Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable – epidemiology,...

1

Introduction

Due to increased international traveling and adventurous tourism to regions with conditions that are conducive for transmitting diseases, imported infectious hemorrhagic fever has become a serious challenge for clinicians and laboratory research (Sung et al. 2001; Pavli and Maltezou 2008). Viral and bacterial pathogens that cause hemorrhagic fever have the potency to result in fulminant disease, accompanied by a high case fatality rate. A significant part of these hemorrhagic fevers originate from rodents as their reservoir host. For this reason the routes of disease transmission, epidemiological patterns and preventative measures overlap significantly. Although outbreaks of rodent-borne hemorrhagic fever and imported cases have been increasingly reported during the past decade, epidemiological and clinical studies are still scarce for several diseases (Colebunders et al. 2002; Bannister 2010). The clinical picture of the rodent-borne

hemorrhagic fevers, particularly in the early phase, is rather non-specific, leading to misdiagnosis and under-recognition. The efficacy of treatment strategies is mainly based on small groups of patients or case reports, rather than randomized controlled trails. This means that making treatment protocols is more anecdotal than evidence based. Vaccines are often unavailable or will not have been approved by the authorities. This review summarizes the epidemiology, diagnosis and treatment of hantaviruses, Leptospira, Lassa virus and New-World arenaviruses as the most significant rodent-borne hemorrhagic fevers. Knowledge of (local) epidemiology, clinical symptoms and adequate diagnostics will aid the clinician in correctly recognizing and diagnosing rodent-borne hemorrhagic fever in patients. Furthermore, adequate treatment and supportive care, preventative measures and new developments are discussed.

REVIEW

Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable – epidemiology, diagnostics and treatment

Marco Goeijenbier1, Jiri Wagenaar1,2,3, Marga Goris3, Byron Martina1, Heikki Henttonen4, Antti Vaheri5, Chantal Reusken6, Rudy Hartskeerl3, Albert Osterhaus1, and Eric Van Gorp1

1Erasmus MC, virology, dr Molenwaterplein 50, Rotterdam, 3015CJ Netherlands, 2Slotervaart hospital, internal medicine, Amsterdam, Netherlands, 3Royal Tropical Institute, biomedical research, Amsterdam, Netherlands, 4Metla, forest research institute, Helsinki, Finland, 5Haartman institute, Virology, Helsinki, Finland, and 6RIVM, Centre for Infectious Disease Control, Bilthoven, Netherlands

AbstractThis review presents an overview of the most important rodent-borne hemorrhagic fever pathogens directly transmitted from rodents to humans, namely Leptospira and hantaviruses, together with the New- and Old-World arenaviruses. These zoonotic diseases frequently share clinical symptoms, transmission routes and other epidemiological features and often have an emerging pattern. Differential diagnostics could benefit from a syndrome-based approach grouping these pathogens. In this review extensive descriptions of the epidemiology, clinical symptoms, diagnostics and treatment are provided including a practical overview, listing clinical features, diagnostics and risk factors for each selected rodent-borne hemorrhagic fever pathogen.Keywords: hantavirus, Lassa fever, Leptospirosis, rodent-borne diseases, south-american haemmorrhagic fever

Address for Correspondence: Marco Goeijenbier, Erasmus MC, virology, dr Molenwaterplein 50, Rotterdam, 3015CJ Netherlands. Email: [email protected]

(Received 07 December 2011; revised 16 April 2012; accepted 16 April 2012)

Critical Reviews in Microbiology, 2012; Early Online: 1–17© 2012 Informa Healthcare USA, Inc.ISSN 1040-841X print/ISSN 1549-7828 onlineDOI: 10.3109/1040841X.2012.686481

Critical Reviews in Microbiology

00

00

1

17

07December2011

16April2012

16April2012

1040-841X

1549-7828

© 2012 Informa Healthcare USA, Inc.

10.3109/1040841X.2012.686481

2012

Rodent-borne hemorrhagic fevers

M. Goeijenbier

Cri

tical

Rev

iew

s in

Mic

robi

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y E

rasm

us M

C o

n 06

/07/

12Fo

r pe

rson

al u

se o

nly.

2 M. Goeijenbier et al.


A summary of the clinical symptoms, laboratory abnomalities and diagnostics are provided in table 1 while the global spread of rodent-borne hemorrhagic fevers is visualized in figure 1.

Methods

Citations were retrieved from PubMed and MEDLINE databases and from locally accessible files of the KIT Royal Tropical Institute Library Amsterdam, the Netherlands. After thorough evaluation we chose the pathogens proven to cause hemorrhagic fever and being directly transmit-ted from rodents to humans (not needing a vector). Databases were searched using the search terms “hanta-virus”, “Leptospirosis”, “Lassa Fever”, “South-American Hemorrhagic Fever (SAHF)”, in combination with “clini-cal symptoms”, “treatment” and “epidemiology”. Titles, abstracts and references were scanned for relevance and implication for clinical settings using the following crite-ria: “epidemiology, clinical symptoms, diagnosis and/or treatment of rodent-borne hemorrhagic fever pathogens”.

HantavirusesHantaviruses are distributed worldwide. The pathogens of the genus were first reported in Asia and soon afterwards in Europe even though the clinical disease had been recognized already 1930s. Subsequently the disease was recognized in the Americas, and seems to be under-recognized in Africa (Jonsson et al. 2010). Two known syndromes are caused by hantaviruses: hemorrhagic fever with renal syndrome (HFRS), with the milder subtype nephropathia epidemica (NE) and the hantavirus cardiopulmonary syndrome (HCPS). HFRS is endemic in large parts of Eastern and Northern Europe and Asia, while small clustered outbreaks of HCPS have been reported in North and South America (Khan and Khan 2003; Maes et al. 2004). NE is prevalent in Europe and transcontinental countries like Russia (Jonsson et al. 2010). While we describe the generally accepted sepa-rated hantavirus syndromes recent publications give rise to the thought that some of the typical symptoms defining HFRS and HPS can actually be caused by both Old- and New- World hantaviruses (Clement et al. 2012).

