Novel Clinical Monitoring Approaches for Reemergence of Diphtheria Myocarditis, Vietnam.

Diphtheria is a life-threatening, vaccine-preventable disease caused by toxigenic Corynebacterium bacterial species that continues to cause substantial disease and death worldwide, particularly in vulnerable populations. Further outbreaks of vaccine-preventable diseases are forecast because of health service disruptions caused by the coronavirus disease pandemic. Diphtheria causes a spectrum of clinical disease, ranging from cutaneous forms to severe respiratory infections with systemic complications, including cardiac and neurologic. In this synopsis, we describe a case of oropharyngeal diphtheria in a 7-year-old boy in Vietnam who experienced severe myocarditis complications. We also review the cardiac complications of diphtheria and discuss how noninvasive bedside imaging technologies to monitor myocardial function and hemodynamic parameters can help improve the management of this neglected infectious disease.

The compensatory reserve index predicts recurrent shock in patients with severe dengue.

BACKGROUND: Dengue shock syndrome (DSS) is one of the major clinical phenotypes of severe dengue. It is defined by significant plasma leak, leading to intravascular volume depletion and eventually cardiovascular collapse. The compensatory reserve Index (CRI) is a new physiological parameter, derived from feature analysis of the pulse arterial waveform that tracks real-time changes in central volume. We investigated the utility of CRI to predict recurrent shock in severe dengue patients admitted to the ICU. METHODS: We performed a prospective observational study in the pediatric and adult intensive care units at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. Patients were monitored with hourly clinical parameters and vital signs, in addition to continuous recording of the arterial waveform using pulse oximetry. The waveform data was wirelessly transmitted to a laptop where it was synchronized with the patient's clinical data. RESULTS: One hundred three patients with suspected severe dengue were recruited to this study. Sixty-three patients had the minimum required dataset for analysis. Median age was 11 years (IQR 8-14 years). CRI had a negative correlation with heart rate and moderate negative association with blood pressure. CRI was found to predict recurrent shock within 12 h of being measured (OR 2.24, 95% CI 1.54-3.26), P < 0.001). The median duration from CRI measurement to the first recurrent shock was 5.4 h (IQR 2.9-6.8). A CRI cutoff of 0.4 provided the best combination of sensitivity and specificity for predicting recurrent shock (0.66 [95% CI 0.47-0.85] and 0.86 [95% CI 0.80-0.92] respectively). CONCLUSION: CRI is a useful non-invasive method for monitoring intravascular volume status in patients with severe dengue.

Predicting deterioration in dengue using a low cost wearable for continuous clinical monitoring.

Close vital signs monitoring is crucial for the clinical management of patients with dengue. We investigated performance of a non-invasive wearable utilising photoplethysmography (PPG), to provide real-time risk prediction in hospitalised individuals. We performed a prospective observational clinical study in Vietnam between January 2020 and October 2022: 153 patients were included in analyses, providing 1353 h of PPG data. Using a multi-modal transformer approach, 10-min PPG waveform segments and basic clinical data (age, sex, clinical features on admission) were used as features to continuously forecast clinical state 2 h ahead. Prediction of low-risk states (17,939/80,843; 22.1%), defined by NEWS2 and mSOFA < 6, was associated with an area under the precision-recall curve of 0.67 and an area under the receiver operator curve of 0.83. Implementation of such interventions could provide cost-effective triage and clinical care in dengue, offering opportunities for safe ambulatory patient 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.

Towards a machine-learning assisted non-invasive classification of dengue severity using wearable PPG data: a prospective clinical study.

