Endothelial and inflammatory pathophysiology in dengue shock: New insights from a prospective cohort study in Vietnam

Abstract

Dengue shock (DS) is the most severe complication of dengue infection; endothelial hyperpermeability leads to profound plasma leakage, hypovolaemia and extravascular fluid accumulation. At present, the only treatment is supportive with intravenous fluid, but targeted endothelial stabilising therapies and host immune modulators are needed. With the aim of prioritising potential therapeutics, we conducted a prospective observational study of adults (≥16 years) with DS in Vietnam from 2019-2022, comparing the pathophysiology underlying circulatory failure with patients with septic shock (SS), and investigating the association of biomarkers with clinical severity (SOFA score, ICU admission, mortality) and pulmonary vascular leak (daily lung ultrasound for interstitial and pleural fluid). Plasma was collected at enrolment, 48 hours later and hospital discharge. We measured biomarkers of inflammation (IL-6, ferritin), endothelial activation (Ang-1, Ang-2, sTie-2, VCAM-1) and endothelial glycocalyx breakdown (hyaluronan, heparan sulfate, endocan, syndecan-1). We enrolled 135 patients with DS (median age 26, median SOFA score 7, 34 required ICU admission, 5 deaths), together with 37 patients with SS and 25 healthy controls. Within the DS group, IL-6 and ferritin were associated with admission SOFA score (IL-6: βeta0.70, p<0.001 & ferritin: βeta0.45, p<0.001), ICU admission (IL-6: OR 2.6, p<0.001 & ferritin: OR 1.55, p<0.001) and mortality (IL-6: OR 4.49, p = 0.005 & ferritin: OR 13.8, p = 0.02); both biomarkers discriminated survivors and non-survivors at 48 hours and all patients who died from DS had pre-mortem ferritin ≥100,000ng/ml. IL-6 most strongly correlated with severity of pulmonary vascular leakage (R = 0.41, p<0.001). Ang-2 correlated with pulmonary vascular leak (R = 0.33, p<0.001) and associated with SOFA score (β 0.81, p<0.001) and mortality (OR 8.06, p = 0.002). Ang-1 was associated with ICU admission (OR 1.6, p = 0.005) and mortality (OR 3.62, p = 0.006). All 4 glycocalyx biomarkers were positively associated with SOFA score, but only syndecan-1 was associated with ICU admission (OR 2.02, p<0.001) and mortality (OR 6.51, p<0.001). This study highlights the central role of hyperinflammation in determining outcomes from DS; the data suggest that anti-IL-1 and anti-IL-6 immune modulators and Tie2 agonists may be considered as candidates for therapeutic trials in severe dengue.

Fig 1. Clinical signs, endpoints and organ support interventions required for patients with dengue shock and septic shock.

The numbers above the bars are the number of patients who were assessed for the corresponding outcomes on each day. Hospital day 1 = enrolment.

Fig 2. Serial pulmonary vascular leak score, depth of pleural effusion and effusion scores in participants with dengue shock and septic shock.

The numbers above the bars are the number of patients who were assessed by lung ultrasound on each day. Hospital day 1 = enrolment.

Fig 3. Serial Reactive hyperaemia index during hospital admission.

Fig 4. Correlation between pulmonary vascular leak score and biomarkers of inflammation, endothelial activation and glycocalyx breakdown at enrolment.

RHI = reactive hyperaemia index, IL-6 = interleukin-6, VCAM-1 = vascular cell adhesion molecule 1, ANP = atrial natriuretic peptide.

Fig 5. Correlation between pulmonary vascular leak score and biomarkers of inflammation, endothelial activation and glycocalyx breakdown at 48 hours after enrolment.

RHI = reactive hyperaemia index, IL6 = interleukin-6, VCAM-1 = vascular cell adhesion molecule 1, ANP = atrial natriuretic peptide.