Transmission and hostHantaviruses are spread from infected rodents to humans (Tsai 1987). Transmission occurs through the inhalation

of aerosols of virus-contaminated feces or urine. Infection through rodent bites via infectious saliva or tissue handling in laboratory settings has also been reported, but is rare (Tsai 1987, Hart and Bennett 1999; Schultze et al. 2002). There are at least 54 hantaviruses of which no less than 22 are known to cause disease in humans (Bi et al. 2008). For some serotypes there is a debate about their pathogenicity in humans like the Tula virus. Each hantavirus seems to be strictly related to one host species, or to closely related host species, like the striped field mouse (Apodemus agrarius) for Hantaan virus that causes HFRS in Asia, the bank vole (Myodes glareolus) for the Puumala virus (PUUV) that causes mild HFRS/NE in Europe and the deer mouse (Peromyscus maniculatus) for the New World Sin Nombre virus, which is one of the causative agents of HCPS (Lee et al. 1982; Tsai 1987a; Stone 1993; Diglisic et al. 1994). It is not uncommon to find spill-over infections, either sero- or RNA-positivity, in secondary species (Plyusnina et al. 2008, Schlegel et al. 2009). In addition to rodents, insectivores, i.e. shrews and moles, are a large group of natural reservoir hosts for hantaviruses (Olsson et al. 2010). Also two different hantaviruses have been recently isolated in Africa from bats. However, transmission from insectivores or bats to humans has not yet been proven (Weiss et al. 2012). Humans are a dead-end host and do not seem to shed the virus. However, human-to-human transmission has been reported in some hantavirus cases of Andes virus infection, and Andes virus antigen has been detected in both the secretory cells of the salivary glands as in urine from patients with HCPS (Martinez et al. 2005; Godoy et al. 2009). Also PUUV RNA has been isolated from the saliva of HFRS patients raising the question if interhuman transmission may occur (Pettersson et al. 2008). Andes virus seems to have a lower sensitivity to the antiviral effect of human saliva compared to other hantaviruses (Hardestam et al. 2009). Case reports of hantavirus infections during pregnancy did not include vertical transmission (Howard et al. 1999). The distribution and incidence of hantavirus infections in humans depends on the availability and the density of the rodent-host. Incidence of PUUV caused NE is highest in Fennoscandia but in recent years outbreaks have occurred in Western and Central-Europe, in addition to the Balkan area. While in Russia PUUV infections are highly endemic in certain regions close to the Volga River. Next to PUUV

AbbreviationsHFRS, hemorrhagic fever with renal syndromeNE, nephropathia epidemicaHCPS, hantavirus cardiopulmonary syndromePUUV, Puumala virusCFR, case fatality rateVCAM-1, vascular cell adhesion moleculeCT-scan, computer tomografie scanELISA, enzyme-linked immunosorbent assaysIFAT, indirect fluorescent antibody testFRNT, focus reduction neutralization test

RRNT, replication reduction neutralization test(RT)-PCR, (reverse transcription) polymerase chain reactionFFP, fresh frozen plasmaAptt, activated partial thromboplastin timeDIC, disseminated intravascular coagulationMAT, Microscopic agglutination testAPD, adenosine diphosphatePEP, post exposure prophylaxisTAT, thrombin-antithrombin complexesICAM-1, intracellular adhesion moleculeNP, nucleocapsidSAHF, South-American hemorrhagic fever

Cri

tical

Rev

iew

s in

Mic

robi

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

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y E

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Rodent-borne hemorrhagic fevers 3


Tab

le 1

. Su

mm

ary

of c

linic

al p

ictu

re, g

lob

al s

pre

ad, d

iagn

osis

for

rod

ent-

bor

ne

hem

orrh

agic

feve

r.

Rod

ent-

bor

ne

hem

orrh

agic

feve

rs

Path

ogen

Dis

ease

Sym

pto

ms

Lab

orat

ory

Dia

gnos

tics

Ref

Han

tavi

rus

Dis

trib

ute

d o

ver

mos

t of

Eu

rop

e in

cub

atio

n p

erio

d 2

–6 w

eeks

Nep

hro

pat

hia

ep

idem

ica

(NE

)Fe

ver,

nau

sea,

hea

dac

he,

bac

kach

e,

abd

omin

al p

ain

, acu

te r

enal

failu

re,

blu

rred

vis

ion

, flan

k p

ain

C

FR <

1 %

Hem

osta

sis:

thro

mb

ocyt

open

ia,

incr

ease

in D

-Dim

er, v

Wf a

ctiv

ity,

A

PT

T a

nd

pro

thro

mb

in fr

agm

ents

in

crea

sed

thro

mb

in g

ener

atio

n

Sero

logy

by

ELI

SA o

r IF

AT

(N

ote

late

SC

in

PU

UV

) P

CR

<

7 d

ays

Low

vire

mia

FR

NT

Bra

un

et a

l. 20

01;

Grc

evsk

a et

al.

1990

; K

aner

va e

t al.

1996

; La

hd

evir

ta 1

982;

M

ust

onen

et a

l. 19

94a;

Set

terg

ren

19

91

Pu

um

ala

viru

s R

eser

voir

: Myo

des

glar

eolu

sG

ener

al: l

euco

cyto

sis,

dec

reas

ed G

FR,

hyp

onat

rem

ia, h

yper

mag

nes

ium

ia

hyp

okal

emia

, hyp

ocal

cem

ia,

hyp

erp

hos

ph

atem

ia lo

w H

DL-

chol

este

rol h

igh

trig

lyce

rid

e le

vels

U

rin

e: p

rote

inu

ria

and

hem

atu

ria

Old

-wor

ld h

anta

viru

ses:

Eu

rop

e an

d A

sia

sero

logi

cal e

vid

ence

in

Wes

t-A

fric

a in

cub

atio

n p

erio

d 1

–6 w

eeks

Hem

orrh

agic

Fev

er R

enal

Sy

nd

rom

e (H

FRS)

Dob

rava

, Seo

ul

and

Han

taan

mos

t im

por

tan

t ca

usa

tive

age

nts

As

in N

E w

ith

mor

e se

vere

hem

or-

rhag

ic m

anif

esta

tion

s ac

ute

gla

uco

ma

Gen

eral

: As

in N

E E

leva

ted

CSF

p

rote

inE

LISA

IF

AT

P

CR

FR

NT

Cvo

risc

ec e

t al.

1986

; K

lem

pa

et a

l. 20

10;

Elis

af e

t al.

1993

; G

rcev

ska

et a

l. 19

90;

Lee

et a

l. 19

83;

Man

asia

et a

l. 19

77;

Pal e

t al.

2005

Hem

osta

sis:

DIG

, in

crea

sed

ble

edin

g ti

me,

dec

reas

ed c

lott

ing

fact

ors

Res

ervo

ir: A

pod

ern

us

sp. R

attu

s sp

. O

ld-w

orld

rod

ents

CFR

10–

15%

Uri

ne:

hem

atu

ria,

hig

h c

once

ntr

atio

n

of T

amm

Hor

sfal

l pro

tein

New

-wor

ld h

anta

viru

ses

clu

s-te

red

ou

tbre

aks

in N

orth

an

d

Sou

th A

mer

ica

Incu

bat

ion

per

iod

9–3

3 d

ays

(med

ian

14–

17)

Han

tavi

rus

Car

dio

pu

lmon

ary

Syn

dro

me

(HC

PS)

Mos

t im

por

tan

t ca

usa

tive

ag

ents

Sin

Nom

bre

an

d A

nd

es

viru

s

Feve

r, m

yalg

ia a

nd

resp

irat

ory

sym

p-to

ms

with

an

acu

te s

witc

h to

resp

ira-

tory

dis

tres

s w

ith p

ulm

onar

y ed

ema

and

pleu

ral e

ffus

ion

with

in 4

8 h

aft

er

infe

ctio

n

Gen

eral

: Lef

t-sh

ifte

d n

eutr

oph

ilic

leu

-ko

cyto

sis,

Lac

tic

acid

osis

, low

ser

um

b

icar

bon

ate,

incr

ease

d h

emat

ocri

t E

leva

ted

asp

arta

te a

min

otra

nsf

eras

e an

d la

ctat

e d

ehyd

roge

nas

e

ELI

SA

IFA

T

PC

R

Farr

199

4,

Jen

ison

et a

l. 19

95;

Moo

len

aar

et a

l. 19

95;

Nol

te e

t al.