BACKGROUND: Dengue epidemics impose considerable strain on healthcare resources. Real-time continuous and non-invasive monitoring of patients admitted to the hospital could lead to improved care and outcomes. We evaluated the performance of a commercially available wearable (SmartCare) utilising photoplethysmography (PPG) to stratify clinical risk for a cohort of hospitalised patients with dengue in Vietnam. METHODS: We performed a prospective observational study for adult and paediatric patients with a clinical diagnosis of dengue at the Hospital for Tropical Disease, Ho Chi Minh City, Vietnam. Patients underwent PPG monitoring early during admission alongside standard clinical care. PPG waveforms were analysed using machine learning models. Adult patients were classified between 3 severity classes: i) uncomplicated (ward-based), ii) moderate-severe (emergency department-based), and iii) severe (ICU-based). Data from paediatric patients were split into 2 classes: i) severe (during ICU stay) and ii) follow-up (14-21 days after the illness onset). Model performances were evaluated using standard classification metrics and 5-fold stratified cross-validation. FINDINGS: We included PPG and clinical data from 132 adults and 15 paediatric patients with a median age of 28 (IQR, 21-35) and 12 (IQR, 9-13) years respectively. 1781 h of PPG data were available for analysis. The best performing convolutional neural network models (CNN) achieved a precision of 0.785 and recall of 0.771 in classifying adult patients according to severity class and a precision of 0.891 and recall of 0.891 in classifying between disease and post-disease state in paediatric patients. INTERPRETATION: We demonstrate that the use of a low-cost wearable provided clinically actionable data to differentiate between patients with dengue of varying severity. Continuous monitoring and connectivity to early warning systems could significantly benefit clinical care in dengue, particularly within an endemic setting. Work is currently underway to implement these models for dynamic risk predictions and assist in individualised patient care. FUNDING: EPSRC Centre for Doctoral Training in High-Performance Embedded and Distributed Systems (HiPEDS) (Grant: EP/L016796/1) and the Wellcome Trust (Grants: 215010/Z/18/Z and 215688/Z/19/Z).

Clinical and aetiological study of hand, foot and mouth disease in southern Vietnam, 2013-2015: Inpatients and outpatients.

BACKGROUND: Hand, foot and mouth disease (HFMD) has been associated with large outbreaks among young children in the Asia-Pacific Region since 1997, including cases of severe illness and death. Severe illness is often associated with enterovirus A71 (EV-A71). Vietnam experienced a large sustained outbreak of 200000 hospitalized cases and over 200 deaths in 2011-12, the large majority occurring in southern Vietnam. METHODS: A prospective observational study was conducted in the outpatient clinics, infectious diseases wards, and paediatric intensive care units of the three main referral centres for the treatment of HFMD in southern Vietnam. Demographic data, basic laboratory parameters, and clinical data were recorded, and molecular diagnostic tests were performed. RESULTS: Between July 2013 and July 2015, a total of 1547 children were enrolled. Four serotypes of enterovirus A (EV-A71, Coxsackievirus (CV) A6, A10, and A16) were responsible for 1005 of 1327 diagnosed cases (75.7%). An unexpected dominance of EV-A71 was found among both inpatients and outpatients, as well as a strong association with severe illness. CV-A6 and CV-A10 emerged in Vietnam during the study period and replaced CV-A16. CV-A10 was associated with different clinical and laboratory characteristics. During admission, 119 children developed a more severe illness. It was found that children with a skin rash showed less progression of severity, but when a rash was present, a macular rash was significantly associated with an increased risk of progression. CONCLUSIONS: This study represents the most comprehensive descriptive HFMD study from Vietnam to date. Co-circulation and replacement of different serotypes has implications for vaccine development and implementation. These findings from a severely affected country add to our understanding of the presentation, progression, and aetiology of HFMD.

Oseltamivir resistance during treatment of influenza A (H5N1) infection.

Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents.

Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma.

In southern Vietnam, a four-year-old boy presented with severe diarrhea, followed by seizures, coma, and death. The cerebrospinal fluid contained 1 white cell per cubic millimeter, normal glucose levels, and increased levels of protein (0.81 g per liter). The diagnosis of avian influenza A (H5N1) was established by isolation of the virus from cerebrospinal fluid, fecal, throat, and serum specimens. The patient's nine-year-old sister had died from a similar syndrome two weeks earlier. In both siblings, the clinical diagnosis was acute encephalitis. Neither patient had respiratory symptoms at presentation. These cases suggest that the spectrum of influenza H5N1 is wider than previously thought.

