onset of symptoms or start of treatment, respectively. Our observations demonstrate that de novo variants emerge, and may be positively selected, during the course of infection. Additionally, based on the 4–7 days post-treatment delay in emergence of oseltamivir-resistant variants in six out of the eight individuals with such variants, we find that limiting sample collection for routine surveillance and diagnostic testing to early timepoints after onset of symptoms can potentially preclude detection of emerging, positively selected variants.

Enterovirus-A71 (EV-A71) cyclically causes hand-foot-mouth disease (HFMD) epidemics in Asian children. An EV-A71 epidemic occurred in Southern Vietnam in 2011, but its scale is not clear. We collected residual sera from non-HFMD Vietnamese inpatients in 2012–2013 to determine seroprevalence of EV-A71 neutralizing antibodies, and measured cross-reactive neutralizing antibody titers against three EV-A71 genogroups. About 23.5% of 1-year-old children in Southern Vietnam has been infected by EV-A71, and the median age of infection was estimated to be 3 years. No significant antigenic variation could be detected among the three EV-A71 genogroups. The high seroprevalence of EV-A71 neutralizing antibody in children living in southern Vietnam indicates the necessity of introducing EV-A71 vaccines in southern Vietnam, particularly for children under 6 months of age. Moreover, it is critical to understand EV-A71 disease burden for formulating national vaccination policy., Author summary Enterovirus-A71 (EV-A71), a member of the enterovirus genus, is a virulent pathogen causing neurological complications. EV-A71 mainly spreads through oral-fecal or oral-oral transmission, as well as respiratory droplets. EV-A71 outbreaks have cyclically occurred throughout some Asian countries since 1997, with millions of people affected. The presence of serum neutralizing antibodies to EV-A71 can represent the prevalence of previous EV-A71 infections and seroprevalence studies are widely used to understand prevalence of infectious diseases. The results of our study demonstrate that about 50% of young children under 3 years of age were infected during the 2011 epidemic in southern Vietnam. The high seroprevalence of EV-A71 neutralizing antibody in children living in southern Vietnam indicates the necessity of introducing EV-A71 vaccines, particularly for children under 6 months of age. Moreover, it is critical to understand EV-A71 disease burden for formulating national vaccination policy in the future.

Encephalitis is a major cause of morbidity and mortality worldwide. The clinical syndrome of encephalitis consists of altered mental status, seizures, neurologic signs, and is often accompanied by fever, headache, nausea, and vomiting. The encephalitis in children has been known that more common than in adult, with the incidence rate of infants was 3.9 times higher than that of people 20-44 years of age. The reported incidence of hospitalization attributed to paediatric encephalitis ranged from 3 to 13 admissions per 100,000 children per year with the overall mortality ranging from 0 to 7%. There are however more than 100 pathogens that can cause encephalitis and accurate diagnosis is challenging. Over 50% of patients with encephalitis are left undiagnosed despite extensive laboratory investigations. Furthermore, recent studies in high-income settings have suggested autoimmune encephalitis has now surpassed infectious aetiologies, mainly due to increased awareness and diagnostic capacity, which further challenges routine diagnosis and clinical management, especially in developing countries. There are limited contemporary data on the causes of encephalitis in children in Vietnam. Improving our knowledge of the causative agents of encephalitis in this resource-constrained setting remains critical to informing case management, resource distribution and vaccination strategy. Therefore, we conduct a prospective observational study to characterise the clinical, microbiological, and epidemiological features of encephalitis in a major children’s hospital in southern Vietnam. Admission clinical samples will be collected alongside meta clinical data and from each study participants. A combination of classical assays (serology and PCR) and metagenomic next-generation sequencing will used to identify the causative agents. Undiagnosed patients with clinical presentations compatible with autoimmune encephalitis will then be tested for common forms of the disease. Finally, using direct- and indirect costs, we will estimate the economic burden of hospitalization and seven days post hospital discharge of paediatric encephalitis in our setting.