1995

; R

iver

s et

al.

2009

; V

erit

y et

al.

2000

Res

ervo

ir: S

igm

odon

tin

ae;

Neo

tom

inae

, th

e n

ew-w

orld

CFR

up

to 5

0%H

emos

tasi

s: th

rom

boc

ytop

enia

Lep

tosp

iros

isW

orld

wid

e d

istr

ibu

tion

. E

nd

emic

in tr

opic

al a

nd

ru

ral

area

s in

cub

atio

n p

erio

d 7

–4 d

ays

An

icte

ric

lep

tosp

iros

is (

Non

sev

ere

dis

ease

)Fe

bri

le il

lnes

s of

su

dd

en o

nse

t. Fe

ver

may

last

for

a w

eek

in th

is b

acte

rae-

mia

sta

te.F

ever

may

ret

urn

aft

er a

re

mis

sion

of 3

–4 d

ays,

hea

dac

he

wit

h

retr

o-or

bit

al p

ain

an

d p

hot

oph

obia

, se

vere

mya

lgia

(m

ain

ly in

the

calf

and

lu

mb

ar a

rea)

, con

jun

ctiv

al s

uff

u-

sion

, an

orex

ia, n

ause

a, v

omit

ing,

an

d

pro

stra

tion

Gen

eral

: Leu

cocy

top

enia

incr

ease

d

liver

tran

sam

inas

es. D

ecre

ased

GFR

Rap

id te

st C

onfi

rmed

by

MA

T O

R P

CR

E

LISA

Bru

ce e

t al.

2005

; K

ate

et a

l. 20

02;

Ko

et a

l 199

9

Res

ervo

ir: m

any;

rod

ents

as

wel

l as

dog

s an

d c

attl

e

Fulm

inan

t dis

ease

Seve

re r

enal

failu

re s

ign

s of

sep

tic

shoc

k (p

ulm

onar

y) h

emor

rhag

e C

FR 5

% u

p to

60%

in L

PH

S

Gen

eral

: dec

reas

ed G

FR, i

ncr

ease

d

CR

P, P

roca

lcit

onin

Lev

ett 2

001;

L

evet

t et a

l. 20

05;

Lin

et a

l. 20

08;

Bh

arti

et a

l. 20

03;

Gou

veia

et a

l. 20

08H

emos

tasi

s: th

rom

boc

ytop

enia

, DIC

, in

crea

sed

fib

rin

ogen

an

d p

rolo

nge

d

pro

thro

mb

in ti

me

(Con

tin

ued

)

Cri

tical

Rev

iew

s in

Mic

robi

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y E

rasm

us M

C o

n 06

/07/

12Fo

r pe

rson

al u

se o

nly.



Icte

ric

lep

tosp

iros

is (W

eil’s

dis

ease

) C

an d

evel

op fr

om a

nic

teri

c le

pto

-sp

iros

is o

r as

a p

rogr

essi

ve il

lnes

s

Cla

ssic

tria

d o

f Jau

nd

ice,

non

-olig

uri

c re

nal

failu

re, a

nd

hem

orrh

age

CFR

5–1

5%

Gen

eral

: dec

reas

ed G

FR, i

ncr

ease

d

CR

P, P

roca

lcit

onin

, Sep

tic

chol

esta

sis

and

incr

ease

d li

ver

tran

sam

inas

es

Bro

om a

nd

Alli

ston

19

48;

Sim

oes

et a

l. 19

69;

Wag

enaa

r et

al.

2007

; Se

nio

r 20

10H

emos

tasi

s: th

rom

boc

ytop

enia

, DIC

, in

crea

sed

AP

TT,

PT

an

d D

-Dim

erLa

ssa

feve

r

Spre

ads

in: W

est A

fric

aE

arly

ph

ase

(Sta

ge 1

) R

eser

voir

: Mas

tom

ys n

atal

ensi

sH

ead

ach

e, fe

ver,

nau

sea,

mu

scu

lar

p

ain

s C

FR 1

%

Hem

osta

sis:

Mod

erat

e th

rom

boc

ytop

e-n

ia. P

late

let d

ysfu

nct

ion

in r

esp

onse

to

AD

P a

nd

col

lage

n

ELI

SA

IFA

T

PC

R (

lon

g vi

rem

ia)

viru

s cu

ltu

re

Ed

ingt

on e

t al.

1972

; Fr

ame

et a

l. 19

70;

Mer

ten

s et

al.

1973

; M

onat

h e

t al.

1975

; W

ood

ruff

et a

l. 19

73E

nd

emic

are

as

Gu

inea

, Sie

rra

Leo

ne,

Nig

eria

,

Lib

eria

an

d Iv

ory

coas

t.

Rep

orts

from

Gh

ana,

Sen

egal

, To

go, B

enin

, Mal

i an

d

Bu

rkin

a Fa

so

Acu

te p

has

e (S

tage

2)

Vom

itin

g, w

ater

y d

iarr

hea

, hae

-m

opty

sis,

hig

h b

leed

ing

ten

den

cy,

ph

aryn

giti

s, p

leu

rati

c p

ain

, hep

atic

p

ain

, flan

k/lo

wer

bac

k p

ain

, alo

pec

ia,

dea

fnes

s C

FR 1

5–20

%

Gen

eral

: Leu

cocy

tosi

s T

ypic

al: I

ncr

ease

am

inot

ran

sfer

ase

(AST

>1

50)

Sero

logy

P

CR

Idem

yor

2010

; O

gbu

et a

l. 20

07;

Bau

sch

et a

l. 20

10

Incu

bat

ion

per

iod

3–1

7 d

ays

Seve

re fo

rm (

Stag

e 3)

30–

50%

of

hos

pit

aliz

ed c

ases

dev

elop

the

seve

re fo

rm o

f Las

sa fe

ver

Per

sist

ent h

igh

feve

r, d

iffu

se c

apill

ary

leak

age,

sev

ere

hem

orrh

age,

nep

hri

-ti

s, k

idn

ey fa

ilure

, hep

atit

is, a

sep

tic

men

ingi

tis,

en

cep

hal

itis

resp

irat

ory

dis

tres

s, p

eric

ard

itis

an

d s

hoc

k.

CFR

36–

52%

Typ

ical

: Hig

h v

irae

mia

Sero

logy

P

CR

Mon

ath

et a

l. 19

75;

Cu

mm

ins

1990

; M

ach

er a

nd

Wol

fe

2006

;Id

emyo

r et

al.

