Serum levels of inflammatory and regulatory cytokines in patients with hemorrhagic fever with renal syndrome

ArticleinBMC Infectious Diseases 11(1):142 · May 2011with13 Reads
Impact Factor: 2.61 · DOI: 10.1186/1471-2334-11-142 · Source: PubMed
Abstract

Hantaviruses are the causative agents of two zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The pathogenesis of HFRS is poorly understood. However, it has been suggested that immune mechanisms, including cytokines, might have an important role in HFRS pathogenesis. Thus, the aim of our study was to investigate cytokine profiles in serum samples of HFRS patients from Slovenia and explore a possible correlation between cytokine levels and disease severity. Acute-phase serum samples from 52 patients, diagnosed with DOBV infection, and 61 patients, diagnosed with PUUV infection, were included in this study. Patients were divided into two groups--severe or mild--based on disease severity. Levels of IL-10, IL-12, INF-γ and TNF-α were measured in the serum samples with commercial ELISA tests. Increased levels of IL-10, INF-γ, and TNF-α were found in almost all the serum samples tested. On average, higher concentrations were detected in patients infected with DOBV than PUUV. Furthermore, significantly higher levels of IL-10 (P=0.001) and TNF-α (P=0.003) were found in patients with a more severe clinical course of disease. The same association between IL-10 (P<0.001) and TNF-α (P=0.021), and the severity of the disease was observed also when only patients infected with DOBV were considered. No differences in cytokine concentrations according to disease severity were observed in patients infected with PUUV. Concentrations of serum IL-12 in HFRS patients were in the normal range, however, higher levels were detected in patients infected with PUUV than in patients infected with DOBV. We suggest that imbalance in production of proinflammatory and regulatory cytokines might be in part responsible for a more severe course of HFRS.

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Available from: Tatjana Avsic Zupanc, Sep 01, 2015
RESEARCH ARTICLE Open Access
Serum levels of inflammatory and regulatory
cytokines in patients with hemorrhagic fever
with renal syndrome
Ana Saksida
*
, Branka Wraber and Tatjana Avšič-Županc
Abstract
Background: Hantaviruses are the causative agents of two zoonotic diseases: hemorrhagic fever with renal
syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The pathog enesis of HFRS is poorly
understood. However, it has been suggested that immune mechanisms, including cytokines, might have an
important role in HFRS pathogenesis. Thus, the aim of our study was to investigate cytokine profiles in serum
samples of HFRS patients from Slovenia and explore a possible correlation between cytokine levels and disease
severity.
Methods: Acute-phase serum samples from 52 patients, diagnosed with DOBV infection, and 61 patients,
diagnosed with PUUV infection, were included in this study. Patients were divided into two groups - severe or
mild - based on disease severity. Levels of IL-10, IL-12, INF-g and TNF-a were measured in the serum samples with
commercial ELISA tests.
Results: Increased levels of IL-10, INF-g, and TNF-a were found in almost all the serum samples tested. On average,
higher concentrations were detected in patients infected with DOBV than PUUV. Furthermore, significa ntly higher
levels of IL-10 (P = 0.001) and TNF-a (P = 0.003) were found in patients with a more severe clinical course of
disease. The same association between IL-10 (P < 0.001) and TNF-a (P = 0.021), and the severity of the disease was
observed also when only patients infected with DOBV were considered. No differences in cytokine concentrations
according to disease severity were observed in patients infected with PUUV. Concentrations of serum IL-12 in HFRS
patients were in the normal ra nge, however, higher levels were detected in patients infected with PUUV than in
patients infected with DOBV.
Conclusions: We suggest that imbalance in production of proinflammatory and regulatory cytokines might be in
part responsible for a more severe course of HFRS.
Background
Hantaviruses, rodent-b orne bunyaviruses, are the etiolo-
gic agents of two zoonotic diseases: hemorrhagic fever
with renal syndrome (HFRS) and hantavirus cardiopul-
monary syndrome (HCPS) [1].
