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Contents lists available at ScienceDirect

Journal of Clinical Virology

journal homepage: www.elsevier.com/locate/jcv

Hantaviruses—Globally emerging pathogens

Detlev H. Kruger a,∗ , Luiz Tadeu Moraes Figueiredo b , Jin-Won Song c , Boris Klempa a,d
a
Institute of Medical Virology, Charité School of Medicine, Berlin, Germany
b
Virus Research Unit, School of Medicine, University of Sao Paulo at Ribeirao Preto, Brazil
c
Department of Microbiology, College of Medicine, Korea University, Seoul, Republic of Korea
d
Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia

a r t i c l e i n f o a b s t r a c t

Article history: Hantaviruses are emerging zoonotic viruses which cause human disease in Africa, America, Asia, and
Received 7 August 2014 Europe. This review summarizes the progress in hantavirus epidemiology and diagnostics during the pre-
Accepted 25 August 2014 vious decade. Moreover, we discuss the influence of ecological factors on the worldwide virus distribution
and give an outlook on research perspectives for the next years.
Keywords: © 2014 Elsevier B.V. All rights reserved.
Hantavirus
Hemorrhagic fever with renal syndrome
Hantavirus cardiopulmonary syndrome
Zoonotic viruses

1. Introduction in outdoor activities, such as rural- and forest-related activities,

Hantavirus disease is a zoonosis. The causative viruses, collec-
tively belonging to the genus Hantavirus of the Bunyaviridae family,
are harbored by small mammals as reservoir hosts and transmitted
to men. In humans, they cause febrile disease, usually named “Hem-
orrhagic Fever with Renal Syndrome” (HFRS) for disease in Asia and
Europe and “Hantavirus Cardiopulmonary Syndrome” (HCPS) in the
Americas with case fatality rates of up to 35–50% [67,48,45,18].
The pathogenesis of hantavirus disease is characterized by changes
in blood coagulation, vasodilatation and disturbances in the bar-
rier function of the capillaries, resulting in extravasion of blood
and inflammatory processes in the affected organs. Since patho-
genesis is highly similar and clinical appearance is overlapping
between both syndromes, comprehensive terms as “hantavirus dis-
ease” or “hantavirus fever” have been suggested to denote the
disease [12,92].
Virus transmission to humans occurs via inhalation of
aerosolized rodent urine, saliva, and feces, rarely by rodent bites.
In the environment, virus particles remain infectious for several
weeks – depending on factors as humidity, temperature, and asso-
ciation with protective proteins [22]. An overview about the risk
factors of hantavirus infections was very recently compiled by
Watson et al. [98]; the most prominent factors are involvement
peridomestic rodent presence, exposure to potentially infected
dust, and outdoor military training. Humans are usually consid-
ered to be dead-end hosts who do not transmit the virus further.
However, indubitable human-to-human transmission of Andes
hantavirus was reported in Argentina and Chile [99,63,9,53,14].
According to the presence of infected animal hosts and their con-
tacts to humans, occurrence of hantavirus disease can be observed
in different climatic zones including subtropics and tropics. Han-
taviruses are considered to belong to the group of emerging viruses;
this has mainly to do with the frequent identification of novel han-
taviruses and their role as human pathogens. There are different
trends in the development of case numbers; whereas in China – the
country with most HFRS cases per year worldwide – the number of
patients seems to decrease because of the vaccination approaches
in this country [23], the number of cases in Europe and particularly
Germany shows a clear increase over the last years [70,46].
Here, we will refer to the progress in hantavirus epidemiology
and diagnostics during the previous decade (see also Box 1) with a
particular focus on infections in tropical areas.
2. Epidemiology
2.1. Africa

Africa is clearly the continent with the most recent scientific

∗ Corresponding author at: Institute of Medical Virology, Helmut-Ruska-Haus,
Charité School of Medicine, Charitéplatz 1, D-10117 Berlin, Germany.
Tel.: +49 30 450525092; fax: +49 30 450525907.
E-mail address: detlev.kruger@charite.de (D.H. Kruger).
progress in terms of hantavirus epizootiology and epidemiology.
Ten years ago, no indigenous African hantaviruses were known,
while today, approximately 10 hantaviruses have been identified
not only in rodents but also shrews and even bats in Africa.

http://dx.doi.org/10.1016/j.jcv.2014.08.033
1386-6532/© 2014 Elsevier B.V. All rights reserved.

