Dengue
Conditions
Keywords
dengue, vascular leak, multi-state models
Brief summary
The goal of this observational study is to investigate the natural history of dengue in hospitalised patients in Vietnam, to better understand the disease process, and utilise the data to improve future clinical trials. The main questions it aims to answer are: In participants hospitalised with dengue in Vietnam: 1. How does dengue illness change over time, particularly the development and recovery of vascular leak (where blood vessels leak)? 2. Can a new statistical approaches describe dengue illness accurately and be suitable for use in future clinical trials? 3. Which blood biomarkers are associated with worsening or improving dengue illness, and what do they tell us about how severe dengue develops? Could these blood biomarkers act as reliable indicators of disease severity and recovery, making them useful outcome measures in future dengue treatment trials? 4. How accurately do simplified diagnostic tests identify dengue compared with laboratory reference methods, and are they suitable for use in research and clinical settings in low- and middle-income countries? Participants will be observed without any intervention throughout their hospitalisation. Participants will be be asked to provide informed consent for: * Recording of their routine clinical data * Regular blood tests * Regular ultrasound scans * A follow up appointment.
Detailed description
Dengue is a life-threatening infection caused by a virus, spread between humans by the bite of mosquitoes. It is present throughout the tropics, including in Vietnam, where cases have dramatically increased in recent years. Dengue causes severe illness predominantly through vascular leak, where patients' blood vessels break down, becoming leaky, leading to fluid from the vessels moving into tissues and organs such as the lungs. However, it is still not fully understand how the virus causes vascular leak, or in which patients it is most likely to occur in. There are no licensed treatments for vascular leak. This is because the mechanism of vascular leak is incompletely understood, making therapeutic targeting difficult. Additionally, when drugs are trialled, many trials have been poorly designed and not included enough patients. To answer our research questions, the investigators will recruit 142 patients admitted to hospital with dengue in Nha Trang, Vietnam who have dengue vascular leak. If they are happy to enter the study, data will be recorded that is already being collected as part of their hospital admission; this will include clinical data (such as blood pressure, pulse and treatments given) and the results of their blood tests. Investigators will also run tests beyond what they would normally have in hospital; this will include the results of regular ultrasound scans and biomarker blood tests (small molecules that can be detected in their blood in response to stress and vascular leak). Most patients have blood tests daily in hospital, and clinicians will aim to take the extra tubes of blood required at the same time, to minimise the number of extra procedures requested from participants. Investigators will put this data it into a statistical model of dengue vascular leak they have been developing, called a multi-state model. These models have previously been used in other areas of medicine, but this would be their first application in dengue and infectious diseases research. Multi-state models aim to track how patients move through different stages of illness over time. Models such as this make better use of all the information collected during a patient's illness. Rather than only looking at a single outcome, such as whether a patient had recovered by a certain day, or how long recovery took, they track how patients move through different stages of dengue over time and how long they spend in each stage. This may give a more complete picture of how treatments affect the course of illness. If successful, it could improve how future dengue clinical trials are designed, helping researchers detect whether new treatments work more quickly and with fewer volunteers. Investigators will also use data and samples collected from this study to explore why vascular leak occurs and evaluate new ways of diagnosing dengue, particularly in low-resource settings. To achieve this, investigators will need to compare patients who have dengue to people who have not got dengue, looking for differences. As such 93 people who do not have dengue (called "control" participants) will be recruited. Some will have a fever from another cause, and others will be healthy volunteers. Comparing these control populations with patients who have dengue helps us understand which findings are specific to dengue and how accurate new dengue tests are. People in these groups will only have a single small blood sample taken and will not receive any treatment or need follow-up visits. Overall, this study aims to support the development of better treatments and more efficient clinical trials for dengue.