In HFRS, the severity of the disease varies depending
on the particular virus involved. H antaan (HTNV) and
Dobrava vir uses (DOBV) tend to pro duce the most
severe disease, with mortality rates 5-10%. Puumala
viru s (PUUV) usually causes a less severe disea se, called
nephropathia epidemica (NE), with mortality rate of less
than 1% and Seoul virus (SEOV) typically produces dis-
ease of intermediate severity with a 1% mortality rate.
Clinically, HFRS presents with sudden onset of fever,
headache and myalgia with renal impairment as the pre-
dominant organ manifestation. Clinical symptoms also
include thrombocytopenia and, in severe cases, hemor-
rhages as a result of the vascular endothelium disfunc-
tion [2-4].
The pathogenesis of HFRS, like that of many other
viral hemorrhagic fevers, is poorly understood. Because
of the lack of suitable animal models, pathogenesis
research is limited to in vitro and rare clinical studies.
Endothelial cells and monocytes are thought to be the
* Correspondence: ana.saksida@mf.uni-lj.si
Institute of Microbiology and Immunology, Faculty of Medicine, University of
Ljubljana, Ljubljana, Slovenia
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© 2011 Saksida et al; licensee BioMed Central Ltd. This is an Open Access a rticle distributed under the terms of the Creative Commons
Attribution License (http://c reativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Page 1
primary cell targets of the viruses, but infection doesn t
seem to have any direct cytopathic effect on t hese cells.
Therefore, it has been suggested that HFRS pathogenesis
is likely to be a complex multifactorial process that
includes contributions from immune responses, platelet
dysfunction, disregulation of endothelial cell barrier
functions and hosts genetic factors [5-7]. Among
immune parameters, certain cytokines such as IL-1,
IL-6, IL-10 and TNF-a were suggested to be involved
in the pathogenesis, since i ncreased levels of these
cytokines were found in patients with HFRS [8-11].
ThepresenceofHFRSinSloveniawasfirstreported
in 1954. Since then, over 300 cases occurring sporadi-
cally or in small epidemics have been documented. Both
severe and mild clinical courses of the disease are
observed, with an overall mortality rate of 3,3%. It has
been demonstrated earlier that in Slovenia DOBV and
PUUV co-exist in a single endemic region and are cap-
able of causing HFRS with significan t differences in dis-
ease severity as well as mortality. Name ly, all fatal HFRS
cases so far have been caused by DOBV infection,
resulting in 8,3% mortality rate for DOBV a ssociated
HFRS. Furthermore, differences in disease severity
within the HFRS cases caused by DOBV have been
noticed. [[12,13], unpublished data].
In light of previous findings, the aim of our study was
to investigate cytokine profiles in serum samples of HFRS
patients from Slovenia. To the best of our knowledge,
this is the first study describing serum cytokine le vels in
patients infected with DOBV. In addition, comparison of
the serum levels of cytokines in patients infected with
DOBV and PUUV, causative agents of HFRS, is described
for the first time. We also explore a possible correlation
between cytokine levels and disease severity.
Methods
Study subjects and sample collection
In Slovenia, 298 HFRS cases were reported between 1985
and July 2010. One-hundred-and-twelve (37.6%) of t he
patients were diagnosed with DOBV and 186 (62.4%)
with PUUV infection. Acute- phase serum samples from
52 patients, diagnosed with DOBV infection, and 61
patients, diagnosed with PUUV infection, were included
in this study. The patients were treated at several i nfec-
tious disease hospitals across the country and clinical
data for the patients was collected retrospectively. During
the course of the disease, the clinical diagnosis was con-
fir med serologically by an indirect immunofluores cen ce
assay (IFA) and enzyme-linked immuno assay (ELISA)
IgM and IgG tests with HTNV, PUUV and DOBV anti-
gens as described previously [12]. The r emains of the
samples were stored in our laboratory at -80°C.
Patients, infected with DOBV or PUUV, were divided
into two groups - severe or mild-moderate - based on
disease severity. Categorization was based on clinical
and laboratory parameters empl oyed i n the pr oposed
Croatian scale for grading the disease severity in patients
with HFRS (Table 1) [14]. Namely, patients with a total
score of 12 or more were defined as having a severe
course of the disease.
