Plasma Levels of Soluble Urokinase-Type Plasminogen Activator Receptor Associate with the Clinical Severity of Acute Puumala Hantavirus Infection

Tuula K Outinen,Satu Mäkelä,Laura Tervo,Niina Mäenpää,Heini Huhtala,Antti Vaheri,Jukka Mustonen,Reetta Huttunen,Janne Aittoniemi,Niklas K Björkström

doi:10.1371/journal.pone.0071335

Tuula K Outinen, Satu Mäkelä + Show 8 more

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https://doi.org/10.1371/journal.pone.0071335

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Abstract

ObjectivesUrokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to β3-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease.DesignA single-centre prospective cohort study.Subjects and MethodsPlasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA).ResultsThe plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0–18.2 ng/ml vs. median 4.7 ng/ml, range 2.4–12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = −0.325, p = 0.001) and minimum hematocrit (r = −0.369, p<0.001).ConclusionPlasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates β3-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease.

Highlights

Hantaviruses cause two clinical syndromes in humans, hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas [1,2]
The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization
The maximum suPAR levels correlated with several variables reflecting the severity of the disease

Summary

Introduction

Hantaviruses cause two clinical syndromes in humans, hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas [1,2]. Puumala hantavirus (PUUV), carried by the bank vole, causes a mild HFRS called nephropathia epidemica (NE) [1,2]. NE is prevalent in Finland, elsewhere in Scandinavia, European Russia, and many parts of Central-Western Europe [1,2]. In Europe, PUUV causes most HFRS cases, and in Finland, 1,000–. The clinical severity of NE varies from subclinical disease to fatal cases. Typical symptoms are sudden high fever, headache, abdominal pain, nausea, backache, and visual disturbances, while serious hemorrhagic manifestations are uncommon [5,6,7,8]. About 5% of hospitalized patients need transiently hemodialysis treat-

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