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Patients with severe dengue who develop severe respiratory failure requiring mechanical ventilation (MV) support have significantly increased mortality rates. This study aimed to develop a robust machine learning-based risk score to predict the need for MV in children with dengue shock syndrome (DSS) who developed acute respiratory failure. This single-institution retrospective study was conducted at a tertiary pediatric hospital in Vietnam between 2013 and 2022. The primary outcome was severe respiratory failure requiring MV in the children with DSS. Key covariables were predetermined by the LASSO method, literature review, and clinical expertise, including age (< 5 years), female patients, early onset day of DSS (≤ day 4), large cumulative fluid infusion, higher colloid-to-crystalloid fluid infusion ratio, severe bleeding, severe transaminitis, low platelet counts (< 20 x 109/L), elevated hematocrit, and high vasoactive-inotropic score. These covariables were analyzed using supervised models, including Logistic Regression (LR), Random Forest (RF), Support Vector Machine (SVM), k-Nearest Neighbor (KNN), and eXtreme Gradient Boosting (XGBoost). Shapley Additive Explanations (SHAP) analysis was used to assess feature contribution. A total of 1,278 patients were included, with a median patient age of 8.1 years (IQR: 5.4-10.7). Among them, 170 patients (13.3%) with DSS required mechanical ventilation. A significantly higher fatality rate was observed in the MV group than that in the non-MV group (22.4% vs. 0.1%). The RF and SVM models showed the highest model discrimination. The SHAP model explained the significant predictors. Internal validation of the predictive model showed high consistency between the predicted and observed data, with a good slope calibration in training (test) sets 1.0 (0.934), and a low Brier score of 0.04. Complete-case analysis was used to construct the risk score. We developed a robust machine learning-based risk score to estimate the need for MV in hospitalized children with DSS.

Severe respiratory distress and acute kidney injury (AKI) are key factors leading to poor outcomes in patients with dengue shock syndrome (DSS). There is still limited data on how much resuscitated fluid and the specific ratios of intravenous fluid types contribute to the development of severe respiratory distress necessitating mechanical ventilation (MV) and AKI in children with DSS. This retrospective study was conducted at a tertiary pediatric hospital in Vietnam between 2013 and 2022. The primary outcomes were the need for MV and renal function within 48 h post-admission. A predictive model for MV was developed based on covariates from the first 24 h of PICU admission. Changes in renal function within 48 h were analyzed using a linear mixed-effects model. A total of 1,278 DSS children with complete clinical and fluid data were included. The predictive performance of MV based on the total intravenous fluid volume administered yielded an AUC of 0.871 (95% CI, 0.836-0.905), while the colloid-to-crystalloid ratio showed an AUC of 0.781 (95% CI, 0.743-0.819) (both P < 0.001). The optimal cut-off point of the cumulative fluid infusion was 181 mL/kg, whereas that of the colloid-to-crystalloid ratio was 1.6. Multivariable analysis identified female patients, severe bleeding, severe transaminitis, excessive fluid resuscitation, and a higher proportion of colloid solutions in the first 24 h as significant predictors of MV in DSS patients. The predictive model for MV demonstrated high accuracy, with a C-statistic of 89%, strong calibration, and low Brier score (0.04). Importantly, a more pronounced decline in glomerular filtration rate was observed in DSS patients who required MV than in those who did not. This study provides insights into optimizing fluid management protocols, highlighting the importance of monitoring fluid volume and the colloid-to-crystalloid ratio during early resuscitation to improve the clinical outcomes of DSS patients.

Background Hand, foot and mouth disease (HFMD) has become a major public health problem across the Asia-Pacific region, and is commonly caused by enterovirus A71 (EV-A71) and coxsackievirus A6 (CV-A6), CV-A10 and CV-A16. Generating pathogen whole-genome sequences is essential for understanding their evolutionary biology. The frequent replacements among EV serotypes and a limited numbers of available whole-genome sequences hinder the development of overlapping PCRs for whole-genome sequencing. We developed and evaluated a non-ribosomal random PCR (rPCR) and next-generation sequencing based assay for sequence-independent whole-genome amplification and sequencing of HFMD pathogens. A total of 16 EV-A71/CV-A6/CV-A10/CV-A16 PCR positive rectal/throat swabs (Cp values: 20.9–33.3) were used for assay evaluation. Results Our assay evidently outperformed the conventional rPCR in terms of the total number of EV-A71 reads and the percentage of EV-A71 reads: 2.6 % (1275/50,000 reads) vs. 0.1 % (31/50,000) and 6 % (3008/50,000) vs. 0.9 % (433/50,000) for two samples with Cp values of 30 and 26, respectively. Additionally the assay could generate genome sequences with the percentages of coverage of 94–100 % of 4 different enterovirus serotypes in 73 % of the tested samples, representing the first whole-genome sequences of CV-A6/10/16 from Vietnam, and could assign correctly serotyping results in 100 % of 24 tested specimens. In all but three the obtained consensuses of two replicates from the same sample were 100 % identical, suggesting that our assay is highly reproducible. Conclusions In conclusion, we have successfully developed a non-ribosomal rPCR and next-generation sequencing based assay for sensitive detection and direct whole-genome sequencing of HFMD pathogens from clinical samples.