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Table 1
Box 1: Most important (clinically relevant) develop- Hantaviruses reported to be pathogenic for humans.
ments during the last 10 years Continent/virus Recognized reservoir host

• Progress on diagnostic methods: Recombinant viral antigens Africa

Sangassou virus (SANGV)a Hylomyscus simus
for use in serology (ELISA, Western blot), Commercial kits for
rapid diagnosis using immune chromatography, Real time America
PCRs Sin Nombre virus (SNV) Peromyscus maniculatus
• Deeper information on molecular epidemiology of han- Monongahela virus (MNGV) Peromyscus maniculatus
New York virus (NYV) Peromyscus leucopus
taviruses and their occurrence in different reservoir hosts
Bayou virus (BAYV) Oryzomys palustris
• New insights into the molecular processes of viral replication
Black Creek Canal virus (BCCV) Sigmodon hispidus
and the pathophysiology of hantavirus infection Andes virus (ANDV) Oligoryzomys longicaudatus
• Decrease of the number of clinical cases in countries with Maciel virus (MACV) Necromys benefactus
immunization programs Bermejo virus (BMJV) Oligoryzomys chacoensis
Araraquara virus (ARQV) Necromys lasiurus
Juquitiba virus (JUQV) Oligoryzomys nigripes
Calomys callidus
Laguna Negra virus (LANV)
Calomys laucha
Several seroepidemiological studies in African humans sug-
Castelo dos Sonhos virus (CASV) Oligoryzomys moojeni
gested the presence of hantaviruses in Africa much earlier (for a Anajatuba virus (ANJV) Oligoryzomys fornesi
comprehensive review, see [100]). However, the first African han-
Asia
tavirus, named Sangassou virus (SANGV), was found in the African
Hantaan virus (HTNV) Apodemus agrarius
wood mouse (Hylomyscus simus) trapped in a forest habitat in Amur/Soochong virus (AMRV/SOOV) Apodemus peninsulae
Guinea first in 2006 [36]. Meanwhile, several other rodent- as well Seoul virus (SEOV) Rattus norvegicus
as shrew-borne hantaviruses were identified in sub-Saharan Africa. Thailand virus (THAIV)a Bandicota indica
The African continent has also played an important role in the Europe
recent change in the dogmatic view on hantaviruses as rodent- Puumala virus Myodes glareolus
borne viruses. Not only due to several shrew borne-viruses, but also Apodemus flavicollis
Dobrava-Belgrade virus Apodemus ponticus
because the very first bat-borne hantaviruses were found in Africa
Apodemus agrarius
(reviewed in [100]). All of these newfound shrew- and bat-borne Tula virus (TULV) Microtus arvalis
hantaviruses were identified only through molecular detection of Seoul virus (SEOV) Rattus norvegicus
viral RNA in wild-living animals. a
So far only serological evidence reported.
SANGV, so far the only African hantavirus isolated on cell cul-
ture, was used in the most recent seroepidemiological studies
in Guinea which utilized a comprehensive battery of serological
monophyletic groups called Andes, Laguna Negra, and Rio Mamore
assays (enzyme-linked immunosorbent assay, immunofluores-
clades [58]. However, numerous hantavirus names are described
cence assay, Western blot analysis, neutralization assays) to
in the literature suggesting existence of many unique hantaviruses
ensure specificity [38,40]. Initial studies demonstrated a hantavirus
although their taxonomical status is unclear or if they are even
seroprevalence of about 1–2% was observed among the human pop-