Enterovirus 71-induced brainstem encephalitis with pulmonary edema and/or neurogenic shock (stage 3B) is associated with rapid mortality in children. In a small pilot study, we found that milrinone reduced early mortality compared with historical controls. This prospective, randomized control trial was designed to provide more definitive evidence of the ability of milrinone to reduce the 1-week mortality of stage 3B enterovirus 71 infections.Prospective, unicenter, open-label, randomized, controlled study.Inpatient ward of a large tertiary teaching hospital in Ho Chi Minh City, Vietnam.Children (≤ 18 yr old) admitted with proven enterovirus 71-induced pulmonary edema and/or neurogenic shock.Patients were randomly assigned to receive intravenous milrinone (0.5 μg/kg/min) (n = 22) or conventional management (n = 19). Both groups received dopamine or dobutamine and intravenous immunoglobulin.The primary endpoint was 1-week mortality. The secondary endpoints included length of ventilator dependence and hospital stay and adverse events. The median age was 2 years with a predominance of boys in both groups. The 1-week mortality was significantly lower, 18.2% (4/22) in the milrinone compared with 57.9% (11/19) in the conventional management group (relative risk = 0.314 [95% CI, 0.12-0.83], p = 0.01). The median duration of ventilator-free days was longer in the milrinone treatment group (p = 0.01). There was no apparent neurologic sequela in the survivors in either group, and no drug-related adverse events were documented.Milrinone significantly reduced the 1-week mortality of enterovirus 71-induced pulmonary edema and/or neurogenic shock without adverse effects. Further studies are needed to determine whether milrinone might be useful to prevent progression of earlier stages of brainstem encephalitis.

Surveillance for Streptococcus pneumoniae resistant to penicillin and other antimicrobial agents is necessary to define the optimal empirical antibiotic therapy for meningitis in resource-poor countries such as Vietnam. The clinical and microbiological features of 100 patients admitted to the Centre for Tropical Diseases in Ho Chi Minh City, Vietnam, between 1993 and 2002 with invasive pneumococcal disease were studied. A penicillin-nonsusceptible pneumococcus (MIC, ≥0.1 μg/ml) was isolated from the blood or cerebrospinal fluid of 8% of patients (2 of 24) between 1993 and 1995 but 56% (20 of 36) during 1999 to 2002 ( P < 0.0001). Pneumococcal isolates resistant to penicillin (MIC, ≥2.0 μg/ml) increased from 0% (0 of 24) to 28% (10 of 36) ( P = 0.002). Only one isolate was ceftriaxone resistant (MIC, 2.0 μg/ml). Penicillin-nonsusceptible pneumococci were isolated from 78% of children younger than 15 years (28 of 36) compared with 25% of adults (16 of 64) ( P = 0.0001). Isolation of a penicillin-nonsusceptible pneumococcus in adults with meningitis was independently associated with referral from another hospital ( P = 0.005) and previous antibiotic therapy ( P = 0.025). Multilocus sequence typing showed that 86% of the invasive penicillin-resistant pneumococcus isolates tested (12 of 14) were of the Spain 23F -1 clone. The serotypes of >95% of the penicillin-nonsusceptible pneumococci were included in the currently available pneumococcal vaccines. Our findings point to the recent introduction and spread of the Spain 23F -1 clone of penicillin-resistant pneumococci in Vietnam. Simple clinical predictors can be used to guide empirical antibiotic therapy of meningitis. Pneumococcal vaccination may help to control this problem.

Point-of-care (POC) diagnostic tests for influenza can considerably shorten the time to clinical decision making. An investigational POC test based on a multiplexed immunoassay was developed by Meso Scale Diagnostics, LLC (MSD), with the objective to make a more sensitive rapid test that can also subtype influenza A viruses (1977 H1, H3, and H5). Between February and November 2010, we conducted a prospective multicenter study at four hospitals in Vietnam and compared the performance of this test to that of the WHO/CDC real-time reverse transcriptase PCR (RT-PCR) on nasal and throat swab specimens from patients presenting with influenza-like illness. Five hundred sixty-three adults and children with a median age of 25 months were enrolled. Sensitivity and specificity of the test with combined results from nasal and throat swab samples were 74.0% (131/177) and 99.7% (351/352), respectively, compared to RT-PCR. The POC test was as sensitive for influenza virus B as for influenza virus A (74.4% [64/86] versus 73.6% [67/91]). The positivity rate was associated with lower cycle threshold values (a marker for higher viral loads), sample type (73.6% for nasal swab versus 52.4% for throat swab), and younger age. A total of 210 (18.7%) out of 1,126 MSD tests failed, and for 34 (6%) of patients, both test samples failed (these were excluded from the performance analysis). Subtyping could be assessed only for influenza virus A/H3N2, as 1977 H1N1 was not circulating at the time and no H5N1-infected patients were enrolled, and was successful only in 9/54 patients infected with H3 influenza virus who had a positive POC test result for influenza virus A. This novel POC test provided highly sensitive detection of influenza viruses A and B compared to the reported sensitivities of other rapid tests. However, 18.7% of tests failed for technical reasons and subtyping for H3 was poor. Drawbacks to the technology include the requirement for a dedicated reader instrument and the need for continual updating of subtyping antibodies within the test array.