2010

Sou

th A

mer

ican

Hae

rnor

rhag

ic F

ever

(SA

HF

)

Incu

bat

ion

per

iod

7–1

4 d

ays

Arg

enti

nea

n h

emor

rhag

ic fe

ver

Jun

in v

iru

s re

stri

cted

to li

mit

ed a

rea

wit

hin

Pam

pas

reg

ion

Cal

omys

sp.

eff

ecti

ve v

acci

ne

avai

lble

Pet

ech

iae

in th

e ax

illa,

sof

t pal

ate,

an

d g

ingi

val m

argi

n. N

euro

logi

cal

sign

s in

clu

din

g ir

rita

bili

ty, l

eth

argy

an

d h

ypor

eflex

ia

Gen

eral

: Leu

cocy

top

enia

Hem

osta

sis:

Th

rom

boc

ytop

enia

Incr

ease

d D

-Dim

er,

TAT,

F1

+F2

Fou

rfol

d in

crea

se in

an

tib

ody

tite

r P

CR

Mol

inas

et a

l. 19

89;

En

ria

et a

l. 20

00;

Ku

nz

2009

Ven

ezu

elan

hem

orrh

agic

feve

r G

uan

arit

o vi

rus

cen

tral

Ven

ezu

la

Zyg

odon

tom

ys b

revi

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the other pathogenic hantaviruses circulating in Europe are: “Dobrava-Belgrade (with the subtypes Dobrava-Ap, Dobrava Af and the milder variant Dobrava-Aa) and Seoul”. Dobrava-Belgrade is transmitted by the yellow-necked mouse (Apodemus flavicollis), infections are reported from South-East Europe with incidence being highest in “Croatia, Slovenia, European Russia, Bosnia-Herzegovina and Hungary” while Dobrava-Aa is more restricted to the North-Eastern parts of Europe like the Baltic States and Russia (Olsson et al. 2010). Saaremaa virus SAAV is found in A. agrarius on the Estonian island Saaremaa, but SAAV RNA has not been found in human cases (Vapalahti et al. 2003). Seoul virus infections in humans appear very rare in Europe apart from laboratory acquired infections. However there are reports describing detection of Seoul virus antibodies in Rattus rattus and Rattus norvegius from Belgium, Portugal and France (Heyman et al. 2004; Heyman et al. 2009). Hantavirus studies from Africa are limited, however there is evidence for hantavirus circulation in West Africa (Guinea, Cote D’Ivoire). Hantaviruses detected in Africa seem to be closely related to other Murinae, Old-world mice and rat, associated hantaviruses (Klempa et al. 2012). Risk factors for hantavirus infection are related to the exposure to rodents and the size of the rodent population (Brummer-Korvenkontio et al. 1982; Howard et al. 1999;

Song 1999; Cantoni et al. 2001; Olsson et al. 2003; Kallio et al. 2009). Presence of rodents or their excreta in and around a home significantly increases this risk (Rivers et al. 2009). In addition using rodent traps, visiting forestry areas and participating in rural/recreational activities increase the risk of infection (Van Loock et al. 1999; Pini 2004; Linard et al. 2007; Winter et al. 2009; Vapalahti et al. 2010). Other risk factors include the handling of firewood, living close to a forest (<50 m), staying in a house which is easy accessible for rodents or re-entering and cleaning a holiday house/cottage after the winter (Van et al. 1999; Pini 2004). For both the New- and Old-world hantaviruses environmental and occupational factors play a role (Van et al. 1999; Armstrong et al. 1995; Pini 2004; Abu et al. 2007; Vapalahti et al. 2010). Besides the risk associated with occupational exposure, particularly in the military, farming industry, and for forest workers and mammalogists/veterinarians, occasional specific outbreaks have been reported in people working with rodents in a laboratory setting (Vapalahti et al. 1995; Clement et al. 1997; Vapalahti et al. 1999). Studies in Europe have shown a correlation between smoking and hantavirus infection, possibly due to impaired ciliary activity in the respiratory tract facilitating hantavirus infection (Van Loock et al. 1999; Vapalahti et al. 2010; Clement et al. 2011). The prevention of rodent infestation and rodent control

Figure 1. Global distribution of the rodent-borne hemorrhagic fever pathogens. Knowledge of the global distribution is important for clinicians. For instance travelers returning from South America may be infected with the SAHF viruses, HCPS viruses and Leptospira, whereas Lassa fever or NE would be considered highly unlikely. Leptospirosis, not added in this figure, occurs on every continent, with higher incidence in (sub)tropical areas.

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seem to be the best way to reduce infection risk (Morse 1994; Clement et al. 1997).

Clinical picture and diagnosisHemorrhagic fever with renal syndromeHFRS is recognizable by the triad of fever, renal failure and hemorrhage. The disease can be divided into five phases: febrile, hypotensive, oliguric, diuretic, and con-valescent. HFRS patients first develop a flu-like syndrome accompanied with atypical complaints like fever, myal-gia, headache and flank pain. The hypotensive phase is thought to be the result of haemodynamic alterations, due to an impaired vascular tone and increased vascu-lar permeability associated with pathological findings of pulmonary edema and retroperitoneal edema (Lukes 1954). Renal failure in HFRS often develops in a late acute stage (Grcevska et al. 1990; Cosgriff 1991). Kidney biopsies show a damaged medulla, interstitial edema and hemorrhage, together with cytotoxic T cell infiltrates and the extravasation of erythrocytes (Ferluga and Vizjak 2008). An elevated, left-shifted, serum leukocyte count and elevated C-reactive protein (CRP) up to a high level such as in bacterial infection, are present. Patients with HFRS may develop serious hemorrhagic complications, starting with petechiae, epistaxis and mucosal bleedings and in a later phase gastrointestinal bleedings, hematuria and pleural bleedings. More rare hemorrhagic events are right atrial hemorrhage (Chun and Godfrey 1984), spleen hemorrhage (Alexeyev et al. 1994) or pituitary hemor-rhage with endocrinal disturbance or even panhypopi-tuitarism (Suh et al. 1995; Pekic et al. 2005). Coagulation disorders range from mild thrombocytopenia to diffuse intravascular coagulation (DIC) (Laine et al. 2010). An in-depth Korean study among HFRS patients showed the prolongation of bleeding time, prothrombin time and partial thromboplastin time, together with decreased plasma activity of factor II, V, VIII, IX, X (Lee 1987).

Depending on the hantavirus species case fatality rate (CFR) in HFRS vary from 0.1 to 15% in hospitalized cases, where patients die due to circulatory and/or renal failure (Tsai 1987a). Asymptomatic cases occur around five to ten times more frequently than symptomatic cases in HFRS (Bi et al. 2008). However, this depends on the type of hantavirus and on human factors. Dobrava-Belgrade subtype Af is known to be the most pathogenic of the Old-World hantaviruses, whereas Puumala causes NE, a milder form of HFRS with CFR of 0.1%. Due to a long incubation time, typically 2–6 weeks, infections con-tracted in areas endemic for a particular hantavirus may obscure differential diagnosis elsewhere.

