Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study

Yacoub, Sophie; Lam, Phung Khanh; Vu, Le Hoang Mai; Le, Thi Lien; Ha, Ngo Thanh; Do, Toan T.; Van, Nguyen Thu; Quyen, Nguyen Than Ha; Duyen, Huynh Thi Le; Kính, Nguyễn Văn; Fox, Annette; Mongkolspaya, Juthathip; Wolbers, Marcel; Simmons, Cameron P.; Screaton, Gavin; Wertheim, Heiman; Wills, Bridget

doi:10.1093/infdis/jiw220

Cited by 45 publications

(56 citation statements)

References 36 publications

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“…Beyond septic DIC, disordered coagulation and hemostasis occurs in many severe infections, ranging from Ebola virus disease to cerebral malaria. Clinical data and experimental models link disturbances in the Angpt/Tie2 pathway to several of these disease states (37,38,(67)(68)(69)(70)(71), raising the possibility that defense of endothelial homeostasis can counteract prothrombotic mechanisms arising from diverse infections.…”

Section: Discussionmentioning

confidence: 99%

Tie2 protects the vasculature against thrombus formation in systemic inflammation

Higgins¹,

Ceunynck

Kellum

et al. 2018

Journal of Clinical Investigation

109

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Section: Discussionmentioning

confidence: 99%

Tie2 protects the vasculature against thrombus formation in systemic inflammation

Higgins¹,

Ceunynck

Kellum

et al. 2018

Journal of Clinical Investigation

109

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“…This timing coincides with the development of severe symptoms and is suggestive of an endothelial response to pericyte dysfunction. Finally, low levels of angiopoietin 1 (Ang1) and elevated levels of its antagonist angiopoietin 2 (Ang2) have been associated with dengue vascular leakage (5, 32), and the Ang1:Ang2 ratio has been proposed as a diagnostic marker for patients at risk of developing severe dengue (33). Ang1 is secreted by pericytes and platelets to increase endothelial barrier function (27), while Ang2, produced by endothelial cells and affecting pericyte coverage, is known to cause pericyte dropout in diabetic retinopathy (27, 34).…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for Perivascular Cells in Amplifying Viral Haemorrhage Induced by Dengue Virus Non-Structural Protein 1

Cheung

Mastrullo

Maselli

et al. 2020

Preprint

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23Dengue is the most prevalent arthropod-borne viral disease affecting humans, with 24 severe dengue typified by potentially fatal microvascular leakage and hypovolaemic shock. 25Blood vessels of the microvasculature are composed of a tubular structure of endothelial cells 26 ensheathed by perivascular cells (pericytes). Pericytes support endothelial cell barrier 27 formation and maintenance through paracrine and contact-mediated signalling, and are critical 28 to microvascular integrity. Pericyte dysfunction has been linked to vascular leakage in 29 noncommunicable pathologies such as diabetic retinopathy, but has never been linked to 30 infection-related vascular leakage. Dengue vascular leakage has been shown to result in part 31 from the direct action of the secreted dengue virus (DENV) non-structural protein NS1 on 32 endothelial cells. Using primary human vascular cells, we show here that NS1 also causes 33 pericyte dysfunction, and that NS1-induced endothelial hyperpermeability is more pronounced 34 in the presence of pericytes. Notably, NS1 specifically disrupted the ability of pericytes to 35 support endothelial cell function in a 3D microvascular assay, with no effect on pericyte viability 36 or physiology. These effects are mediated at least in part through contact-independent 37 paracrine signals involved in endothelial barrier maintenance by pericytes. We therefore 38 identify a role for pericytes in amplifying NS1-induced microvascular hyperpermeability in 39 severe dengue, and thus show that pericytes can play a critical role in the aetiology of an 40 infectious vascular leakage syndrome. These findings open new avenues of research for the 41 development of drugs and diagnostic assays for combating infection-induced vascular 42 leakage, such as severe dengue.43 44 45 46 47 3 SIGNIFICANCE STATEMENT 48 The World Health Organisation considers dengue one of the top ten global public 49 health problems. There is no specific antiviral therapy to treat dengue virus and no way of 50 predicting which patients will develop potentially fatal severe dengue, typified by vascular 51 leakage and circulatory shock. We show here that perivascular cells (pericytes) amplify the 52 vascular leakage-inducing effects of the dengue viral protein NS1 through contact-53 independent signalling to endothelial cells. While pericytes are known to contribute to 54 noncommunicable vascular leakage, this is the first time these cells have been implicated in 55 the vascular effects of an infectious disease. Our findings could pave the way for new 56 therapies and diagnostics to combat dengue, and potentially other infectious vascular leakage 57 syndromes. 58 59 60 61 62 63 64 65 66 67 68 69 355 MR/R010315/1 to KM and a

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“…Altered microcirculation, which we have shown is worse in dengue patients with more severe plasma leakage [9], may play a role in the increased lactate levels, although further studies are required to link the microcirculatory perfusion abnormalities with higher lactate levels.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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BackgroundDengue 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 findingsWe 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/SignificanceEcho-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.

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Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study

Cited by 45 publications

References 36 publications

Tie2 protects the vasculature against thrombus formation in systemic inflammation

Tie2 protects the vasculature against thrombus formation in systemic inflammation

A Critical Role for Perivascular Cells in Amplifying Viral Haemorrhage Induced by Dengue Virus Non-Structural Protein 1

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

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