Prognostic Models in Dengue

Reliable prediction models in dengue would facilitate early identification of patients likely to progress to more severe disease, potentially improving patient management. However, most published studies have limitations with respect to their modelling strategy, sample size, and Chosen clinical outcomes, and to date none have exploited longitudinal data. Moreover, only a few studies have examined outcomes in patients presenting with dengue shock syndrome (DSS), the most severe form of the disease. This thesis aims to overcome these limitations by using two large prospective datasets describing a) 1719 children with established DSS and b) 2598 children hospitalized with dengue. First, the population of children with DSS was characterized, and profound DSS, a composite outcome reflecting the need for intensive supportive care, was established as a suitable outcome for prognostic research in this population. Second, risk factors for profound DSS were identified and included in a robust prediction model. Based on this model, a simple score chart for use in clinical practice was derived. Third, risk factors for progression to DSS among children hospitalized with dengue were identified, and a prognostic model for progression to DSS was carefully developed. However, this model displayed only moderate performance and had limited clinical utility. Lastly, differences between acute and chronic diseases, and the implications for dynamic prediction modeling based on longitudinal data, are discussed. A case study of dynamic prediction modeling for development of DSS suggested that (1) the current platelet count can be used to improve baseline models that rely on enrolment values only, and (2) simple conditional dynamic models displayed similar performance to more complex joint models in this situation

Prognosis of neonatal tetanus in the modern management era: an observational study in 107 Vietnamese infants.

OBJECTIVES: Most data regarding the prognosis in neonatal tetanus originate from regions where limited resources have historically impeded management. It is not known whether recent improvements in critical care facilities in many low- and middle-income countries have affected indicators of a poor prognosis in neonatal tetanus. We aimed to determine the factors associated with worse outcomes in a Vietnamese hospital with neonatal intensive care facilities. METHODS: Data were collected from 107 cases of neonatal tetanus. Clinical features on admission were analyzed against mortality and a combined endpoint of 'death or prolonged hospital stay'. RESULTS: Multivariable analysis showed that only younger age (odds ratio (OR) for mortality 0.69, 95% confidence interval (CI) 0.48-0.98) and lower weight (OR for mortality 0.06, 95% CI 0.01-0.54) were significantly associated with both the combined endpoint and death. A shorter period of onset (OR 0.94, 95% CI 0.88-0.99), raised white cell count (OR 1.17, 95% CI 1.02-1.35), and time between first symptom and admission (OR 3.77, 95% CI 1.14-12.51) were also indicators of mortality. CONCLUSIONS: Risk factors for a poor outcome in neonatal tetanus in a setting with critical care facilities include younger age, lower weight, delay in admission, and leukocytosis

Visual and biochemical evidence of glycocalyx disruption in human dengue infection, and association with plasma leakage severity

Background: Dengue is the most common arboviral infection globally; a minority of patients develop shock due to profound plasma leak through a disrupted endothelial barrier. Understanding of the pathophysiology underlying plasma leak is incomplete, but emerging evidence indicates a key role for degradation of the endothelial glycocalyx. Methods: We conducted an observational study in Vietnam to evaluate the sublingual microcirculation using sidestream darkfield imaging in (1) outpatients with confirmed dengue (2) patients hospitalized with dengue and (3) outpatients with other febrile illness (OFI). We estimated the glycocalyx degradation by measuring the perfused boundary region (PBR hf) and an overall microvascular health score (MVHS) with the software application GlycoCheckTM at enrolment, 48 h later and hospital discharge/defervescence. We measured plasma syndecan1 and endocan at the same time-points. We compared PBR hf, MVHS, syndecan1 and endocan, between (1) outpatients with confirmed dengue vs. OFI and (2) patients with dengue subdivided by clinical severity of plasma leak. Results: We included 75 patients with dengue (41 outpatients, 15 inpatients, 19 in intensive care) and 12 outpatients with OFI. Images from 45 patients were analyzed using GlycoCheckTM. There was no significant difference in PBR hf or MVHS between outpatients with dengue and OFI. Median plasma syndecan1 was not significantly different in outpatients with dengue vs. OFI, while median plasma endocan was significantly lower among patients with dengue vs. OFI during the critical phase. In patients with dengue, PBR hf was higher in patients with Grade 2 vs. Grade 0 plasma leakage during the critical phase (PBR hf 1.96 vs. 1.36 μm for Grade 2 vs. Grade 0 plasma leakage on days 4–6, respectively, p < 0.001). Median levels of plasma syndecan1 and endocan were higher in Grade 2 vs. Grade 0 plasma leakage, especially during the critical phase (Syndecan1 2,613.8 vs. 125.9 ng/ml for Grade 2 vs. Grade 0 plasma leakage on days 4–6, respectively, p < 0.001, and endocan 3.21 vs. 0.16 ng/ml for Grade 2 vs. Grade 0 plasma leakage on days 4–6, respectively). Conclusions: We present the first human in vivo evidence of glycocalyx disruption in dengue, with worse visual glycocalyx damage and higher plasma degradation products associated with more severe plasma leak