Nephropathia epidemicaNephropathia epidemica is considered to be a mild form of HFRS caused by PUUV with a CFR below 1% and hemorrhagic manifestations in only about 10% of the symptomatic patients. Up to 80% of the infections with PUUV remain asymptomatic. Patients who do develop the disease usually present with fever and

acute renal failure. Accompanying symptoms are abdominal pain, nausea, blurred vision, flank pain and headache. Most patients with NE recover from the acute renal failure within 6 months. Follow-up studies have proven an increased hypertension risk >10 years post infection (Mustonen et al. 1994a; Settergren 1991; Settergren 2000; Braun et al. 2001; Miettinen et al. 2006). Respiratory complaints can also arise during NE (Kanerva et al. 1996). A lung biopsy will show a local immune response with elevated expression of VCAM-1 (Rasmuson et al. 2011a). Clinical chemistry may show high serum creatinine and urea, hematuria and proteinuria in the acute phase. More than half of the patients presenting with NE show cardiac involvement. This varies from abnormalities on the electrocardiogram (t-top inversion) to, in rare cases, pericardial effusion (Lähdevirta 1982; Mäkela et al. 2009). In severe cases NE patients may develop encephalitis (Hindfelt 1989) or more hemorrhages like petechiae, hematuria or epistaxis (Bahr et al. 2006). Patients infected with PUUV showed coagulation activation, marked by an almost 24-fold D-dimer increase (Laine et al. 2010). Disease severity was reported to correlate with plasma IL-6 levels instead of CRP (Outinen et al. 2010). Procalcitonin is also elevated in PUUV infections. The broad range in serum procalcitonin in PUUV makes it unsuitable to distinguish from bacterial infection. However, there is a correlation between procalcitonin and the severity NE (Jereb et al. 2011). The symptoms in children do not differ greatly from adults with HFRS/NE (Peco-Antic et al. 1992). However, NE does seem to take a less severe course in children (Mustonen et al. 1994b).

Hanta cardiopulmonary syndromeHCPS-causing hantaviruses mainly target the lungs (Farr 1994; Jenison et al. 1995; Jonsson et al. 2010). HCPS begins with signs of fever, myalgia and respira-tory symptoms, followed by the acute onset of severe respiratory distress (Gasparetto et al. 2007; Goncalves et al. 2010). Clinical characteristics are not specific and are therefore not useful when differentiating between HCPS and other diseases. However, the combina-tion of dizziness, nausea and the absence of a cough with a low platelet count, low serum bicarbonate and elevated hematocrit can be typical of a HCPS case (Moolenaar et al. 1995). Besides respiratory distress, patients with HCPS show a decreased cardiac output and dysrhythmias (Jenison et al. 1995). HCPS is char-acterized by edema due to endothelial dysfunction instead of severe hemorrhage. Patients could develop thrombocytopenia and bleeding complications, but respiratory distress due to edema is the main cause of death. CT images may show thickening of interlobular septa, ground-glass opacities, and occasionally small ill-defined nodular opacities (Gasparetto et al. 2007; Goncalves et al. 2010). The acute onset of the respira-tory distress leads to hypoxia, cardiac insufficiency,

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high intubation rates and a need for inotropics (Verity et al. 2000; Rivers et al. 2009). Case fatality rates vary from 30 to 60% in hospitalized cases (Khan et al. 1996; Verity et al. 2000; Rivers et al. 2009; Jonsson et al. 2010). However, recent studies have shown that extracorporeal membrane oxygenation (ECMO) seems to drastically decrease mortality rates in HCPS (Dietl et al. 2008). Histopathological examination of the lungs shows interstitial and alveolar edema, sporadic alveolar hemorrhage, and mild interstitial pneumonia (Ferreira et al. 2000). The clinical picture in children does not seem to differ from that in adults with hantavirus cardiopulmonary syndrome (Ramos et al. 2001).

Hantavirus diseaseRecent papers debate the absolute difference between HFRS and HCPS hantavirus syndromes. Sometimes symptoms overlap and HFRS cases presented with acute respiratory failure without signs of kidney involvement and the other way around in HCPS patients (Rasmuson et al. 2011b; Clement et al. 2012). Therefore they sug-gest to use the term “hantavirus disease” for all hanta-virus related described syndromes.

Diagnostics

Since almost all acute cases have IgM and IgG antibod-ies against the nucleocapsid protein of hantaviruses, serological diagnostics are most commonly used for verifying hantavirus infection using indirect IgG and IgM enzyme-linked immunosorbent assays (ELISA), IgM capture ELISAs or immunofluorescence assays (IFA) (Jenison et al. 1995; Linderholm and Elgh 2001; Jonsson et al. 2010). A high level of cross reactivity exists in hantavirus serology. Cross reactivity occurs within the group of Serotype 1 “Dobrava-Belgrade virus, Saaremaa virus, Seoul virus and Hantaan virus” and within the Serotype 2 group “Puumala virus, Tula virus, Topografov virus and Sin-Nombre-like viruses” (Vapalahti et al. 2003). Because of this high level of cross reactivity, a focus reduction neutralization test (FRNT) remains the gold-standard in hantavirus serology. However, specific neutralizing antibodies are not yet produced in the acute phase of infection. More recently, a replication reduction neutralization test (RRNT), which is based on a quantitative RT-PCR technique, showed promising results in efficiently and rapidly detecting hantavirus-neutralizing anti-bodies (Maes et al. 2009b). PCR can be performed on blood and serum samples during the first days after the onset of the symptoms. One-step RT-PCR assays for hantavirus detection showed high sensitivity and specificity (Aitichou et al. 2005; Bi et al. 2008). However, the molecular diagnosis of acute infec-tions can be difficult, since the viraemic stage is often limited to the incubation period prior to the onset of

the symptoms and shortly afterwards (Bi et al. 2008; Vaheri et al. 2008). Rapid immunochromatographic IgM-antibody diagnostic tests have been evaluated in different studies. Hujakka et al. found a 96-100% sensitivity and specificity for the specific immunoas-says developed for Dobrava, Puumala and Hantaan hantaviruses. Combined rapid tests are less sensitive (Hujakka et al. 2003).

TreatmentIn HFRS the initiation of prompt and proper supportive treatment is crucial. This support comprises measures such as monitoring fluid balance, diuresis, kidney function and the use of FFP/transfusions in the treatment of hemorrhagic complications (Escutenaire and Pastoret 2000; Hjertqvist et al. 2010). Ribavirin treatment can be useful in the very early phase of HFRS by reducing the risk of hemorrhagic events and the severity of renal insufficiency (Huggins et al. 1991; Yang et al. 1991; Bi et al. 2008; Rusnak et al. 2009). Treatment with interferon only inhibits the virus in vitro, while adjunctive prednisolone treatment showed no beneficial outcome (Gui et al. 1987; Qian et al. 1990). An open label trial and a double-blind clinical trial only showed the adverse effects of the ribavirin treatment in HCPS, but no beneficial effects (Chapman et al. 1999; Mertz et al. 2004). For the time being, the treatment of HCPS will mainly depend on critical care management which includes the avoidance of fluid overload, vasopressors to maintain cardiac output, and the use of extracorporeal membrane oxygenation in severe cases (Mertz et al. 2004; Mertz et al. 2006; Bi et al. 2008). Trials in Asia have shown a promising reduction of HFRS, with conventional vaccines, but these have not been approved by the responsible western authorities (Maes et al. 2009a; Schmaljohn 2009). Problems for developing a European vaccine arise from the different circulating serovars (Maes et al. 2009a; Schmaljohn 2009). No vaccine for HCPS has been tested in humans so far. It is believed that individuals experiencing a hantavirus infection, acute or without knowing it, develop lifelong immunity (Maes et al. 2009a; Schmaljohn 2009).