highly similar to the established hantavirus species. In this review,
ulation of Guinea and the South African Cape Region, respectively
for the scope of clarity, we use the names as they were originally
[38,100]. Moreover, hantavirus antibodies were retrospectively
reported without judging the taxonomical status of the reported
detected in 3 (4.4%) of 68 patients with fever of unknown origin
viruses (Table 1, Fig. 1).
from Sangassou village in Guinea. In one pediatric patient suffering
Studies in Brazil showed that Araraquara virus (ARQV), harbored
from typical HFRS symptoms, the presence of SANGV-specific IgM
by Necromys lasiurus [90], seems to be one of the most virulent
antibodies was shown and in a serum sample taken one year later
hantaviruses, leading to HCPS with 50% case fatality rate [17].
neutralizing anti-SANGV IgG antibodies were detected [38].
ARQV’s rodent host developed an opportunistic behavior, adapting
These data indicate that hantavirus infections may be an under-
to human anthropogenic changes, further increasing ARQV public
estimated medical problem in Africa. Further studies are clearly
health concerns [89,72]. Similarly, Castelo dos Sonhos virus (CASV)
necessary but are hampered by the lack of appropriate antigens
is harbored by Oligoryzomys moojeni, a rodent that lives in an exten-
from African rodent-, shrew-, and bat-borne hantaviruses. Recent
sively deforested area of lumber commerce and cattle breeding at
advances in next-generation-sequencing technologies and gene
the northern Amazon [54].
synthesis will probably enable researchers to overcome these dif-
The eco-epidemiology of hantaviruses depends on the micro-
ficulties in the near future.
habitat of its reservoir [58]. Thus, landscape composition, climate
and seasonality, as well as human agricultural activity and
2.2. The Americas environmental degradation, are important factors of hantavirus
epidemiology. In the southwest of North America outbreaks of
About 4000 HCPS cases have been reported in the Americas since HCPS cases have been shown to correlate with weather and espe-
1993 caused by thirty hantavirus strains. [18]. In North America cially precipitation [34]. The ecology of SNV in the 1993 outbreak at
Sin Nombre virus (SNV) is the most prominent hantavirus caus- Four Corners showed that an increased precipitation augmenting
ing cardiopulmonary syndrome [34] while Andes virus (ANDV) is food availability increased hantavirus reservoir populations [34].
the most important pathogenic hantavirus in South America. In Longitudinal studies with Peromyscus maniculatus and SNV also
Central America, Choclo virus (CHOV), harbored by Oligoryzomys revealed that the decrease in species richness and the prepon-
fulvescens, causes HCPS in Panama [97], a country belonging to derance of males are factors that contribute to virus maintenance
the tropical/subtropical zone. Other recognized pathogenic han- [8].
taviruses and their associated reservoir hosts are listed in Table 1. An increased prevalence of ARQV infection in its natural-
In South America, the diversity and distribution of hantaviruses reservoir Necromys lasiurus correlated with environmental
are highly complex. In phylogenetic analyses, the majority of degradation and the dry winter season in Brazil. Human environ-
the South American hantavirus strains fall into three major mental change (e.g. increased grassland) favored the abundance

