Evidence map›Paper›PMID 31526718›Full record

ArticleEBioMedicine2019

High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity.

Chun-Yu Lin, Constantinos Kolliopoulos, Chung-Hao Huang, Jyrki Tenhunen, Carl-Henrik Heldin, Yen-Hsu Chen, Paraskevi Heldin

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
23citing papers in PubMed, 4 pooled it
6.0field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

23 citing papers in PubMed, 4 syntheses or guidelines pooled it, 56 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Dengue and the heart.Cardiovascular journal of Africa
    Pooled it
  5. Dengue NS1 as a Driver of Immune-Mediated Pathogenesis.Tropical medicine and infectious disease · 2026
    Review
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  14. Lymphangiogenesis and Lymphatic Barrier Dysfunction in Renal Fibrosis.International journal of molecular sciences · 2022
    Review
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Surveying the Vampire Bat (Journal of proteome research · 2021
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 4 institutions in 3 countries.

Chun-Yu LinDepartment of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden; Division of Infectious Diseases, Department of Internal Medicine, Infection Control Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgical Sciences, Uppsala University, Akademiska Hospital, 751 85 Uppsala, Sweden.
Constantinos KolliopoulosDepartment of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden.
Chung-Hao HuangDivision of Infectious Diseases, Department of Internal Medicine, Infection Control Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
Jyrki TenhunenDepartment of Surgical Sciences, Uppsala University, Akademiska Hospital, 751 85 Uppsala, Sweden; Critical Care Medicine Research Group, Department of Intensive Care, Tampere University Hospital, Tampere, Finland.
Carl-Henrik HeldinDepartment of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden.
Yen-Hsu ChenSchool of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Deparent of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan. Electronic address: infchen@gmail.com.
Paraskevi HeldinDepartment of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden. Electronic address: evi.heldin@imbim.uu.se.
Uppsala University · SEKaohsiung Medical University · TWNational Yang Ming Chiao Tung University · TWUppsala University Hospital · SE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundA main pathological feature of severe dengue virus infection is endothelial hyper-permeability. The dengue virus nonstructural protein 1 (NS1) has been implicated in the vascular leakage that characterizes severe dengue virus infection, however, the molecular mechanisms involved are not known.

methodsA cohort of 250 dengue patients has been followed from the onset of symptoms to the recovery phase. Serum hyaluronan levels and several other clinical parameters were recorded. The effect of NS1 treatment of cultured fibroblasts and endothelial cells on the expressions of hyaluronan synthetic and catabolic enzymes and the hyaluronan receptor CD44, were determined, as have the effects on the formation of hyaluronan-rich matrices and endothelial permeability.

findingsElevated serum hyaluronan levels (≥70 ng/ml) during early infection was found to be an independent predictor for occurrence of warning signs, and thus severe dengue fever. High circulating levels of the viral protein NS1, indicative of disease severity, correlated with high concentrations of serum hyaluronan. NS1 exposure decreased the expression of CD44 in differentiating endothelial cells impairing the integrity of vessel-like structures, and promoted the synthesis of hyaluronan in dermal fibroblasts and endothelial cells in synergy with dengue-induced pro-inflammatory mediators. Deposited hyaluronan-rich matrices around cells cultured in vitro recruited CD44-expressing macrophage-like cells, suggesting a mechanism for enhancement of inflammation. In cultured endothelial cells, perturbed hyaluronan-CD44 interactions enhanced endothelial permeability through modulation of VE-cadherin and cytoskeleton re-organization, and exacerbated the NS1-induced disruption of endothelial integrity.

interpretationPharmacological targeting of hyaluronan biosynthesis and/or its CD44-mediated signaling may limit the life-threatening vascular leakiness during moderate-to-severe dengue virus infection. FUND: This work was supported in part by grants from the Swedish Cancer Society (2018/337; 2016/445), the Swedish Research Council (2015-02757), the Ludwig Institute for Cancer Research, Uppsala University, the Ministry of Science and Technology, Taiwan (106-2314-B-037-088- and 106-2915-I-037-501-), Kaohsiung Medical University Hospital (KMUH103-3 T05) and Academy of Finland. The funders played no role in the design, interpretation or writing of the manuscript.

Indexed as

BiomarkersCapillary PermeabilityCell LineCytokinesDengueDengue VirusEndothelial CellsEndothelium, VascularFluorescent Antibody TechniqueHumansHyaluronic AcidInflammation MediatorsMacrophagesModels, BiologicalPrognosisProtein BindingBiomarkersCytokinesHyaluronic AcidInflammation MediatorsViral Nonstructural ProteinsCD44CytokinesDengueHAS2HYAL2HyaluronanTGFbetaVascular leakageVE-cadherin

Identifiers

PMID31526718
PMCPMC6838418
OpenAlexW2972855747

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.