LeptospirosisLeptospirosis has been recognized as an emerging infectious disease with severe repercussions all over the world. Large outbreaks are closely related to heavy rainfall and flooding. The global incidence of endemic leptospirosis has been estimated at 5 per 100,000 head of population and that of epidemic leptospirosis at 14 per 100,000 (Report of the Second Meeting of the Leptospirosis Burden Epidemiology Reference Group, World Health organization, 2011, Geneva). Incidence rates are the highest in tropical areas such as southern Asia and South America (Bharti et al. 2003; Pappas et al. 2008). The disease has also emerged as an illness that impacts adventure tourists, especially those who par-ticipate in water sports. Incidence rates may vary due to

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the difficult diagnosis of leptospirosis and unfamiliarity, and the fact that incidence rates can vary significantly per year (Bharti et al. 2003; Pavli and Maltezou 2008).

Transmission and hostPathogenic Leptospira enter the environment through the shedding of bacteria via the urine of chronically infected hosts (Kariv et al. 2001; Levett 2001). Two different trans-mission routes are described: (i) indirectly, through con-tact with infected water or soil, which is probably the main route for most serovars, and (ii) directly, through contact with infected animal urine or tissues (Hansman et al. 1966; Ratnam et al. 1983). These transmission routes are visualized in Figure 2. Different hosts can carry Leptospira serovars (Everard et al. 1995; Barwick et al. 1998). Rodents and insectivores, particularly rats, are thought to be the

major carrier-animals, but dogs, pigs, cattle and horses are also considered to be reservoirs. Infected rodents stay asymptomatic and are thought to chronically shed Leptospira (Levett 2001). Infection through abraded skin in humans seems to be the most common portal of entry (Broom and Alston 1948; Sasaki et al. 1993; Morgan et al. 2002). However, infection can also occur after contact with exposed mucous membranes of the nose, mouth and eyes (Sasaki et al. 1993; Haake et al. 2002). The presence of Leptospira in mesenteric lymph nodes in autopsy studies is suggestive for an oral transmission route for leptospi-rosis (Morgan et al. 2002). Infections with Leptospira are reported from all over the world. The infection risk most frequently correlates with rainfall, flooding, soil satura-tion and stagnant water pools on walking paths (Simoes et al. 1969; Ko et al. 1999; Barcellos and Sabroza 2001; Levett 2001). Walking barefoot or living close to a sewer or trash belt also increases the risk of infection. Moreover, the incidence in many regions is at its highest during the rainy season. Outbreaks are seen after natural disasters like flooding and hurricanes (Gaynor et al. 2007). Rural and jungle areas in particular seem to provide the envi-ronmental conditions that are the most conducive for the survival and transmission of leptospires. However, urban leptospirosis occurs in areas with high rodent densities like city slums (Vinetz et al. 1996; Wuthiekanun et al. 2007). The incidence is the highest in resource lim-ited settings in Asia, South America and probably Africa however data is limited. In Europe the highest incidence rates are reported from European part of Russia, Croatia and Ukraine (Pappas et al. 2008). Studies show a higher infection incidence in men, and this is the highest in men of working age (20–60 years old). This observation is prob-ably due to occupational risk factors (De Gues et al. 1977; Van et al. 1998). During the past decades, recreational exposure is a factor of growing importance (Thornley et al. 2002). Recreational activities related to leptospirosis infection include water-related activities such as canoe-ing, rafting and swimming (CDC report, 1996; Narita et al. 2005; Yanagihara et al. 2007; Monahan et al. 2009). Indeed, outbreaks after sports events, mainly sports which includes water contact like triathlon or rafting, have been reported (Plank and Dean 2000; Morgan et al. 2002). There are reports of adventure tourists who were infected after jungle tracking or cave exploring, or a specific occurrence of wading through small streams in a mangrove forest in Malaysia (Wagenaar et al. 2004a; Guron et al. 2006).

Clinical picture and diagnosisThe presentation of patients with acute leptospirosis can vary greatly (Levett 2001; Wagenaar et al. 2007). Infections often remain asymptomatic or patients will develop a mild disease. Acute leptospirosis usually presents with one or more of the following symptoms: a fever of sudden onset, chills, headache, severe myalgia, conjunctival suffusion, anorexia, nausea, vomiting, and prostration (Bharti et al. 2003). Severe disease is rapidly progressive with a high case fatality rate. The

Figure 2. Routes of transmission in rodent borne hemorrhagic fever. Transmission of Rodent Borne hemorrhagic fever causing pathogens can occur directly via aerosol inhalation (hanta, Lassa, SAHF) or contact with skin and mucosa (leptospirosis). Furthermore indirect transmission is possible by non-rodent animals (often in leptospirosis). Birds do not seem to play a role in transmission routes of leptospirosis. Hantaviruses and the new- and old-world arenaviruses were thought to be restricted to rodent reservoir hosts. However, hantaviruses have also recently been isolated from insectivores and African bats, although transmission to human has not been proven yet (Weiss et al. 2012). Other HF causing pathogens can circulate in rodents and be transmitted via a vector like Ricketssia and Omsk hemorrhagic fever.

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classic triad of icterus, kidney failure and hemorrhagic diathesis is often recognized as Weil’s disease (Senior 2010). However, atypical presentation of severe disease constitutes an important pitfall. The icterus seen in leptospirosis seems to be the result of a septic cholestasis instead of acute hepatitis. Indeed, liver function tests are only mildly impaired during acute disease. Severe leptospirosis can cause life threatening bleeding complications. There is evidence that both an impaired primary- and secondary play a role. Primary hemostasis is impaired, due to thrombocytopenia, which frequently occurs during leptospirosis (Medeiros et al. 2010). Furthermore, patients with severe leptospirosis often have a prolonged activated partial thromboplastin time (APTT) and raised thrombotic markers like D-Dimer and Prothrombin up to DIC, according to the International Society on Thrombosis & Hemostasis criteria (Wagenaar et al. 2007; Wagenaar et al. 2010). Despite these disturbances in primary and secondary hemostasis there seems to be a role for endothelial cell dysfunction in leptospirosis. In vitro pathogenic Leptospira interfere with the endothelial cell barrier function (Martinez-Lopez et al. 2010). A severe form of bleeding disorders in leptospirosis is the Leptospirosis Associated Pulmonary Hemorrhage Syndrome (LPHS). This syndrome is a major cause of hemorrhagic fever in developing countries, causing a fulminant presentation with heavy pulmonary bleeding and mortality ranging up to 75 or 80% (Gouveia et al. 2008; Ko et al. 2009; Abela-Ridder et al. 2010). Symptoms are coughing, hemoptysis, often recognized at a late stage after intubation, and in around 50% of the cases there is a patchy infiltration seen on X-thorax. Based on clinical symptoms, leptospirosis is hard to distinguish from other endemic pathogens. During several outbreaks leptospirosis has often been under-recognized and misdiagnosed with, for example, dengue fever. CRP is elevated in acute phase of severe leptospirosis. Furthermore, there are some promising studies about experimental markers (soluble ST-2, long pentraxin-3 (PTX3) and procalcitonin) (Wagenaar et al. 2009a; Wagenaar et al. 2009b; Crouzet et al. 2011).