IntroductionThe clinical syndrome of neonatal sepsis, comprising signs of infection, septic shock and organ dysfunction in infants ≤4 weeks of age, is a frequent sequel to bloodstream infection and mandates urgent antimicrobial therapy. Bacterial characterisation and antimicrobial susceptibility testing is vital for ensuring appropriate therapy, as high rates of antimicrobial resistance (AMR), especially in low-income and middle-income countries, may adversely affect outcome. Ho Chi Minh City (HCMC) in Vietnam is a rapidly expanding city in Southeast Asia with a current population of almost 8 million. There are limited contemporary data on the causes of neonatal sepsis in Vietnam, and we hypothesise that the emergence of multidrug resistant bacteria is an increasing problem for the appropriate management of sepsis cases. In this study, we aim to investigate the major causes of neonatal sepsis and assess disease outcomes by clinical features, antimicrobial susceptibility profiles and genome composition.Method and analysisWe will conduct a prospective observational study to characterise the clinical and microbiological features of neonatal sepsis in a major children’s hospital in HCMC. All bacteria isolated from blood subjected to whole genome sequencing. We will compare clinical variables and outcomes between different bacterial species, genome composition and AMR gene content. AMR gene content will be assessed and stratified by species, years and contributing hospital departments. Genome sequences will be analysed to investigate phylogenetic relationships.Ethics and disseminationThe study will be conducted in accordance with the principles of the Declaration of Helsinki and the International Council on Harmonization Guidelines for Good Clinical Practice. Ethics approval has been provided by the Oxford Tropical Research Ethics Committee 35-16 and Vietnam Children’s Hospital 1 Ethics Committee 73/GCN/BVND1. The findings will be disseminated at international conferences and peer-reviewed journals.Trial registration numberISRCTN69124914; Pre-results.

Enterovirus 71 (EV71) frequently causes fatal infections in young children in Asia. In 2011, EV71 epidemics occurred in southern Vietnam. We conducted genetic and antigenic analysis of the EV71 isolates and found that 94% of them were genotype C4a related to two lineages circulating in China and 6% were genotype C5 which have circulated in Vietnam since 2003. Antigenic variants were not detected. EV71 vaccines are being developed. Longitudinal enterovirus surveillance data are critical to formulate vaccination policy in Vietnam.

BACKGROUND : Previous studies have demonstrated that >90% of HIV-uninfected infants serorevert, as seen in the results of enzyme immunoassay (EIA) testing by 12 months of age, making it feasible to confirm or rule out infection. We assessed the reliability of EIA in a cohort of Vietnamese infants. METHODS : HIV-exposed, uninfected infants enrolled in a parent diagnostic and monitoring study from February 2005 through August 2006 were eligible for inclusion in a prospective cohort study of HIV-EIA performance. Testing using 2 standard assays (Genscreen HIV 1/2 version 2, Bio-Rad; Murex 1.2.0, Murex Biotech) was initiated at 12 months of age. Infants were categorized as EIA-negative (seroreverted; negative Genscreen), EIA-indeterminate (positive Genscreen, negative Murex), or EIA-positive (Genscreen and Murex positive). RESULTS : Of 273 infants included in the study, 59 (22%) were EIA-negative at 12 months, 131 (48%) were indeterminate, and 83 (30%) were EIA-positive; specificity 21.6 (95% confidence interval: 16.6, 26.3). Infants with positive EIAs at 12 months were 74% more likely than EIA-indeterminate infants to test indeterminate or positive at 18 months (risk ratio, 1.74, 95% confidence interval: 1.15, 2.64; P = 0.03). CONCLUSIONS : Expectations regarding infant seroreversion by standard EIAs should be reassessed to reflect potential cross-regional differences in their performance.