Since the study was retrospective, informe d consent
from the patients was not obtained. Instead, the
research was approved by the National Medical Ethics
Committee of the Republic of Slovenia. Also, the princi-
ples of the Helsinki Declaration, the Oviedo Convention
on Human Rights and Biomedicine and the S lovene
Code of Medical Deontology were followed in the con-
duct of this research. No a dditional sample was taken
for the purpose of the study.
Cytokine assays
Serum levels o f IL-10, IL-12, INF-g and TNF-a were
measured retrospectively with commercial ELISA tests.
Namely, for the determination of IL-10, IL-12 and INF-
g,Endogen
®
Human IL-10 ELISA kit, Endogen
®
Total
Human IL-12 ELISA kit, and Endogen
®
Human INF-g
ELISA kit (all Pierce Biotechnology, Inc.) were used.
ELISA Quantikine HS Human TNF-a Immunoassay
(R&D Systems, Inc.) test was used to measure T NF-a
concentrations. The limits of detection for IL-10, IL-12,
INF-g and TNF-a were < 3 pg/ml, < 5 pg/ml, < 2 pg/ml
and < 0.106 pg/ml, respectively. Normal values for
IL-10, IL-12, INF-g and TNF-a were determined to be <
7.65 pg/ml, < 258 pg/ml, < 1 pg/ml and < 2.42 pg/m l,
respectively. They were mea sured in serum sa mples of
healthy adult blood donors by the Laboratory for Allergy
and Cytokine Diagnostics at the Institute of Microbiol-
ogy and Immunology, Medical Faculty, Ljubljana,
Slovenia.
Statistical analysis
Results were analysed using the statistical software pack-
age SPSS 17.0 f or Windows (SPSS Inc.). The relation-
ship between the variables and the clinical classific ation
was evaluated using Mann-Whitney or Kruskal-Wallis
tests f or co ntinuous variables. The correlation among
variables was assessed with Pearsons test and multiple
linear regression. P values of < 0.05 w ere c onsidered
significant.
Results
Clinical data
Fifty- two patients with confirmed acute DOBV infection
and 61 patients with confirmed PUUV infection were
enrolled in the study. On the basis of their case records ,
30 pat ients, infected with DOBV, were categorized as
having severe disease and 22 as having mild-moderate
disease. From patients infected with PUUV 19 were
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categorized as having severe disease and 42 as having
mild-moderate dis ease. The main clinical characteristics
and laboratory values of patients gr oups are summar-
ized in Tables 2 and 3.
Cytokine levels
Concentrations of IL- 10, IL-12 and INF-g were deter-
mined retrospectively in all serum samples. Due to the
limited volume of available samples, levels of TNF-a
could only be measured in 46 and 55 serum samples of
patients infected with DOBV and PUUV, respectively
(Table 4). Elevated lev els of IL-10, INF-g and TNF-a
were de tected in almo st a ll the samp les tested, regard-
less of the causative agent or the clinical course of the
disease. On the contrary, concentra tions of IL-12 were
in the normal range, even more, detected levels of IL-12
in patients i nfected with DOBV were significantly lower
than values detected in healthy blood donor volunteers
(P = 0.006) (data not shown). Serum concentrations of
IL-12 were higher in patients infected with PUUV than
Table 1 Scale for grading the disease severity in patients with HFRS
Signs and symptoms Score
1. SHOCK, HYPOTENSION
a
Shock 10
Hypotension, systolic blood pressure < 90 mm Hg 5
Tachycardia, heart rate > 120/min 2
2. HAEMORRHAGES
a
Massive: blood transfusion needed 5
Internal (melena, hematemesis, hemoptysis, intracranial) 3
Epistaxis 2
Petechiae, conjuctival injection, enanthema 1
3. GENERAL SYMPTOMS
Body temperature > 40°C 2
Seizure 2
Blurred vision 1
Vomiting and diarrhea 1
Anuria/oliguria 1
Dialysis requirement 1
4. Laboratory parameters