DiagnosticsThe gold-standard test is the Microscopic Agglutination Test (MAT). This test requires a dark-field microscope to determine agglutination titers (Ahmed et al. 2009; Chirathaworn et al. 2009; Tullu and Karande 2009). Because leptospirosis antibodies are formed 5–7 days after the onset of the disease, MAT is particularly accurate in its later phases (Ahmed et al. 2009; Chirathaworn et al. 2009). Paired serum testing is necessary to determine seroconversion or a significant rise in titer. MAT titers can be indicative for infecting serogroups. However, the MAT is laborious, expensive and needs highly trained personal, so it can only be performed in specialized labo-ratories. The results of an MAT may be compromised by background titers in patients from endemic regions and cross-agglutinating antibodies (Levett et al. 2005; Gouveia

et al. 2008; Chirathaworn et al. 2009). A combination of MAT with Enzyme-linked immunosorbent assay (ELISA) for the detection of IgM antibodies against Leptospira increases sensitivity (Vijayachari et al. 2006; Tullu and Karande 2009). PCR is useful in the first 5 days of the dis-ease and a validated RT-PCR is available (Ahmed et al. 2009). Cultures are usually not used for clinical practice but they do have relevance for the identification of reser-voir hosts and epidemiological studies and they can be retrieved from blood and CSF fluids before the tenth day of the illness. Usually urine cultures can be positive after the seventh day of the disease (Dutta and Christopher 2005; Tullu and Karande 2009). There are multiple rapid tests for leptospirosis diagnostics. For example, antibody-coated gold nanoparticles for the early detec-tion of Leptospira in urine has proven highly sensitive and relatively cheap way of early diagnosis compared to PCR (Chirathaworn et al. 2009). Latex-based agglutina-tion rapid tests show a sensitivity of around 70% in the early phase of the disease, becoming more sensitive later (Smits et al. 2001a). Immunochromotography-based rapid tests based on crude antigen, if properly used, can show good sensitivity (Smits et al. 2001b). However, in endemic regions, due to high seroprevalence, such a format can have a limited value (Wagenaar et al. 2004b).

TreatmentTreatment with penicillin G results in lower morbidity and causes no harmful side effects in acute leptospirosis. The treatment is most effective during the first 5 days after symptom development (Guidugli et al. 2000). However, most cases still develop severe disease either due to late start of treatment or treatment failure (Brett–Major & Coldren 2012). Doxycycline has been proven to be an alternative to penicillin, although it is prescribed for mild cases (Griffith et al. 2006). In an open label random-ized trial 1 g of intravenous ceftriaxone had comparable effectivity to pencillin G treatment (Panaphut et al. 2003). Prophylactic doxycycline reduces severe complications of leptospirosis and symptomatic disease. However, there is a debate as to whether it prevents infection or only affects the severity of the disease (Pavli and Maltezou 2008; Brett-Major and Lipnick 2009). The side effects of a weekly 200 mg oral dosage of doxycycline should be taken into account (Brett-Major et al. 2009; Galloway et al. 2009). The treatment of icteric leptospirosis and LPHS is more complicated and should be restricted to tertiary centers, if available (Trivedi et al. 2009). In these severe forms of leptospirosis supportive care is often necessary (Trivedi et al. 2001; Trivedi et al. 2009). Besides mechani-cal ventilation, inotropic therapy and renal dialysis, treat-ment of the bleeding disorders can be considered with fresh frozen plasma (FFP) and thrombocyte transfusions.

Lassa feverLassa fever affects two to three million people in West Africa annually, with an estimated CFR of 15–20% in hospitalized cases. It was first described in 1969 in Lassa, a town in

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northeast Nigeria, as causative agent of a hemorrhagic fever causing fulminant disease. Although only 20–30 imported cases to Europe are described, most of them were fatal, mainly due to lack of awareness of the risk, delay in diagnosis and delay in initiation of therapy (Gunther et al. 2000). While nosocomial transmission often occurs in West Africa, imported cases of Lassa into Europe have never shown human-to-human transmission in hospital settings, with the exception of seroconversion in a healthcare worker in 2003 (Haas et al. 2003). Lassa fever is endemic in Guinea, Sierra Leone, Nigeria, Liberia and Ivory Coast. The disease also occurs in Ghana, Senegal, Togo, Benin, Mali and Burkina Faso.(Drosten et al. 2003; Fichet-Calvet and Rogers 2009; Saluzzo et al. 1988; Safronetz et al. 2010) The disease is caused by the Old-World arenavirus Lassa; an enveloped, single-stranded, bi-segmented RNA virus (Ogbu et al. 2007). The virus has a small and a large genome segment. Four lineages are identified: Josiah (Sierra Leone), GA391 (Nigeria), LP (Nigeria) and strain AV, which was isolated when imported into Germany and is closely related to Josiah (Bowen et al. 2000; Gunther et al. 2000).

Transmission and hostLassa virus is restricted to one host, the African multi-mammate rat (Mastomys natalensis), other Mastomys species do not seem to shed the virus (Lecompte et al. 2006). This rodent breeds frequently, produces large numbers of offspring and is distributed widely through-out west, central, and the eastern parts of the African continent (Charrel and de Lamballerie 2010). Mastomys natalensis is a commensal rodent, readily colonizing human settlements, thereby increasing the risk of rodent-human contact. When infected, these rodents carry and excrete the virus lifelong. Human infection occurs after inhalation of aerosolized excreta (often urine), consum-ing contaminated foods or by direct contact with abraded skin (Cummins 1990; Ogbu et al. 2007). Human-to-human transmission occurs through direct contact with blood or bodily secretions from infected persons. Living close to someone who had signs of infection in the past 12 months, was associated with almost a twofold infec-tion risk in Guinea (Kerneis et al. 2009). Working in a hos-pital or laboratory without proper hygiene precautions also increases the risk of infection (Frame et al. 1979; Leifer et al. 1970). These findings confirm the need for barrier nursing techniques and strict hygiene measures (Fisher-Hoch 2005). Other risk factors include activi-ties that increase rodent contact, such as poor housing conditions and rodent infestation (Bonner et al. 2007). An exacerbating factor is that the multimammate rat is a known delicacy and food source in West Africa. Hunting them and consuming their meat is therefore a consider-able risk factor (Ter Meulen et al. 1996).

