AbstractDengue shock (DS) is the most severe complication of dengue infection; endothelial hyperpermeability leads to profound plasma leakage, hypovolaemia & extravascular fluid accumulation. At present, the only treatment is supportive intravenous fluid, but endothelial stabilising therapies and host-immune modulators are needed. No studies have followed up survivors of DS to assess resolution of inflammation and endothelial activation, functional or economic outcomes
I performed a prospective observational study in Vietnam recruiting 135 adults within 24 hours of diagnosis of DS. Comparator groups included septic shock (SS, n=37) and healthy controls (n=25). Clinical assessments for organ failure and pulmonary vascular leakage by lung ultrasound were performed daily for ≤7days. Peripheral artery tonometry was conducted at enrolment, 48-hours later, and hospital discharge. Plasma was collected for inflammatory, endothelial and glycocalyx biomarkers at the same time-points. Patients were followed up at 1-, 3- and 6-months post-discharge with: endothelial and inflammatory biomarkers, Montreal Cognitive Assessment (MoCA), EQ-5D-5L functional assessment and an economic questionnaire. Economic and EQ-5D-5L assessments were also performed at 12-months. I also evaluated SOFA, a modified SOFA, and delta SOFA scores as potential endpoints for future clinical trials in severe dengue.
With respect to DS, I found that IL6 and ferritin were associated with enrolment SOFA score, need for ICU admission and mortality. Both biomarkers discriminated between survivors and non-survivors at 48-hours and all patients who died had ferritin >100,000ng/ml. Angiopoietin-1 and angiopoietin-2 were both associated with mortality. IL6 and angiopoietin2 correlated with pulmonary vascular leakage. Of the glycocalyx biomarkers, only syndecan-1 was associated with ICU admission and mortality. Heparan sulfate was significantly higher in patients with SS versus DS. Peripheral artery tonometry did not correlate with biomarkers or clinical outcomes. The SOFA score and its derivatives were strongly associated with clinical outcomes including mortality. During follow-up, patients with DS had high EQ-5D-5L scores at all timepoints, and although mildly impaired at hospital discharge, median MoCA scores returned to normal by 1-month. However, a sub-group of patients with DS and SS had persistently raised IL6 and ferritin until 6-months post discharge. Catastrophic costs were common after DS and SS, and frequency increased when productivity costs were considered.
Overall, this work highlights the central role of hyperinflammation in determining outcomes from DS, and it is the first to report persistent subclinical inflammation in a subset of survivors. The results suggest that immune modulation and Angiopoietin-Tie2 directed therapeutics should be prioritised for DS and support further study to determine long-term inflammatory and cardiovascular outcomes after DS and SS.
|Date of Award
|Martin Llewelyn (Supervisor)