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Fig. 1. Global map showing the geographical distribution of the clinically most important hantaviruses (borders of tropical zone are marked). In bold, viruses serologically
and molecularly demonstrated in patients; in italics, viruses indicated by serological methods only. AMRV/SOOV, Amur/Soochong virus (Korea, Russia and China); ANJV,
Anajatuba virus (Brazil); ANDV, Andes virus (Argentina and Chile); ARQV, Araraquara virus (Brazil); BAYV, Bayou virus (USA); CASV, Castelo dos Sonhos virus (Brazil); CHOV,
Choclo virus (Panama); DOBV, Dobrava-Belgrade virus (Central, East, and South Europe); HTNV, Hantaan virus (Asia, in particular China and Korea); JUQV, Juquitiba virus
(Brazil); LANV, Laguna Negra virus (Brazil); PUUV, Puumala virus (Europe); SANGV, Sangassou virus (Guinea); SEOV, Seoul virus (Korea, China and probably world-wide);
SNV, Sin Nombre virus (USA); THAIV, Thailand virus (Thailand, Cambodia, India); TULV, Tula virus (Central Europe).

of opportunistic species of the Sigmodontinae rodents (Necromys
lasiurus, Akodon sp., and Calomys tener), which are often hantavirus
carriers [72].
2.3. Asia
Asia is the continent with the longest historical record of han-
tavirus infection. HTNV and Seoul virus (SEOV) are the major
causative agents of HFRS in Asia. Approximately 300–500 HFRS
cases are reported annually with a mean case fatality rate of 1–4%
in Korea [47,84]. More than 11,000 HFRS cases are reported nation-
wide in China, including southern China [102].
SEOV is considered to be present worldwide due to the cos-
mopolitan distribution of rats as its reservoir hosts. Nevertheless,
SEOV is dominantly present in Asia, while reports from other parts
in the world are rather exceptional. In Vietnam and Singapore,
14–34% of rats showed antibodies against SEOV. This virus has also
been identified in R. flavipectus, R. losea and R. nitidus from southern
China [102].
Several Rattus-borne hantaviruses were reported in the trop-
ical region of Asia, including THAIV from the greater bandicoot
rat (Bandicota indica) in Thailand [30,66] and SERV from the Asian
house rat (Rattus tanezumi) in Serang, Indonesia [69]. There are
indications that THAIV can cause human disease [66,19].
The pathogenicity of the vole-borne hantaviruses in Asia is cur-
rently unknown. However, about 5–7% of acute-phase sera from
HFRS cases occurring annually in Korea show a four-fold or higher
IgM antibody titer to Puumala virus (PUUV) than to HTNV despite
the fact that PUUV and the bank vole (Myodes glareolus), as the
reservoir host of PUUV in Europe, are absent. This finding sug-
gests that some of the other vole-borne hantaviruses present in
Asia might be responsible for a small proportion of HFRS cases. The
obvious putative candidate could be MUJV (Fig. 2), identified in the
royal vole (also called Korean red-backed vole; Myodes regulus) in
Korea [84].
For the group of the newlyfound shrew- and bat-borne han-
taviruses including Imjin virus (MJNV) and Jeju virus (JJUV) in
Korea, studies are still need to investigate whether these viruses
cause human infections and disease. However, anti-TPMV anti-
bodies have been found in sera from a patient with high fever of
unknown etiology in Thailand, suggesting that TPMV might be a
human pathogen [62,85–88,4].
2.4. Europe
Hantavirus infections are reported from many European
countries while the annual case numbers are highly variable
across different countries as well as different years. For the period
2000–2009, the annual average number of diagnosed cases in
Europe was reported to be 3138 [24].
In terms of epidemiology, there are two important disease-
causing hantaviruses in Europe. Generally speaking, Western and
Northern Europe is dominated by PUUV transmitted by bank voles
(Myodes glareolus), which is the most common arvicolid rodent
species in Europe. On the other hand, South-Eastern Europe is dom-
inated by DOBV infections, transmitted from mice of the genus
Apodemus.
PUUV, the causative agent of a mild form of HFRS, also desig-
nated as nephropathia epidemica (NE), has been detected widely in
Europe. In some countries, such as Finland, Germany, Sweden and
the European part of Russia, thousands of PUUV cases can occur in
epidemic peak years [46,94]. The last outbreak years in Germany
(2007, 2010, 2012) positively influenced public and medical aware-
ness of the disease and led to massive progress in accumulation of
genomic sequence data obtained directly from patients, as well as
from bank voles and enabled the designation of certain virus strains
to defined geographic high-risk regions [25,13].
With a case fatality rate up to 12% for the respective disease,
DOBV is the most life-threatening European hantavirus which is
responsible for almost all fatal HFRS cases in Europe. Recently,