Serum urea and/or creatinine > 5-times the normal value 5
> 4-times the normal value 4
> 3-times the normal value 3
> 2-times the normal value 2
Trombociti < 20 × 10
9
/L 2
<50×10
9
/L 1
AST, ALT > 5-times the normal value 2
3-4-times the normal value 1
Lung X-ray pneumonitis 2
pleural effusion 1
a
In group 1 and 2, only the signs/symptoms with the highest score are considered
Table 2 Occurence of different clinical and laboratory
findings in patients with HFRS according to the causative
agent
Finding DOBV (n = 52) PUUV (n = 61)
Fever > 39°C 89% 81%
Backache or abdominal pains 90% 61%
Blurred vision 40% 35%
Haemorrhagic manifestations
a
55% 28%
Thrombocytopenia (< 50 × 10
9
cells/l) 42% 38%
Oliguria (< 0.5 l urine/24 hrs) 66% 39%
Serum creatinine (μmol/l)
b
622 (89-1157)* 368 (77-1420)*
Urea (mmol/l)
b
30 (5,1-76,2)* 17,6 (4,2-48,2)*
Dialysis requirement 49% 9%
a
Most frequent haemorrhagic manifestati ons: conjuctival injection, petechiae,
hematemesis, melena.
b
Normal values: thrombocytes 140-360 × 10
9
cells/l, serum creatinine 44-97
μmol/l, urea 2,8-7,5 mmol/l.
* Given as mean (min-max) of highest values detected
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in patients infected with DOBV, but the difference was
not significant (P =0.18).AlsoserumlevelsofIL-12
detected in PUUV infected patients did not differ from
normal values (P = 0.34). In DOBV infected patients
mean concentrations of IL-10 and INF-g were higher
than in patients infected with PUUV, however the differ-
ences were not significant (P =0.17andP =0.36).No
considerable difference was observed in TNF- a levels
between patients infected with DOBV and PUUV (P =
0.17) (Figure 1).
When patients were divided according to disease
severity, rega rdless of the causative agen t, s ignificantly
higher levels of IL-10 and TNF-a were detected in the
patients with severe disease course ( P = 0.001 and P =
0.003). (Figure 2). In DOBV infected patients higher
levels of all measured cytokines were detected in
patients with severe disease co urse than in patients wit h
mild-moderate d isease course. Significant differences
were observed for IL-10 (P <0.001)andTNF-a (P =
0.021), while detected values of IL-12 and INF-g were
not significantly different between these two patients
groups ( P = 0.26 and P = 0.09) (Figure 3).
For the patients diagnosed with PUUV infection, no
significant differences in cy tokine concentrations were
observed regarding the disease severity. Higher mean
levels of IL-12 (P = 0.97) and INF-g (P =0.71)were
detected in patients with severe than with mild-moder-
ate disease course, while the opposite was true for IL-10
(P = 0.87) and TNF-a (P = 0.12) (Figure 3).
When cytokine levels were compared acco rding to the
day of illness the sample was taken, no time dependence
could be observed for any group of patients, regardless
of the causative agent or the clinical course of the dis-
ease (data not shown).
Discussion
Growing e vidence exists that immune mechanisms
rather than direct viral cytopathology ar e responsible for
the changes in vascular permeability, the principal
abnormality, in bot h HFRS and HCPS [6,15]. Activation
of hantavirus specific CD8+ T cells and cytokine pro-
duction seem to be of special importance, since high
level s of these ce lls have be en found in blood, lung, and
kidney tissues of HCPS and HFRS patients [16-18].
This study is the first to describe serum cytokine
levels in patients infected with DOBV and also to com-
pare the detected lev els in patien ts infected with DOBV
and PUUV. In our study, increa sed levels of IL-10, INF-
g,andTNF-a were found in serum samples of most
HFRS patients. On average, higher concentration s were
detected in patients infected with DOBV than PUUV.