Background To investigate the knowledge, attitudes, and practices of the healthcare professionals (HCPs) including physicians and nurses regarding dengue transmission, diagnosis and clinical classification using the warning signs of World Health Organization (WHO) 2009 classification. Results Out of 471 respondents from three countries, 80.9% of physicians and 74% of nurses did not receive previous training regarding the dengue infection. The majority of respondents could identify the primary dengue vector (86%), while only a third of HCPs knew the biting time of dengue mosquitoes. Only half of our respondents knew about immunity induced by serotypes; Moreover, half of our participants could determine the diagnostic tests. On the other hand, about 90% of the respondents took responsibility for talking to the patients about preventive measures. Our respondents also showed wide variations in definition of warning signs listed in the WHO 2009 classification. Multivariate analysis linked the impact of different cofactors including prior training on dengue infection, type of profession, frequency of taking care of dengue patients and country on how HCPs defined these warning signs. Conclusions This study could declare the variation in employing the warning signs listed in the WHO 2009 classification. We have figured that most of the HCPs did not take prior training on the dengue viral infection; Also, we found gaps in the knowledge regarding various topics in dengue fever. This paper recommends the gathering of efforts to establish the proper knowledge of dengue infection and the warning signs listed by the WHO.

Background. The growth benefits of cotrimoxazole during early antiretroviral therapy (ART) are not well characterized. Methods. Individuals enrolled in the Therapeutics Research, Education, and AIDS Training in Asia Pediatric HIV Observational Database were included if they started ART at ages 1 month–14 years and had both height and weight measurements available at ART initiation (baseline). Generalized estimating equations were used to identify factors associated with change in height-for-age z-score (HAZ), follow-up HAZ ≥ −2, change in weight-for-age z-score (WAZ), and follow-up WAZ ≥ −2. Results. A total of 3217 children were eligible for analysis. The adjusted mean change in HAZ among cotrimoxazole and non-cotrimoxazole users did not differ significantly over the first 24 months of ART. In children who were stunted (HAZ < −2) at baseline, cotrimoxazole use was not associated with a follow-up HAZ ≥ −2. The adjusted mean change in WAZ among children with a baseline CD4 percentage (CD4%) >25% became significantly different between cotrimoxazole and non-cotrimoxazole users after 6 months of ART and remained significant after 24 months (overall P < .01). Similar changes in WAZ were observed in those with a baseline CD4% between 10% and 24% (overall P < .01). Cotrimoxazole use was not associated with a significant difference in followup WAZ in children with a baseline CD4% <10%. In those underweight (WAZ < −2) at baseline, cotrimoxazole use was associated with a follow-up WAZ ≥ −2 (adjusted odds ratio, 1.70 vs not using cotrimoxazole [95% confidence interval, 1.28–2.25], P < .01). This association was driven by children with a baseline CD4% ≥10%. Conclusions. Cotrimoxazole use is associated with benefits to WAZ but not HAZ during early ART in Asian children.

BACKGROUND: Hand foot and mouth disease (HFMD) is a disease of public health importance across the Asia-Pacific region. The disease is caused by enteroviruses (EVs), in particular enterovirus A71 (EV-A71). In EV-A71-associated HFMD, the infection is sometimes associated with severe manifestations including neurological involvement and fatal outcome. The availability of a robust diagnostic assay to distinguish EV-A71 from other EVs is important for patient management and outbreak response. METHODS: We developed and validated an internally controlled one-step single-tube real-time RT-PCR in terms of sensitivity, linearity, precision, and specificity for simultaneous detection of EVs and EV-A71. Subsequently, the assay was then applied on throat and rectal swabs sampled from 434 HFMD patients. RESULTS: The assay was evaluated using both plasmid DNA and viral RNA and has shown to be reproducible with a maximum assay variation of 4.41 % and sensitive with a limit of detection less than 10 copies of target template per reaction, while cross-reactivity with other EV serotypes was not observed. When compared against a published VP1 nested RT-PCR using 112 diagnostic throat and rectal swabs from 112 children with a clinical diagnosis of HFMD during 2014, the multiplex assay had a higher sensitivity and 100 % concordance with sequencing results which showed EVs in 77/112 (68.8 %) and EV-A71 in 7/112 (6.3 %). When applied to clinical diagnostics for 322 children, the assay detected EVs in throat swabs of 257/322 (79.8 %) of which EV-A71 was detected in 36/322 (11.2 %) children. The detection rate increased to 93.5 % (301/322) and 13.4 % (43/322) for EVs and EV-A71, respectively, when rectal swabs from 65 throat-negative children were further analyzed. CONCLUSION: We have successfully developed and validated a sensitive internally controlled multiplex assay for rapid detection of EVs and EV-A71, which is useful for clinical management and outbreak control of HFMD.