Interventions
None listed
Sponsors
Liverpool School of Tropical Medicine
Nagasaki University
Pasteur Institute, Nha Trang
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
(hospitalised cohort): * Meet the 2009 WHO criteria for dengue with warning signs or severe dengue AND * Are being admitted as an inpatient AND * Have documented standard-of-care laboratory confirmation of dengue (defined as either positive by molecular assay (e.g. reverse transcription polymerase chain reaction) OR positive by antigen testing (non-structural protein-1) OR positive Immunoglobulin M (IgM) combined with clinical diagnosis of dengue by attending physician. AND * Were born in Vietnam (only for platelet phenomics substudy) Inclusion Criteria (diagnostic control cohort): * Have a documented fever at assessment AND * Have a documented negative standard-of-care dengue test, with no clinical diagnosis of dengue AND * Were born in Vietnam (only for platelet phenomics substudy) Inclusion Criteria (platelet control cohort): * Vietnamese-born adults ≥16 years of age with no history of febrile illness in the preceding 14 days.
Exclusion criteria
* Receiving an experimental dengue treatment during their illness. * Inability to provide written, informed consent AND no legal guardian able to provide written, informed consent in the event of incapacity. * Clinician-determined unsuitability for recruitment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Degree of vascular leak | From enrollment until day 10 of illness, or discharge | Presence and severity of vascular leak (none, moderate, severe) per Tomashek et al. 2018 consensus definitions - composite of change of haematocrit from baseline, presence of ascites/pleural effusion by point of care ultrasound and presence of respiratory/cardiovascular compromise. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Viral dynamics | From enrollment until day 10 of illness, or discharge | Dengue viral load by reverse-transcriptase polymerase chain reaction (copies per microlitre) |
| Degree of thrombocytopenia | From enrollment until day 10 of illness or discharge | Presence and severirty of thrombocytopenia (none, moderate, severe) per Tomashek et al. 2018 consensus definitions - measured by platelet count (10\^9/L) |
| Degree of bleeding | From enrollment until day 10 of illness or discharge | Presence and severirty of bleeding (none, moderate, severe) per Tomashek et al. 2018 consensus definitions - composite score measured by presence/absence of clinical bleeding, requirement for local intervention, cardiovascular compromise, requirement for blood transfusion. |
| Modified sequenetial organ failure score (mSOFA) | From enrollment until day 10 of illness or discharge | mSOFA score composite score (0-24) with 6 systems assessed, each component contributing 0-4 points to the overal score. Systems assessed: respiratory system (peripheral saturations of oxygen/fraction inspired oxygen, mmHg), Coagulation (platelet count / microlitre), Liver function (Bilirubin, mg/dl), Cardiovascular system (mean arterial pressure / pulse pressure, mmHg), Central nervous system (glasgow coma score), renal function (creatinin, mg/dL or urine output, mL/day) |
| Volume of Intravenous Fluid Received in 24 hours | From enrollment until day 10 of illness or discharge | Fluid type and volume (mL) |
| Dengue Clinical Severity | From enrollment until day 10 of illness or discharge | Dengue clinical severity classification per WHO 2009 criteria (dengue without warning signs, dengue with warning signs, severe dengue) |
| Concentration of a panel of plasma biomarkers of endothelial dysfunction, inflammation and platelet dysfunction. | From enrollment until day 10 of illness, or discharge | Longitudinal measurement of biomarkers such as Syndecan-1, Angiopoietin 1/2, VCAM-1, CRP, Ferritin, platelet function assay, platelet-leucocyte aggregate assay, platelet receptor panel |
| Performance of plasma biomarkers of dengue vascular leak as robust secondary endpoints in future dengue interventional trials. | From enrollment until day 10 of illness or discharge | Correlation of biomarker values with clinical and model outcomes |
| Performance of dengue diagnostic platforms, for use in participant screening in low- and middle-income countries. | At enrollment | Diagnostic accuracy of novel LAMP assay compared to reference standard and RDT: sensitivity, specificity and predictive values of diagnostic platforms against RT-PCR as reference and RDTs as standard of care. |
| Multi-state model evaluation: model fit | From enrollment until day 10 of illness or discharge | Goodness of fit of model compared to observed data, as assessed by Akaike information criteria (AIC) values, Bayesian information criteria (BIC) values and Likelihood-ratio test (p-value) |
| Multi-state model evaluation - precision | Assessed at 3 days and 5 days post admission | Confidence in model parameters: 95% confidence interval width around 3- and 5-day probabilities of all state transition pairs (probability with 95% confidence interval) |
Countries
Vietnam
Contacts
CONTACTMatthew JW Kain
Outcome results
None listed