Furthermore, in patients infected with DOBV, higher
levels of these cytokines were found in patients with a
more severe clinical course of disease. No differ ences in
cytokine concentrations according to disease severity
were observed in patients infected with PUUV. It has
previously been established, that severe cases of HFRS
in Slovenia are mainly caused by DOBV, while infection
Table 3 Comparisson of different clinical and laboratory findings in patients infected with DOB Vand PUUV according
to disease severity
Finding DOBV PUUV
mild-moderate (n = 22) severe (n = 30) mild-moderate (n = 42) severe (n = 19)
Haemorrhages 36,4% 76,7% 21,4% 47,4%
Thrombocytopenia < 50 × 10
9
/l 27,3% 56,7% 33,3% 52,6%
Oliguria < 0.5 l/24 hrs 31,8% 73,3% 19,0% 73,7%
Dialysis requirement 18,2% 76,7% 0% 36,8%
Serum creatinine (μmol/l) 418 (89-1058)* 781 (311-1157)* 246 (77-742)* 669 (271-1420)*
Urea (mmol/l) 21,9 (5,1-51,6)* 36,4 (10,8-76,2)* 13,3 (4,2-48,2)* 28,1 (12,7-45,7)*
* Given as mean (min-max) of highest values detected
Table 4 Cytokine concentrations in acute serum samples of patients with HFRS according to the causative agent and
disease severity
Patient group Mean levels (min-max) of cytokines (pg/ml)
IL-10 IL-12 INF-g TNF-a
DOBV 292.5 (2.24-6600) 100.4 (1.94-544) 89.1 (0-1916) 9.8 (0-62.5)
severe 474.4 (12.4-6600) 97.7 (10.9-544) 131.5 (0-1916) 12.3 (1.87-62.5)
mild-moderate 44.4 (2.24-328) 104.0 (1.94-440) 31.4 (0-354) 6.3 (0-17)
PUUV 130.3 (6.63-2120) 139.2 (0.98-637) 24.1 (0.43-692) 10.8 (0-138)
severe 89.9 (15.5-731) 151.1 (2.49-570) 46.6 (1.61-692) 7.6 (2.47-15.2)
mild-moderate 148.6 (6.63-2120) 133.8 (0.98-637) 14.0 (0.43-203) 12.3 (0-138)
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with PUUV usually results in a milder form of disease
[12,13]. This has once again been confirmed with
patients included in this study, since the occurrence and
intensity of clinical and laboratory findings were higher
in patients infected with DOBV than PUUV. T herefore,
it is expectable, that the differences in disease severity in
patients infected with PUUV are smaller.
Increased levels of TNF-a have also been demonstrated
in studies of patients with Korean hemorrhagic fever and
patients with HCPS. However, no association with disease
severity could be established in either of these studies
[8,19,20]. Increased levels of TNF-a, IL-6 and IL-10 have
previously been detected in patients with NE, where
TNF-a levels were found t o correlate with hypotension
and serum NO levels and plasma IL-6 levels were asso-
ciated with a more severe form of NE [9,11]. In addition,
increased IL-10 and TNF-a production was demonstrated
in cynomolgous monkeys infected with wild-type PUUV,
where highest concentrations of TNF-a were detected in
the most affected monkey [21]. High IL-10 and TNF-a
serum values were also found in patients with severe
course of dengue hemorrhagic fever and Argentine
hemorrhagic fever, which have similar cli nical presenta-
tions to HFRS [22-24].
On the basis of the results of our and previous studies,
we believe that i mbalance in production of proinflam-
matory and regulatory cytokines might be associated
with disease severity in HFRS. Similar has been pro-
posed for HCPS, where a mixed Th1/Th2 immune
response was observed in serum samples of HCPS
patients and the levels of T h1 cytokines correlated with
disease severity [19].
In our opinion, a strong inflammatory response to virus
particles and immune complexes, mainly represented by
Figure 1 Comparison of serum cytokine concentrations in patients with acute HFRS according to the causative agent of the di sease.
Horizontal bars show median values. Dotted lines represent the upper limits of normal values.