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Fig. 2. Phylogenetic tree of rodent-, shrew-, and bat-borne hantaviruses (with and without known pathogenicity in humans). Viruses found in (sub)tropical regions are
marked by arrows. Moreover, viruses with evident human pathogenicity are highlighted by boldface in the case that infections were serologically and molecularly proven
or by use of italics if there is serological evidence only (cp. Fig. 1). The phylogenetic tree was constructed on the basis of partial L segment sequences (306 nucleotides) in
the MEGA6 program by using the Maximum Likelihood (GTR + G evolutionary model). Scale bar indicates an evolutionary distance of 0.2 substitutions per position in the
sequence. AMRV/SOOV, Amur/Soochong virus; ALTV, Altai virus; ANDV, Andes virus; ANJV, Anajatuba virus; ARQV, Araraquara virus; ARRV, Ash River virus; ARTV, Artybash
virus; ASAV, Asama virus; ASIV, Asikkala virus; AZGV, Azagny virus; BAYV, Bayou virus; BCCV, Black Creek Canal virus; BOGV, Boginia virus; BOWV, Bowé virus; CADV, Cano
Delgadito virus; CASV, Castelo dos Sonhos virus; CBNV, Cao Bang virus; CHOV, Choclo virus; DOBV, Dobrava-Belgrade virus; HOKV, Hokkaido virus; HUPV, Huanqpi virus;
HTNV, Hantaan virus; JEJV, Jeju virus; JMSV, Jemez Springs virus; JUQV, Juquitiba virus; KILV, Kilimanjaro virus; KKMV, Kenkeme virus; LHEV, Lianghe virus; LNV, Laguna
Negra virus; LQUV, Longquan virus; MAPV, Maporal virus; MGBV, Magboi virus; MJNV, Imjin virus; MOUV, Mouyassué virus; MTNV, Montano virus; MUJV, Muju virus; NVAV,
Nova virus; OXBV, Oxbow virus; PHV, Prospect Hill virus; PUUV, Puumala virus; QDLV, Qiandao Lake virus; RIOMV, Rio Mamore virus; RKPV; Rockport virus; RPLV, Camp
Ripley virus; SANGV, Sangassou virus; SEOV, Seoul virus; SERV, Serang virus; SWSV, Seewis virus; SNV, Sin Nombre virus; THAIV, Thailand virus; TGNV, Tanganya virus;
TPMV, Thottapalayam virus; TULV, Tula virus; ULUV, Uluguru virus; VLAV, Vladivostok virus; XSV, Xuan Son virus.

DOBV epidemiology and evolution have been extensively reviewed
[65,39]. Severe human infections by viruses of the Dobrava geno-
type (associated with A. flavicollis) are mainly reported from
South-East (SE) Europe. Sochi genotype (associated with A. pon-
ticus) causes severe human infections in the Black Sea coast region
of Russia. The DOBV genotype Kurkino (associated with A. agrarius)
is present in Central and SE Europe and was reported to cause large
HFRS outbreaks in central regions of European Russia [37,39].
Recently and quite surprisingly, human SEOV infections were
reported from the United Kingdom and were associated not only
with wild living rats [31] but also pet rats [32,91]. Pet rats were
recently identified to harbor SEOV also in Sweden [49] and, more-
over, severe SEOV infection in a pregnant woman was recently
reported from France [50].
Tula virus (TULV) is often considered as non-pathogenic,
however, there are single reports about patients suffering from
infections by this virus [35,101]. Since 2007, numerous novel han-
taviruses were discovered in non-rodent hosts, mainly shrews
and moles (Fig. 2) but their clinical relevance is currently unclear
(reviewed in [41]).
3. Laboratory methods
Usual laboratory findings in both HFRS and HCPS are thrombocy-
topenia, increased haematocrit, leukocytosis, and increased serum
creatinine. Other laboratory markers depend on the preferentially
targeted organ and its failure. Hantavirus isolation in cell culture
is not a routine procedure for laboratory diagnosis because it is

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Table 2
Laboratory methods used for hantavirus diagnostics in humans.

Method Advantages Disadvantages Perspectives

Serological methods
IgG and IgM ELISAs and IgM
capture ELISAs
Indirect immunofluorescence
assay
Immunoblot
Neutralization test
Immunochromatographic test
– Can be used in all phases of the
disease
– Sensitive
– Low cost and easy to perform
– Detection of anamnestic IgG
(seroprevalence studies)
– Cross-reactivity allows to detect
unexpected viruses
– Allows to detect IgG and IgM
antibodies
– More specific than ELISA
– More sensitive and specific than
ELISA
– Allows to detect antibody response
to distinct viral antigens
– The most specific serological assay
– Rapid (test takes 15–30 min)
– Detects IgM and IgG antibodies in
patient sera
– Easy to perform
– Low cost
– Cross-reactivity does not allow fine
serotyping
– Low sensitivity
– Subjective visual analysis
– More laborious than ELISA
– More expensive and time consuming
than ELISA
– Laborious, time consuming and
expensive
– Requires at least BSL-3 conditions
– Cross-reactivity does not allow fine
serotyping
Improvement of antigens for
hantavirus-specific antibody detection
(broadly cross-reactive for screening;
specific antigens of new viruses for
directed antibody search)
Increasing use of the technique including
more than one fluorescent target
Improvement of this technique for
hantavirus-specific antibody detection
New approaches to
– facilitate fast and reliable reading of test
results
– avoid the use of viable viruses
Improvement of antigens to increase
sensitivity and specificity of antibody
detection