Background. Infections with community-acquired methicillin-resistant Staphyloccus aureus (CA-MRSA) are emerging worldwide. We investigated an outbreak of severe CA-MRSA infections in children following out-patient vaccination. Methods and Findings. We carried out a field investigation after adverse events following immunization (AEFI) were reported. We reviewed the clinical data from all cases. S. aureus recovered from skin infections and from nasal and throat swabs were analyzed by pulse-field gel electrophoresis, multi locus sequence typing, PCR and microarray. In May 2006, nine children presented with AEFI, ranging from fatal toxic shock syndrome, necrotizing soft tissue infection, purulent abscesses, to fever with rash. All had received a vaccination injection in different health centres in one District of Ho Chi Minh City. Eight children had been vaccinated by the same health care worker (HCW). Deficiencies in vaccine quality, storage practices, or preparation and delivery were not found. Infection control practices were insufficient. CA-MRSA was cultured in four children and from nasal and throat swabs from the HCW. Strains from children and HCW were indistinguishable. All carried the Panton-Valentine leukocidine (PVL), the staphylococcal enterotoxin B gene, the gene complex for staphylococcal-cassette-chromosome mectype V, and were sequence type 59. Strain HCM3A is epidemiologically unrelated to a strain of ST59 prevalent in the USA, although they belong to the same lineage. Conclusions. We describe an outbreak of infections with CA-MRSA in children, transmitted by an asymptomatic colonized HCW during immunization injection. Consistent adherence to injection practice guidelines is needed to prevent CA-MRSA transmission in both in- and outpatient settings. © 2007 Chi Thuong et al.

Background. To date no studies on the incidence of Haemophilus influenzae type b (Hib) disease, Hib carrier rates in infants and children or the proportion of bacterial meningitis cases caused by Hib in Vietnam have been performed. The availability of safe and highly effective Hib vaccines makes such information important. Methods. The bacterial etiology of a sample of infants and children with pneumonia and meningitis seen at Pediatric Hospital No. 1 in Ho Chi Minh City was studied by culture and latex agglutination of blood, cerebrospinal fluid, urine and pleural fluid. The carriage rate of pneumococci and Hib was studied in a sample of outpatient children. Results. Hib caused 53% of 34 culture-proven bacterial meningitis cases and pneumococci caused 18%. Of 31 meningitis cases diagnosed by latex agglutination, 39% were caused by Hib and 55% by pneumococci. Ninety percent of cases of Hib meningitis occurred in children

Enterovirus A71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD) and is particularly prevalent in parts of Southeast Asia, affecting thousands of children and infants each year. Revealing the evolutionary and epidemiological dynamics of EV-A71 through time and space is central to understanding its outbreak potential. We generated the full genome sequences of 200 EV-A71 strains sampled from various locations in Viet Nam between 2011 and 2013 and used these sequence data to determine the evolutionary history and phylodynamics of EV-A71 in Viet Nam, providing estimates of the effective reproduction number (R e ) of the infection through time. In addition, we described the phylogeography of EV-A71 throughout Southeast Asia, documenting patterns of viral gene flow. Accordingly, our analysis reveals that a rapid genogroup switch from C4 to B5 likely took place during 2012 in Viet Nam. We show that the R e of subgenogroup C4 decreased during the time frame of sampling, whereas that of B5 increased and remained >1 at the end of 2013, corresponding to a rise in B5 prevalence. Our study reveals that the subgenogroup B5 virus that emerged into Viet Nam is closely related to variants that were responsible for large epidemics in Malaysia and Taiwan and therefore extends our knowledge regarding its associated area of endemicity. Subgenogroup B5 evidently has the potential to cause more widespread outbreaks across Southeast Asia. IMPORTANCE EV-A71 is one of many viruses that cause HFMD, a common syndrome that largely affects infants and children. HFMD usually causes only mild illness with no long-term consequences. Occasionally, however, severe infection may arise, especially in very young children, causing neurological complications and even death. EV-A71 is highly contagious and is associated with the most severe HFMD cases, with large and frequent epidemics of the virus recorded worldwide. Although major advances have been made in the development of a potential EV-A71 vaccine, there is no current prevention and little is known about the patterns and dynamics of EV-A71 spread. In this study, we utilize full-length genome sequence data obtained from HFMD patients in Viet Nam, a geographical region where the disease has been endemic since 2003, to characterize the phylodynamics of this important emerging virus.