Economic evaluation of population-based type 2 diabetes mellitus screening at different healthcare settings in Vietnam

Introduction: Few economic evaluations have assessed the cost-effectiveness of screening type-2 diabetes mellitus (T2DM) in different healthcare settings. This study aims to evaluate the value for money of various T2DM screening strategies in Vietnam. Methods: A decision analytical model was constructed to compare costs and quality-adjusted life years (QALYs) of T2DM screening in different health care settings, including (1) screening at commune health station (CHS) and (2) screening at district health center (DHC), with no screening as the current practice. We further explored the costs and QALYs of different initial screening ages and different screening intervals. Cost and utility data were obtained by primary data collection in Vietnam. Incremental cost-effectiveness ratios were calculated from societal and payer perspectives, while uncertainty analysis was performed to explore parameter uncertainties. Results: Annual T2DM screening at either CHS or DHC was cost-effective in Vietnam, from both societal and payer perspectives. Annual screening at CHS was found as the best screening strategy in terms of value for money. From a societal perspective, annual screening at CHS from initial age of 40 years was associated with 0.40 QALYs gained while saving US$ 186.21. Meanwhile, one-off screening was not cost-effective when screening for people younger than 35 years old at both CHS and DHC. Conclusions: T2DM screening should be included in the Vietnamese health benefits package, and annual screening at either CHS or DHC is recommended

Development and validation of a new measurement instrument to assess internship experience of medical doctors in low-income and middle-income countries

Routine surveys are used to understand the training quality and experiences of junior doctors but there are lack of tools designed to evaluate the training experiences of interns in low-income and middle-income countries (LMICs) where working conditions and resource constraints are challenging. We describe our process developing and validating a 'medical internship experience scale' to address this gap, work involving nine LMICs that varied in geographical locations, income-level and internship training models. We used a scoping review of existing tools, content validity discussions with target populations and an expert panel, back-and-forth translations into four language versions and cognitive interviews to develop and test the tool. Using data collected from 1646 interns and junior medical doctors, we assessed factor structure and assessed its reliability and validity. Fifty items about experiences of medical internship were retained from an initial pool of 102 items. These 50 items represent 6 major factors (constructs): (1) clinical learning and supervision, (2) patient safety, (3) job satisfaction, (4) stress and burnout, (5) mental well-being, and (6) fairness and discrimination. We reflect on the process of multicountry scale development and highlight some considerations for others who may use our scale, using preliminary analyses of the 1646 responses to illustrate that the tool may produce useful data to identify priorities for action. We suggest this tool could enable LMICs to assess key metrics regarding intern straining and initial work experiences and possibly allow comparison across countries and over time, to inform better internship planning and management

Kinetics of cardiovascular and inflammatory biomarkers in paediatric dengue shock syndrome