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TNF-a and INF-g, causing changes in vascular permeabil-
ity, could c ontribute to a more severe clinical course of
HFRS. Also, high production of inflammatory cyt okines
in turn leads to increased productio n of regulatory cyto-
kines, such as IL-10, and possibly to immunosuppression.
IL-10 also promotes further antibody production, likely
resulting in even higher number of immune complexes,
which deposi t on capi llary walls and in tissues. At the
same time, IL-10 inhibits cell-mediated immunity by
down regulating IL-12 expression, thus interfering with
phagocytosis and clearance of immune complexes. This
can cause formation of new inflammation sites or even a
systemic inflammatory response. O ur hypothesis is
further supported with low IL-12 levels found in patients
infected with DOBV. We believe that higher levels of
IL-12 in patients infected with PUUV help to enable the
development of cell-mediated immunity, resulting in a
more successful clearance of immune complexes and
consequently in a milder form of disease.
Similar has been hypothesiz ed fo r patients with sepsis
caused by gramnegative bacteria, where a strong inflam-
matory response to lipopolisaharid in bacterial wall,
characterized by c ytokines suc h as TNF-a,IL-1,IL-6
and IL-12, i s thought to trigger a strong regulatory
response, with high levels of IL-10. This could lead into
immunosuppression and con sequently in the worst
cases cause a multi-organ failure [25].
Conclusions
To conclude, the results of our study favor the hypothesis
that cytokine production imbalance might contribute to a
more severe clinical course of HFRS. Nevertheless, further
immunological studies are needed to clarify, whether this
imbalance is a cause or a result of the clinical symptoms
Figure 2 Comparison of serum cytokine conc entrations in patients with acute HFRS according to the clinical course of the disease.
Horizontal bars show median values. Dotted lines represent the upper limits of normal values.
Saksida et al. BMC Infectious Diseases 2011, 11:142
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we are observing. Also, additional factors are undoubtedly
involved in the pathogenesis of HFRS.
Acknowledgements
We thank the following infectologists for their help in retrieving patients
case records: dr. Stanka Lotrič-Furlan, prof. dr. Franc Srle, dr. Jernej Pajek,
Polonca Furlan, mag. Emil Pal, Vanda Kostevc-Zorko, Zmago Novak, and
Dimitrij Klančič. Also, we are grateful to Mateja Jelovšek and Bojana Žiberna
for their meticulous technical assistance.
Authors contributions
AS has written the manuscript, participated in the design and coordination
of the study, recruited and analysed patients data, and performed statistical
analysis. BW participated in the design of the study and determined and
interpreted the cytokine levels. TAŽ participated in the design and
coordination of the study and helped to recruit patients samples and
clinical data. All authors have been involved in revising the manuscript and
have read and approved the final version.
Competing interests
The authors declare that they have no competing interests.
Received: 24 February 2011 Accepted: 23 May 2011
Published: 23 May 2011
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Pre-publication history
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doi:10.1186/1471-2334-11-142
Cite this article as: Saksida et al.: Serum levels of inflammatory and
regulatory cytokines in patients with hemorrhagic fever with renal
syndrome. BMC Infectious Diseases 2011 11:142.