Cardio-haemodynamic assessment and venous lactate in severe dengue: Relationship with recurrent shock and respiratory distress.

BACKGROUND: Dengue can cause plasma leakage that may lead to dengue shock syndrome (DSS). In approximately 30% of DSS cases, recurrent episodes of shock occur. These patients have a higher risk of fluid overload, respiratory distress and poor outcomes. We investigated the association of echocardiographically-derived cardiac function and intravascular volume parameters plus lactate levels, with the outcomes of recurrent shock and respiratory distress in severe dengue. METHODS/PRINCIPLE FINDINGS: We performed a prospective observational study in Paediatric and adult ICU, at the Hospital for Tropical Diseases (HTD), Ho Chi Minh City, Vietnam. Patients with dengue were enrolled within 12 hours of admission to paediatric or adult ICU. A haemodynamic assessment and portable echocardiograms were carried out daily for 5 days from enrolment and all interventions recorded. 102 patients were enrolled; 22 patients did not develop DSS, 48 had a single episode of shock and 32 had recurrent shock. Patients with recurrent shock had a higher enrolment pulse than those with 1 episode or no shock (median: 114 vs. 100 vs. 100 b/min, P = 0.002), significantly lower Stroke Volume Index (SVI), (median: 21.6 vs. 22.8 vs. 26.8mls/m2, P<0.001) and higher lactate levels (4.2 vs. 2.9 vs. 2.2 mmol/l, P = 0.001). Higher SVI and worse left ventricular function (higher Left Myocardial Performance Index) on study days 3-5 was associated with the secondary endpoint of respiratory distress. There was an association between the total IV fluid administered during the ICU admission and respiratory distress (OR: 1.03, 95% CI 1.01-1.06, P = 0.001). Admission lactate levels predicted patients who subsequently developed recurrent shock (P = 0.004), and correlated positively with the total IV fluid volume received (rho: 0.323, P = 0.001) and also with admission ALT (rho: 0.764, P<0.001) and AST (rho: 0.773, P<0.001). CONCLUSIONS/SIGNIFICANCE: Echo-derived intravascular volume assessment and venous lactate levels can help identify dengue patients at high risk of recurrent shock and respiratory distress in ICU. These findings may serve to, not only assist in the management of DSS patients, but also these haemodynamic endpoints could be used in future dengue fluid intervention trials.

Viral etiology of encephalitis in children in southern Vietnam: results of a one-year prospective descriptive study.

BACKGROUND: Acute encephalitis is an important and severe disease in children in Vietnam. However, little is known about the etiology while such knowledge is essential for optimal prevention and treatment. To identify viral causes of encephalitis, in 2004 we conducted a one-year descriptive study at Children's Hospital Number One, a referral hospital for children in southern Vietnam including Ho Chi Minh City. METHODOLOGY/PRINCIPAL FINDINGS: Children less than 16 years of age presenting with acute encephalitis of presumed viral etiology were enrolled. Diagnostic efforts included viral culture, serology and real time (RT)-PCRs. A confirmed or probable viral causative agent was established in 41% of 194 enrolled patients. The most commonly diagnosed causative agent was Japanese encephalitis virus (n = 50, 26%), followed by enteroviruses (n = 18, 9.3%), dengue virus (n = 9, 4.6%), herpes simplex virus (n = 1), cytomegalovirus (n = 1) and influenza A virus (n = 1). Fifty-seven (29%) children died acutely. Fatal outcome was independently associated with patient age and Glasgow Coma Scale (GCS) on admission. CONCLUSIONS/SIGNIFICANCE: Acute encephalitis in children in southern Vietnam is associated with high mortality. Although the etiology remains unknown in a majority of the patients, the result from the present study may be useful for future design of treatment and prevention strategies of the disease. The recognition of GCS and age as predictive factors may be helpful for clinicians in managing the patient.