Molecular methods
Conventional RT-PCR – Fast, sensitive and specific technique
– Allows to diagnose hantavirus
infection in the viremic phase
– Allows to obtain nucleotide
sequences of the viral genome
Real time RT-PCR – Faster than conventional RT-PCR
– High sensitivity and specificity
– Lower risk of contamination than for
conventional RT-PCR
– Quantitative assay
Microarray – Fast, sensitive and specific
– Allows simultaneous detection of 10
to thousands of virus genes
Next-generation sequencing – “Open view” technique being useful
for virus discovery and total
sequencing
– Does not allow to diagnose
hantavirus infection after the viremic
phase
– More expensive than serologic
methods
– More expensive than conventional
RT-PCR
– Amplicons usually too short for
further sequence analyses
– Still too expensive and complex for
routine use
– Still too expensive and complex for
routine use
Useful for virus discovery (genus-reactive
assays) and evolutionary studies
Increase the specificity of the test using
multiple targets
Cost reduction
Simplification of data analysis
Reduction of costs
Improvements in virus enrichment
techniques and bioinformatics

Virological methods
Isolation in cell culture
Immunohistochemistry by
immunofluorescent test and
enzyme immunoassay
– Allows further virological and
functional studies
– Allows diagnosis on infected tissues
of organs (lungs, heart, etc.)
– Laborious and time-consuming
– Can only be performed by trained
personnel in BSL-3 laboratories
– Low success rate
– Mostly post-mortem use
– Requires laborious preparations
New cell cultures and techniques to
enhance efficiency of hantavirus isolation
Putative application in living patients by
new detection methods (?)

laborious, time-consuming and can only be performed by trained
personnel in biosafety level 3 laboratories [95].
Considering that HFRS and HCPS are rapidly progressive dis-
eases often confused with other severe diseases such as bacterial
sepsis and leptospirosis, it is important to have a highly specific
rapid diagnostic assays. Sensitive diagnostic tests have been devel-
oped based on detection of specific antibodies or the viral genome
(Table 2).
The specific diagnostics of hantavirus infections is usually
based on serological approaches, such as ELISA, immunoblot, or
immunofluorescence. In almost all cases, antibodies of IgM and IgG
classes can be detected at onset of clinical symptoms [44,55,94].
The IgM titers disappear after few months, however, in some cases
IgM was found as late as 2 years after the acute phase. Very rarely
the appearance of IgG might be delayed. An additional diagnostic
problem is the detection of unspecific (false positive) IgM, leading
to IgM-positive, IgG-negative constellations. In general, however,
the IgM ELISA is useful for diagnosis during the later clinical course
of hantavirus infections [52]. The immunoblot has also been used
for the serologic diagnosis of hantavirus infection. It is more sensi-
tive and specific compared with ELISA and has been used to confirm
the presence of antibodies when ELISA results are dubious [80]. In
Asia, Europe, and North America, immunochromatographic assays
as point-of-care tests have been developed [2,15,59,93].
Using the serological assays, the antibodies of the patient react
best with antigen from the respective virus, which was responsible
for the infection. However, in certain cases these tests do not allow
a typing of the patient’s serum [76]. The focus-reduction neutral-
ization test (FRNT) and its variants allow more specific annotation
of the infecting virus species. Neutralizing antibodies are directed
against the viral envelope proteins and are less cross-reactive than
the antibodies directed against the dominant nucleocapsid protein.
In this assay, different viable hantavirus strains/species are com-
pared by their neutralization with patient serum. This method is
time- and labor-consuming and requires a BSL-3 safety laboratory.
Moreover, the FRNT is unable to identify new viruses which are not
part of the virus collection investigated in the test (in this case the
virus type most related to the new virus would be neutralized best).

