A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant

Antonen, Jaakko; Leppänen, Ilona; Tenhunen, Jyrki; Arvola, Pertti; Mäkelä, Satu; Vaheri, Antti; Mustonen, Jukka

doi:10.3109/00365548.2012.755268

Cited by 60 publications

(50 citation statements)

References 14 publications

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“…Interferon and replication inhibitors are efficacious prophylactically but not in viremic or symptomatic patients (5, 21, 98). However, one Puumala virus patient recovered after being given a dose of the bradykinin antagonist icatibant (90) and this supports a role for bradykinin in HFRS pathogenesis (39). However, further studies are needed to determine if icatibant or several additional therapeutics provided to the patient played a key role in recovery (90).…”

Section: Discussionmentioning

confidence: 80%

“…In fact even inapparent cellular stresses like breathing-directed cyclic stretching of the pulmonary endothelium (88, 89) may contribute to capillary leakage when uncoupled from normal MEC integrity. The cause of vascular leakage during hantavirus diseases has been speculated to stem from a wide range of effectors, including growth factors, kinins, immune responses, cytokines, T cells, and permeability factors (18–20, 29, 31, 32, 35, 36, 39, 77, 90). Although several factors are likely to contribute to permeability, immunosuppression of HV patients has no effect on the disease (21) and recent findings suggest that immune responses are not determinants of vascular leakage in animal models of ANDV infection (13, 22, 23).…”

Section: Discussionmentioning

confidence: 99%

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The Andes Virus Nucleocapsid Protein Directs Basal Endothelial Cell Permeability by Activating RhoA

Gorbunova

Simons

Gavrilovskaya

et al. 2016

mBio

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Andes virus (ANDV) predominantly infects microvascular endothelial cells (MECs) and nonlytically causes an acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). In HPS patients, virtually every pulmonary MEC is infected, MECs are enlarged, and infection results in vascular leakage and highly lethal pulmonary edema. We observed that MECs infected with the ANDV hantavirus or expressing the ANDV nucleocapsid (N) protein showed increased size and permeability by activating the Rheb and RhoA GTPases. Expression of ANDV N in MECs increased cell size by preventing tuberous sclerosis complex (TSC) repression of Rheb-mTOR-pS6K. N selectively bound the TSC2 N terminus (1 to 1403) within a complex containing TSC2/TSC1/TBC1D7, and endogenous TSC2 reciprocally coprecipitated N protein from ANDV-infected MECs. TSCs normally restrict RhoA-induced MEC permeability, and we found that ANDV infection or N protein expression constitutively activated RhoA. This suggests that the ANDV N protein alone is sufficient to activate signaling pathways that control MEC size and permeability. Further, RhoA small interfering RNA, dominant-negative RhoA(N19), and the RhoA/Rho kinase inhibitors fasudil and Y27632 dramatically reduced the permeability of ANDV-infected MECs by 80 to 90%. Fasudil also reduced the bradykinin-directed permeability of ANDV and Hantaan virus-infected MECs to control levels. These findings demonstrate that ANDV activation of RhoA causes MEC permeability and reveal a potential edemagenic mechanism for ANDV to constitutively inhibit the basal barrier integrity of infected MECs. The central importance of RhoA activation in MEC permeability further suggests therapeutically targeting RhoA, TSCs, and Rac1 as potential means of resolving capillary leakage during hantavirus infections.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

The Andes Virus Nucleocapsid Protein Directs Basal Endothelial Cell Permeability by Activating RhoA

Gorbunova

Simons

Gavrilovskaya

et al. 2016

mBio

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“…The pathogenesis of this has not been fully elucidated, but it may involve the release of bradykinin, which increases vascular permeability in various pathological conditions. Indeed, the selective bradykinin type 2 receptor antagonist, icatibant, was successfully administered in 2 cases of life-threatening PUUV infection [48,49] . In imaging studies of PUUV-infected patients, signs of fluid accumulation and edema have been frequently found [50] .…”

Section: Discussionmentioning

confidence: 99%

Glomerular Proteinuria Predicts the Severity of Acute Kidney Injury in Puumala Hantavirus-Induced Tubulointerstitial Nephritis

Mantula

Outinen

Clément

et al. 2017

Nephron

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Background:Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome is common in many European countries. The typical renal histologic lesion is acute tubulointerstitial nephritis. We examined the type and kinetics of urine protein excretion and prognostic significance of proteinuria for the severity of acute kidney injury (AKI) in acute PUUV infection. Methods: The amount of dipstick albuminuria at hospital admission was analyzed in 205 patients with acute PUUV infection. Dipstick albuminuria at admission was graded into 3 categories: 0-1+, 2+, and 3+. In 70 patients, 24-h urinary excretion of protein, overnight urinary excretion of albumin, immunoglobulin (Ig) G, and α1-microglobulin also were measured over 3 consecutive days during the hospital stay. Results: Maximum median daily proteinuria, overnight albuminuria, and IgG excretion were observed over 5 days, while that of creatinine values was observed 9 days after the onset of the disease. The medians of maximum plasma creatinine levels during hospital stay were different in the 3 categories of dipstick albuminuria: 0-1+: 98 µmol/L (58-1,499), 2+: 139 µmol/L (71-829), and 3+: 363 µmol/L (51-1,285; p < 0.001). Dipstick albuminuria ≥2+ at admission could be detected in 89% of the patients who subsequently developed severe AKI. Glomerular proteinuria, but not tubular proteinuria (α1-microglobulin), correlated with the severity of the emerging AKI. Conclusion: In acute PUUV infection, maximum median proteinuria values preceded the most severe phase of AKI by a few days. A highly useful finding for clinical work was that a quick and simple albuminuria dipstick test at hospital admission predicted the severity of the upcoming AKI.

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“…• Vascular leakage is described for virtually all forms of Hantavirus infection, and while the mechanism remains unknown, it is believed to involve inflammatory immune responses. • Presently, treatment options for NE as well as other Hantavirus-associated pathologies are limited [46,47]. For these reasons, future studies into the inflammatory mechanism of hantavirus infection will lead to greater understanding of disease pathogenesis and, in turn, may lead to improved treatment strategies and options for healthcare practitioners.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Inflammatory cytokines kinetics define the severity and phase of nephropathia epidemica

et al. 2014

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A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant

Cited by 60 publications

References 14 publications

The Andes Virus Nucleocapsid Protein Directs Basal Endothelial Cell Permeability by Activating RhoA

The Andes Virus Nucleocapsid Protein Directs Basal Endothelial Cell Permeability by Activating RhoA

Glomerular Proteinuria Predicts the Severity of Acute Kidney Injury in Puumala Hantavirus-Induced Tubulointerstitial Nephritis

Inflammatory cytokines kinetics define the severity and phase of nephropathia epidemica

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