Hand, Foot, and Mouth Disease (HFMD) is a major public health issue in the Asia-Pacific region. Our research program aims to address unanswered questions about clinical, epidemiology, pathogen evolution, cost of illness, and host-genetic makers associated with severe HFMD in Vietnam. A multi-hospital-based observational study has been conducted at three referral hospitals in Ho Chi Minh City, Vietnam since 2013. Demographic, clinical data, and cost of illness were collected alongside clinical specimens. Multiplex PCR and next-generation sequencing were employed to identify enterovirus serotypes and to study pathogen evolution, respectively. A genome-wide association-based approach was used to explore genetic markers of disease severity. From 2013 to 2017, 2,191 HFMD patients were enrolled. More than twenty enterovirus serotypes were detected in 84.3 per cent of patients. EV-A71 was the major cause, accounting for 22 per cent of total number of cases, followed by CV-A6 (21%), CV-A16 (13%), and CV-A10 (8%). Interestingly, these four common enteroviruses replaced each other during the study period. EV-A71 and CV-A6 were the two most predominant viruses detected in 2013 and 2014. However, CV-A6 was replaced by CV-A16 and CV-A10 in 2015 and 2016, respectively. A total of 396 whole-genome sequences (EV-A71 (n = 200), CV-A6 (n = 98), CV-A10 (n = 66), and CV-A16 (n = 32)) were obtained. Phylogenetic analysis showed that EV-A71 subgenogroup B5 has replaced C4 in 2012, and, since then, B5 has continued to circulate predominantly, while C4 has been sporadically detected. All Vietnamese CV-A6 isolates belonged to genogroup A, which has caused large outbreaks of HFMD worldwide. Costs of illness varied between disease severities, ranging from $USD 244 [95% confidence interval (95% CI): 230–258] per patient for grade 2A (mild) to $USD 1984 (95% CI: 1,752–2,227) for grade 3 (severe). The genome-wide association study identified two genetic markers potentially associated with severe HFMD. The results highlight that active surveillance and understanding pathogen evolution are essential to inform public health in prioritizing the development of intervention strategies. Efforts to unravel the evolutionary process of Vietnamese CV-A10 and CV-A16 in relation to global strains are ongoing. An independent cohort is needed to replicate the preliminary findings of the genome-wide association study.

Hand, foot and mouth disease (HFMD) is an emerging infection with pandemic potential. Knowledge of neutralizing antibody responses among its pathogens is essential to inform vaccine development and epidemiologic research. We used 120 paired-plasma samples collected at enrollment and >7 days after the onset of illness from HFMD patients infected with enterovirus A71 (EV-A71), coxsackievirus A (CVA) 6, CVA10, and CVA16 to study cross neutralization. For homotypic viruses, seropositivity increased from <60% at enrollment to 97%-100% at follow-up, corresponding to seroconversion rates of 57%-93%. Seroconversion for heterotypic viruses was recorded in only 3%-23% of patients. All plasma samples from patients infected with EV-A71 subgenogroup B5 could neutralize the emerging EV-A71 subgenogroup C4. Collectively, our results support previous reports about the potential benefit of EV-A71 vaccine but highlight the necessity of multivalent vaccines to control HFMD.

Abstract Background This retrospective hospital-based surveillance aimed to assess the epidemiology, causative pathogens trend, and serotypes distribution of pneumococcal meningitis among children aged under 5 years with bacterial meningitis in Southern Vietnam after the introduction of pentavalent vaccine in the Expanded Program on Immunization (EPI). Methods From 2012 to 2021, cerebrospinal fluid samples were collected from children aged under 5 years with suspected bacterial meningitis at Children's Hospitals 1 and 2 in Ho Chi Minh City. Probable bacterial meningitis (PBM) cases were identified using biochemistry and cytology. Real-time polymerase chain reaction was used to confirm cases of confirmed bacterial meningitis (CBM) caused by Streptococcus pneumoniae, Haemophilus influenzae, or Neisseria meningitidis. Streptococcus pneumoniae serotyping was performed. Results Of the 2560 PBM cases, 158 (6.2%) were laboratory-confirmed. The CBM proportion decreased during the 10-year study and was associated with age, seasonality, and permanent residence. Streptococcus pneumoniae was the most common pathogen causing bacterial meningitis (86.1%), followed by H influenzae (7.6%) and N meningitidis (6.3%). The case-fatality rate was 8.2% (95% confidence interval, 4.2%–12.2%). Pneumococcal serotypes 6A/B, 19F, 14, and 23F were the most prevalent, and the proportion of pneumococcal meningitis cases caused by the 10-valent pneumococcal conjugate vaccine (PCV) serotypes decreased from 96.2% to 57.1% during the PCV eras. Conclusions Streptococcus pneumoniae is the most frequent causative agent of bacterial meningitis in children aged under 5 years in Southern Vietnam over the last decade. Policymakers may need to consider introducing PCVs into the EPI to effectively prevent and control bacterial meningitis. After the introduction of the Hib vaccine in the EPI, bacterial meningitis patterns among children under 5 in Southern Vietnam have shifted, with Streptococcus pneumoniae being the most common causative pathogen. Policymakers should prioritize introducing PCVs into the EPI. Graphical Abstract Graphical Abstract