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At least some of the disadvantages of the FRNT can be overcome by
usage of recombinant vesicular stomatitis virus pseudotypes bear-
ing hantavirus envelope glycoproteins as shown by Ogino et al. [61].
The hantavirus genome can be rapidly detected by reverse
transcription-PCR, in clinical samples such as blood, saliva or
organ fragments, since the first day after onset of illness [64,74].
Some reported RT-PCR assays use primers selected for match-
ing high homology regions in the N protein of hantavirus [16].
Based on a conserved region of the L segment, a genus-wide “Pan-
Hanta-RT-PCR” has been developed which enables the detection of
established as well as novel hantaviruses and is broadly used for
screening purposes [36].
The real-time RT-PCR is a rapid and sensitive test that allows the
diagnosis of hantavirus infections and also can determine the virus
load in clinical samples [1,43,51,68,74]. However, despite being
commonly used, PCR has an important limitation: the test is only
positive if viremia is still present, meaning only in the acute phase
of illness. Furthermore, some human infections are often so short-
lived or lowly viremic (PUUV), that the virus often can be missed,
even with the most sensitive PCR techniques.
In summary, the combination of serologic tests, such as IgM/IgG
ELISAs, with the RT-PCR is highly sensitive and a desirable approach
for the laboratory diagnosis of hantavirus infection. For virus typ-
ing and identification of new viruses, characterization of viral
nucleotide sequences is the method of choice. Moreover, the molec-
ular phylogenetic analysis allows a “fine classification” of the
respective virus strain and an estimation of its relatedness with
known species.
The newfound shrew-, mole-, and bat-borne hantaviruses show
very high sequence diversity in comparison with rodent-borne
viruses. It seems that there is no serological cross-reactivity with
the ‘conventional’ hantaviruses widely used as antigens in diag-
nostic assays (e.g. HTNV, PUUV, SNV, ANDV), as it was shown for
Thottapalayam virus [11,77]. This fact most likely explains why
these viruses remained undetected for such a long period of time.
There are first reports suggesting that shrew-borne hantaviruses
might be pathogenic for humans [62,82]. It is one of the major
tasks for the next decade to implement antigens of these newly
identified hantaviruses into the routine serologic procedures and
to clarify whether these viruses infect humans and cause disease.
4. Treatment and prophylaxis
Treatment of disease is based on the clinical symptoms and
occasionally includes hemodialysis, oxygenization, and/or shock
therapy. There is no specific antiviral chemotherapy available. Riba-
virin is the only established antiviral drug with some in vitro and
in vivo-effects against hantavirus replication [81,60]. However, its
action is rather virus-nonspecific and its therapeutic use leads to
side effects, such as anemia. The efficacy of ribavirin therapy given
to HTNV-infected suckling mice showed higher survival rate in
the ribavirin-treated mice than the placebo control group [28].
There are controversial results about benefit on the basis of clin-
ical studies. A double-blind placebo-controlled trial with HFRS
patients in China showed a sevenfold reduction in morbidity in
the ribavirin-treated group as well as reduction in fatalities [29].
Using intravenous ribavirin for treating HFRS patients with infec-
tions acquired in Korea, the low rate of oliguria (3%) and the absence
of dialysis requirement in the treatment cohort (33 individuals) is
supportive of the idea that ribavirin given early results in decreased
severity of renal insufficiency [71]. On the other hand, trials in
patients suffering from HCPS yielded rather disappointing results
[10,56].
There are various other treatment options under investigation
as summarized by Refs. [57,33,45,75,60]. These approaches include
Please cite this article in press as: Kruger DH, et al. Hantaviruses—Globally emerging pathogens. J Clin Virol (2014),
http://dx.doi.org/10.1016/j.jcv.2014.08.033
defined synthetic substances, as nucleoside and pyrazine deriva-
tives as well as peptide derivatives mainly targeting the cellular
␣v ␤3 integrin receptor used for cell adsorption of (pathogenic)
hantaviruses. Other promising new ideas for the therapy of han-
tavirus disease include the use of a bradykinin receptor antagonist
(bradykinin is involved in vasodilatation and increased vascular
permeability) or passive immune therapy with human plasma
based on similar findings in the hamster model. The severe
capillary leakage syndrome presented by a patient infected by
PUUV was treated with icatibant, a bradykinin receptor antago-
nist, with a positive response [3]. Passive immune therapy with
human plasma of convalescent individuals with hantavirus infec-
tion could be used based on similar findings in the hamster model
[27].
Because of the supposed immunopathogenesis of hantavirus