Glycocalyx disruption and hyperinflammatory responses are implicated in the pathogenesis of dengue-associated vascular leak, however little is known about their association with clinical outcomes of patients with dengue shock syndrome (DSS). We investigated the association of vascular and inflammatory biomarkers with clinical outcomes and their correlations with clinical markers of vascular leakage. We performed a prospective cohort study in Viet Nam. Children ≥5 years of age with a clinical diagnosis of DSS were enrolled into this study. Blood samples were taken daily during ICU stay and 7–10 days after hospital discharge for measurements of plasma levels of Syndecan-1, Hyaluronan, Suppression of tumourigenicity 2 (ST-2), Ferritin, N-terminal pro Brain Natriuretic Peptide (NT-proBNP), and Atrial Natriuretic Peptide (ANP). The primary outcome was recurrent shock. Ninety DSS patients were enrolled. Recurrent shock occurred in 16 patients. All biomarkers, except NT-proBNP, were elevated at presentation with shock. There were no differences between compensated and decompensated DSS patients. Glycocalyx markers were positively correlated with inflammatory biomarkers, haematocrit, percentage haemoconcentration, and negatively correlated with stroke volume index. While Syndecan-1, Hyaluronan, Ferritin, and ST-2 improved with time, ANP continued to be raised at follow-up. Enrolment Syndecan-1 levels were observed to be associated with developing recurrent shock although the association did not reach the statistical significance at the P < 0.01 (OR = 1.82, 95% CI 1.07–3.35, P = 0.038). Cardiovascular and inflammatory biomarkers are elevated in DSS, correlate with clinical vascular leakage parameters and follow different kinetics over time. Syndecan-1 may have potential utility in risk stratifying DSS patients in ICU

Heart rate variability measured from wearable devices as a marker of disease severity in tetanus

Tetanus is a disease associated with significant morbidity and mortality. Heart rate variability (HRV) is an objective clinical marker with potential value in tetanus. This study aimed to investigate the use of wearable devices to collect HRV data and the relationship between HRV and tetanus severity. Data were collected from 110 patients admitted to the intensive care unit in a tertiary hospital in Vietnam. HRV indices were calculated from 5-minute segments of 24-hour electrocardiogram recordings collected using wearable devices. HRV was found to be inversely related to disease severity. The standard deviation of NN intervals and interquartile range of RR intervals (IRRR) were significantly associated with the presence of muscle spasms; low frequency (LF) and high frequency (HF) indices were significantly associated with severe respiratory compromise; and the standard deviation of differences between adjacent NN intervals, root mean square of successive differences between normal heartbeats, LF to HF ratio, total frequency power, and IRRR, were significantly associated with autonomic nervous system dysfunction. The findings support the potential value of HRV as a marker for tetanus severity, identifying specific indices associated with clinical severity thresholds. Data were recorded using wearable devices, demonstrating this approach in resource-limited settings where most tetanus occurs

Assessing the efficacy and safety of magnesium sulfate for management of autonomic nervous system dysregulation in Vietnamese children with severe hand foot and mouth disease.

BACKGROUND: Brainstem encephalitis is a serious complication of hand foot and mouth disease (HFMD) in children. Autonomic nervous system (ANS) dysregulation and hypertension may occur, sometimes progressing to cardiopulmonary failure and death. Vietnamese national guidelines recommend use of milrinone if ANS dysregulation with Stage 2 hypertension develops. We wished to investigate whether magnesium sulfate (MgSO4) improved outcomes in children with HFMD if used earlier in the evolution of the ANS dysregulation (Stage 1 hypertension). METHODS: During a regional epidemic we conducted a randomized, double-blind, placebo-controlled trial of MgSO4 in children with HFMD, ANS dysregulation and Stage 1 hypertension, at the Hospital for Tropical Diseases in Ho Chi Minh city. Study participants received an infusion of MgSO4 or matched placebo for 72 h. We also reviewed data from non-trial HFMD patients in whom milrinone failed to control hypertension, some of whom received MgSO4 as second line therapy. The primary outcome for both analyses was a composite of disease progression within 72 h - addition of milrinone (trial participants only), need for ventilation, shock, or death. RESULTS: Between June 2014 and September 2016, 14 and 12 participants received MgSO4 or placebo respectively, before the trial was stopped due to futility. Among 45 non-trial cases with poorly controlled hypertension despite high-dose milrinone, 33 received MgSO4 while 12 did not. There were no statistically significant differences in the composite outcome between the MgSO4 and the placebo/control groups in either study (adjusted relative risk (95%CI) of [6/14 (43%) vs. 6/12 (50%)], 0.84 (0.37, 1.92), p = 0.682 in the trial and [1/33 (3%) vs. 2/12 (17%)], 0.16 (0.01, 1.79), p = 0.132 in the observational cohort). The incidence of adverse events was similar between the groups. Potentially toxic magnesium levels occurred very rarely with the infusion regime used. CONCLUSION: Although we could not demonstrate efficacy in these studies, there were no safety signals associated with use of 30-50 mg/kg/hr. MgSO4 in severe HFMD. Intermittent outbreaks of HFMD are likely to continue across the region, and an adequately powered trial is still needed to evaluate use of MgSO4 in controlling hypertension in severe HFMD, potentially involving a higher dose regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 AUG 2013). Trial sponsor: University of Oxford