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Saksida et al. BMC Infectious Diseases 2011, 11:142
http://www.biomedcentral.com/1471-2334/11/142
Page 8 of 8
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    • "The long-term prognosis of nephropathia epidemica (NE) caused by Puumala virus is favorable and most patients fully recover renal function [19]. Several previous studies reported an association of pro-inflammatory cytokines and severity of hantavirus infections [14,23242526. There are only few reports about the role of anti-inflammatory and suppressive cytokines such as TGF-β in hantavirus infection. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Hantaviruses are emerging zoonotic pathogens which cause hemorrhagic fever with renal syndrome, an immune-mediated pathogenesis is discussed. The aim of the present study was to investigate the role of TGF-β expression in acute hantavirus infection. Results We retrospectively studied 77 patients hospitalised with acute Puumala infection during a hantavirus epidemic in Germany in 2012. Hantavirus infection was confirmed by positive anti-Puumala hantavirus IgG and IgM. Plasma levels of transforming growth factor (TGF)-β1 and TGF-β2 were analysed. Based on glomerular filtration rate on admission, patients were divided in mild and severe course of disease. Puumala virus RNA was detected by PCR amplification of the viral L segment gene. Out of 77 Puumala virus infected patients, 52 (68%) were male. A seasonal distribution was detected in our cohort with a peak in summer 2012, the highest incidence was observed in the age group of 30–39 years. Puumala virus RNA was detectable in 4/77 cases. Patients with severe disease had a significant longer hospital stay than patients with mild disease (6.2 vs 3.6 days). Thrombocyte count (186 vs 225 per nl), serum TGF-β1 (74 vs 118 ng/l) and TGF-β2 (479 vs 586 pg/l) were significantly lower in severe compared to mild disease. However, C-reactive protein (CRP) was significantly higher in patients with severe disease (62 vs 40 mg/l). TGF-β1/Cr was the most sensitive and specific marker associated with renal dysfunction. Conclusion High serum CRP and low serum TGF-β in the early phase of hantavirus infection is associated with a severe course of disease. Our results support the hypothesis of an immune-mediated pathogenesis in hantavirus infection.
    Full-text · Article · Apr 2015 · BMC Immunology
    • "High levels of proinflammatory cytokines are detected in sera from hantavirus-infected patients especially TNF-α (Linderholm et al., 1996; Mori et al., 1999; Borges et al., 2008; Klingstrom et al., 2008; Sadeghi et al., 2011; Saksida et al., 2011; Libraty et al., 2012; Kyriakidis and Papa, 2013). TNF-α is released by activated antiviral immune cells such as neutrophils, NK cells and CD8 + T cells as well as hantavirus-infected DC and macrophages (Raftery et al., 2002; Marsac et al., 2011; Shin et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Viral hemorrhagic fever caused by hantaviruses is an emerging infectious disease for which suitable treatments are not available. In order to improve this situation a better understanding of hantaviral pathogenesis is urgently required. Hantaviruses infect endothelial cell layers in vitro without causing any cytopathogenic effect and without increasing permeability. This implies that the mechanisms underlying vascular hyperpermeability in hantavirus-associated disease are more complex and that immune mechanisms play an important role. In this review we highlight the latest developments in hantavirus-induced immunopathogenesis. A possible contribution of neutrophils has been neglected so far. For this reason, we place special emphasis on the pathogenic role of neutrophils in disrupting the endothelial barrier.
    Full-text · Article · Mar 2015 · Frontiers in Microbiology
    • "Upregulated levels of soluble EC receptors: E-Selectin (Takala et al., 2000 ), intercellular adhesion molecule (ICAM; Han et al., 2010), and tumor necrosis factor receptor (TNFR)-1 (Kyriakidis and Papa, 2013) are released into circulation during acute HFRS. While there is no evidence on EC activation in HCPS, the upregulation of proinflammatory cytokines: interleukin (IL)-6, tumor necrosis factor (TNF)-α, and interferon (IFN-γ) that all are capable of activating the endothelium, have been reported in both hantavirus diseases (Linderholm et al., 1996; Peters et al., 1999; Klingstrom et al., 2002; Abel Borges and Figueiredo, 2008; Sadeghi et al., 2011; Saksida et al., 2011; Korva et al., 2013; Kyriakidis and Papa, "
    [Show abstract] [Hide abstract] ABSTRACT: Hantavirus, a genus of rodent- and insectivore-borne viruses in the family Bunyaviridae, is a group of emerging zoonotic pathogens. Hantaviruses cause hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome in man, often with severe consequences. Vascular leakage is evident in severe hantavirus infections, and increased permeability contributes to the pathogenesis. This review summarizes the current knowledge on hantavirus interactions with hematopoietic and endothelial cells, and their effects on the increased vascular permeability.
    Full-text · Article · Dec 2014 · Frontiers in Microbiology
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