disease, steroid-based anti-inflammatory treatment options seem
to be particularly promising and were described in single case
reports, most recently for a case of prolonged and non-resolving
renal failure [5]. However, one clinical trial [96] did not find a clear
benefit due to methylprednisolone treatment.
Up to now hantavirus chemotherapy and vaccine development
are hampered by the lack of adequate animal models of hantavirus-
associated disease. The Old World hantaviruses do not cause overt
disease in any animal species apart from nonhuman primates,
which have been shown to develop mild symptoms similar to HFRS
in humans after infection with PUUV [20,42,83]. For New World
hantaviruses, Syrian hamster has been established as disease model
[26,73,7].
Two post-exposure prophylaxis strategies using human poly-
clonal antibody, the first on the basis of fresh frozen plasma (FFP)
from a HCPS survivor and the second, using IgY/IgYDFc antibodies
purified from the eggs of DNA-vaccinated ducks, were both tested
in Syrian hamsters infected with ANDV [6].
The development of new vaccines is based on approaches
that use recombinant virus proteins, recombinant viruses, or DNA
vaccines [21,45,79]. “Classical” active immunization against han-
tavirus infections on the basis of inactivated virus preparations
is used in countries like China and Korea, however, there are no
licensed vaccines available in any other regions [78,102,23]. There-
fore, exposition prophylaxis is the most important approach to
prevent hantavirus infections. All these efforts focus on the preven-
tion of contacts between humans and potentially infectious small
mammals or their excreta [45,98].
5. Conclusions and outlook on the next decade (see also
Box 2)
In the next years, we expect an extended search for hantavirus
occurrence and epidemiology in geographical “terrae incognitae”
of all continents, including Africa and Australia. This includes the
quest to identify the presence of (new) hantaviruses in (new) hosts
and the clinical relevance of newly discovered hantaviruses. The
finding of new hantaviruses requires the development of respective
serodiagnostic tools to investigate their seroepidemiology and their
clinical relevance in infected patients. When the circulation of clin-
ically important new hantaviruses is verified, an awareness among
physicians and the public should be developed and the hantavirus-
associated clinical syndromes should be included in national and
regional surveillance systems.
There is an urgent need for the development of specific treat-
ment and vaccination options. Regarding the diversity of hantavirus
species it seems necessary to generate vaccines that induce a high
degree of cross-reactivity. This might become an even more urgent
problem in the case that shrew- and mole-borne hantaviruses turn
out to be significant human pathogens also.
G Model
JCV-3150; No. of Pages 9 ARTICLE IN PRESS
D.H. Kruger et al. / Journal of Clinical Virology xxx (2014) xxx–xxx
Box 2: Research perspectives for the next years
• To discover new Hantaviruses in different reservoir hosts and
to resolve their significance as human pathogens
• To discover antiviral and immunomodulatory drugs for treat-
ment of hantavirus infections
• To develop new immunogenic and safe hantavirus vaccines
• To understand the pathogenesis of hantavirus disease
• To study the importance of environmental changes and other
risk factors on hantavirus infections of humans
The further establishment of animal models should enable han-
tavirus pathogenesis studies and the development of vaccines and
therapeutics. This will help to dissect the role of host defense
components in protective immunity against hantaviruses after
infection/vaccination and to prove the concept of hantavirus-
induced immunopathogenesis.
It is conceivable that not every human individual infected with
a pathogenic hantavirus develops symptoms. Thus, it should be
investigated whether different qualities of virus-induced T-cell
responses are involved in the different outcomes of hantavirus
infection, i.e., hantavirus clearance without or with symptoms
(immunopathogenesis).
Finally, changes in the normal natural environment, including
factors such as deforestation, invasion of humans and virus reser-
voirs in new habitats, climate changes, can influence the risk of
hantavirus distribution and transmission in tropical zones must be
investigated.
Funding
Work from the laboratories of the authors was supported by
various research grants. Writing of this review paper was not sup-
ported by special funding.
Competing interests
None declared.
Ethical approval
None.
Acknowledgement
We thank Jan ter Meulen (Seattle, WA) for encouragement and
helpful suggestions, Ric Yanagihara (Honolulu, HI) for critical read-
ing, and Christina Grübel (Berlin) for her help in manuscript editing.
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Please cite this article in press as: Kruger DH, et al. Hantaviruses—Globally emerging pathogens. J Clin Virol (2014),
http://dx.doi.org/10.1016/j.jcv.2014.08.033