Risk factors for disease severity and mortality of children with Covid-19: A study at a Vietnamese Children's hospital.

INTRODUCTION: To find out risk factors for disease severity and mortality of pediatric COVID-19 in the fourth wave of COVID-19 in Vietnam. METHODS: 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. RESULTS: 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 CRP >20 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. CONCLUSIONS: 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.

Clinical and laboratory factors associated with neonatal sepsis mortality at a major Vietnamese children's hospital.

Sepsis is a major cause of neonatal mortality and children born in low- and middle-income countries (LMICs) are at greater risk of severe neonatal infections than those in higher-income countries. Despite this disparity, there are limited contemporaneous data linking the clinical features of neonatal sepsis with outcome in LMICs. Here, we aimed to identify factors associated with mortality from neonatal sepsis in Vietnam. We conducted a prospective, observational study to describe the clinical features, laboratory characteristics, and mortality rate of neonatal sepsis at a major children's hospital in Ho Chi Minh City. All in-patient neonates clinically diagnosed with probable or culture-confirmed sepsis meeting inclusion criteria from January 2017 to June 2018 were enrolled. We performed univariable analysis and logistic regression to identify factors independently associated with mortality. 524 neonates were recruited. Most cases were defined as late-onset neonatal sepsis and were hospital-acquired (91.4% and 73.3%, respectively). The median (IQR) duration of hospital stay was 23 (13-41) days, 344/524 (65.6%) had a positive blood culture (of which 393 non-contaminant organisms were isolated), and 69/524 (13.2%) patients died. Coagulase-negative staphylococci (232/405; 57.3%), Klebsiella spp. (28/405; 6.9%), and Escherichia coli (27/405; 6.7%) were the most isolated organisms. Sclerema (OR = 11.4), leukopenia <4,000/mm3 (OR = 7.8), thrombocytopenia <100,000/mm3 (OR = 3.7), base excess < -20 mEq/L (OR = 3.6), serum lactate >4 mmol/L (OR = 3.4), extremely low birth weight (OR = 3.2), and hyperglycaemia >180 mg/dL (OR = 2.6) were all significantly (p<0.05) associated with mortality. The identified risk factors can be adopted as prognostic factors for the diagnosis and treatment of neonatal sepsis and enable early risk stratification and interventions appropriate to reduce neonatal sepsis in LMIC settings.

Study protocol: The clinical features, epidemiology, and causes of paediatric encephalitis in southern Vietnam.

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.

Seroprevalence of EV-A71 neutralizing antibodies following the 2011 epidemic in HCMC, Vietnam.

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.

Clinical features, antimicrobial susceptibility patterns and genomics of bacteria causing neonatal sepsis in a children's hospital in Vietnam: protocol for a prospective observational study.

INTRODUCTION: The 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 ANALYSIS: We 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 DISSEMINATION: The 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 NUMBER: ISRCTN69124914; Pre-results.

Phylodynamics of Enterovirus A71-Associated Hand, Foot, and Mouth Disease in Viet Nam.

UNLABELLED: 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 (Re) 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 Re 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.

Genetic and antigenic characterization of enterovirus 71 in Ho Chi Minh City, Vietnam, 2011.

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.

Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial.

OBJECTIVE: 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. DESIGN: Prospective, unicenter, open-label, randomized, controlled study. SETTING: Inpatient ward of a large tertiary teaching hospital in Ho Chi Minh City, Vietnam. PATIENTS: Children (≤ 18 yr old) admitted with proven enterovirus 71-induced pulmonary edema and/or neurogenic shock. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Clinical validation of a point-of-care multiplexed in vitro immunoassay using monoclonal antibodies (the MSD influenza test) in four hospitals in Vietnam.

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.

Failure of human immunodeficiency virus enzyme immunoassay to rule out infection among polymerase chain reaction-negative Vietnamese infants at 12 months of age.

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.

Emergence in Vietnam of Streptococcus pneumoniae resistant to multiple antimicrobial agents as a result of dissemination of the multiresistant Spain(23F)-1 clone.

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, > or =0.1 micro g/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, > or =2.0 micro g/ml) increased from 0% (0 of 24) to 28% (10 of 36) (P = 0.002). Only one isolate was ceftriaxone resistant (MIC, 2.0 micro g/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.