Lovastatin for the Treatment of Adult Patients With Dengue: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Dengue endangers billions of people in the tropical world, yet no therapeutic is currently available. In part, the severe manifestations of dengue reflect inflammatory processes affecting the vascular endothelium. In addition to lipid lowering, statins have pleiotropic effects that improve endothelial function, and epidemiological studies suggest that outcomes from a range of acute inflammatory syndromes are improved in patients already on statin therapy. METHODS: Following satisfactory review of a short pilot phase (40 mg lovastatin vs placebo in 30 cases), we performed a randomized, double-blind, placebo-controlled trial of 5 days of 80 mg lovastatin vs placebo in 300 Vietnamese adults with a positive dengue NS1 rapid test presenting within 72 hours of fever onset. The primary outcome was safety. Secondary outcomes included comparisons of disease progression rates, fever clearance times, and measures of plasma viremia and quality of life between the treatment arms. RESULTS: Adverse events occurred with similar frequency in both groups (97/151 [64%] placebo vs 82/149 [55%] lovastatin; P = .13), and were in keeping with the characteristic clinical and laboratory features of acute dengue. We also observed no difference in serious adverse events or any of the secondary outcome measures. CONCLUSIONS: We found lovastatin to be safe and well tolerated in adults with dengue. However, although the study was not powered to address efficacy, we found no evidence of a beneficial effect on any of the clinical manifestations or on dengue viremia. Continuing established statin therapy in patients who develop dengue is safe.Chinese Clinical Trials Registration. ISRCTN03147572

Acceptance and user experiences of a wearable device for the management of hospitalized patients in COVID-19–designated wards in Ho Chi Minh City, Vietnam: action learning project

Background: Wearable devices have been used extensively both inside and outside of the hospital setting. During the COVID-19 pandemic, in some contexts, there was an increased need to remotely monitor pulse and saturated oxygen for patients due to the lack of staff and bedside monitors. Objective: A prototype of a remote monitoring system using wearable pulse oximeter devices was implemented at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, from August to December 2021. The aim of this work was to support the ongoing implementation of the remote monitoring system. Methods: We used an action learning approach with rapid pragmatic methods, including informal discussions and observations as well as a feedback survey form designed based on the technology acceptance model to assess the use and acceptability of the system. Based on these results, we facilitated a meeting using user-centered design principles to explore user needs and ideas about its development in more detail. Results: In total, 21 users filled in the feedback form. The mean technology acceptance model scores ranged from 3.5 (for perceived ease of use) to 4.4 (for attitude) with behavioral intention (3.8) and perceived usefulness (4.2) scoring in between. Those working as nurses scored higher on perceived usefulness, attitude, and behavioral intention than did physicians. Based on informal discussions, we realized there was a mismatch between how we (ie, the research team) and the ward teams perceived the use and wider purpose of the technology. Conclusions: Designing and implementing the devices to be more nurse-centric from their introduction could have helped to increase their efficiency and use during the complex pandemic period