Clinical picture and diagnosisAbout 80% of patients infected with the Lassa fever virus will develop subclinical or mild disease. After the incuba-tion period of 1–3 weeks patients first develop a high fever,

general weakness and malaise. These symptoms occur typically 4–7 days upon the onset of disease followed by a typical pharyngitis (with yellow-white patches) and more non-specific symptoms such as headache, back-, chest- or abdominal pain, nausea and vomiting, diar-rhea, conjunctivitis, coughing and proteinuria (Edington and White 1972; Monath et al. 1974; McCormick 1986a; Frame 1989). In endemic areas, the best discriminating symptoms in this early phase seem to be the combination of proteinuria and pharyngitis (160;161). When progress-ing into the next stage (after 7 days), clinical hallmarks typically include a facial edema, neurological disorders, such as convulsions and encephalopathy and bleeding. Hemorrhagic manifestations vary from mucosal bleed-ings (gums, nose & eyes) to severe internal bleeding from the stomach, bowel, kidney, brain and heart. These conditions only occur in one third of the patients and are associated with death (Frame et al. 1979; Richmond and Baglole 2003). There are no data supporting evidence for DIC in severe Lassa, since coagulation markers are almost always within normal range. Hemorrhage seems to be the result of endothelial cell dysfunction induced by a direct or indirect toxic effect on the endothelial cell by the virus and by inflammatory cytokines. Indeed, post-mortem findings show a generally damaged vas-cular endothelium, characterized by edema in the submucosa, subcapsular hemorrhages in the liver, hem-orrhage and edema in the myocardium, gross edema in the intestine and a focal pneumonitis (Edington and White 1972; Woodruff et al. 1973). There is some evi-dence that a diminished primary hemostasis may add to the hemorrhagic diathesis since acute phase plasma from Lassa fever patients show the inhibition of APD, collagen and sodium-arachidonate-induced platelet aggregation (Cummins 1990). Moreover, plasma derived from patients with Lassa fever inhibits aggregation and thromboxane generation in normal platelets (Chen and Cosgriff 2000). In this stage with severe hemorrhages, shock and sometimes encephalitis, CFR increases to 38–52% (McCormick et al. 1987; Macher and Wolfe 2006). Patients may die in the late stage (>14 days) from shock and respiratory distress due to pleural effusion, possibly complicated with hemoptysis. When patients recover, deafness, hair loss and long-term psychiatric complica-tions are reported (Richmond and Baglole 2003; Macher and Wolfe 2006).

DiagnosticsThe first choice of diagnostics is an ELISA detecting anti-Lassa IgM and/or IgG antibodies (Emmerich et al. 2006). ELISA has shown sensitivity up to a 100% in experimental settings (Emmerich et al. 2006; Panning et al. 2010). Due to a persistent high viraemia for at least 10–15 days, PCR techniques are useful during a prolonged time in Lassa infection. Viral RNA has been isolated from patients’ semen up to 3 months post infection (Demby et al. 1994). However, due to a high sequence diversity (up to 30%)

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between Lassa virus strains false negative results cannot be excluded (Panning et al. 2010).

TreatmentRibavirin is considered effective in Lassa fever (Richmond and Baglole 2003; Bausch et al. 2010). The treatment is effective in any stage of the disease (Holmes et al. 1990; Bausch et al. 2010). A 10-day dosage of 15 mg per kg body-weight in acute disease was shown to effectively decrease mortality, CFR and morbidity (McCormick et al. 1986b). The treatment should start as soon as possible, preferably in the first 6 days of the disease. Intravenous therapy has a better clinical outcome than oral ribavirin (McCormick et al. 1986b; Richmond and Baglole 2003). Ribavirin was also proven useful as a high-risk post exposure prophy-laxis (PEP). A dose of 800 mg, once a day, proved to be as effective as PEP in a small cohort (n = 23) from Liberia (Hadi et al. 2010).

Despite the availability of antiviral treatment addi-tional supportive care is often needed. Fluid replacement and blood transfusions, in particular, may be necessary (McCormick 1986a; Amorosa et al. 2010). No vaccina-tion is available yet but there are promising results with a replication-competent vaccine expressing the Lassa virus glycoproteins (Geisbert et al. 2005).

South-American hemorrhagic feversIsolated in 1958, the Junin virus (JUNV) was held respon-sible for a severe hemorrhagic syndrome that caused den-gue-like symptoms in a clustered outbreak in Argentina. Argentinean hemorrhagic fever (AHF) is endemic in a lim-ited area in the Pampas in Argentina. Outbreaks occur from March to June. Its incidence sharply decreased after the availability of an effective vaccine and neutralizing anti-body treatment (Carballal et al. 1988; Enria and Pinheiro 2000). JUNV was the first of the New-World arenavirus to be discovered. Other SAHF viruses include: Machupo, the causative agent of Bolivian hemorrhagic fever (BHF), Guanarito, the causative agent of Venezuelan hemorrhagic fever (VHF), and Sabia virus, the causative agent of a hem-orrhagic fever case in Brazil. These New-World arenaviruses are, in general, confined to certain areas and rodent-host species. VHF, whose causative agent Guanarito virus was isolated in 1989, occurs in a rather well defined area in cen-tral Venezuela and peaks every year during harvest season (from November to January) (De Manzione et al. 1998). The causative agent of BHF, the Machupo virus, was isolated in 1964 after an outbreak with severe hemorrhagic disease with a CFR around 20%. This disease can also have outbreaks in rural areas, often related to agricultural work taking place during the dry season (from May to October).

Transmission and hostTransmission is thought to occur in a similar way to hanta-virus and Lassa disease, i.e. through infective aerosols (Carballal et al. 1988; Enria and Pinheiro 2000). Person-to-person transmission and nosocomial infections

have been described for BHF (Enria and Pinheiro 2000; Colebunders et al. 2002). The main natural reservoirs of Junin virus (AHF) in Argentina are the dry land vesper mouse (Calomys musculinus) and the small vesper mouse (Calomys laucha). For the Machupo virus this is the large vesper mouse (Calomys callosus) and for Guanarito virus the short tailed zygodont (Zygodontomys brevicauda). The Sabia virus has only been related to one human case of the disease and the natural reservoir is, as yet, unknown (Salas et al. 1998; Enria and Pinheiro 2000). Risk factors are mainly linked to agricultural work and rodent-infested villages. Adult male agricultural workers are mostly at risk, but children and other adults of both sexes can also contract the disease. Despite several laboratory infections there are no reports of SAHF cases outside of the SAHF endemic areas. As the incubation periods for SAHF vary from 7 to 14 days, travel-related import to non-endemic countries might occur (Bannister 2010).

Clinical picture and diagnosisAfter an incubation period of 7–14 days patients with AHF, BHF and/or VHF first develop a non-specific flu-like syndrome. Other symptoms include coughing, pros-tration, abdominal pain, lumbar and muscle pain, severe headache, conjunctival injection, facial flushing, and generalized lymphadenopathy (CDC-report 1994; de et al. 1998; Aguilar et al. 2009). Compared to Lassa, patients with SAHF have a higher tendency to develop serious neurological signs, such as encephalitis and cranial hem-orrhages. Hemorrhagic complications consist mainly of petechiae, conjunctival hemorrhages, mucosal bleed-ing and gastrointestinal bleeding with melena. Bleeding normally starts after 5 days of illness. Laboratory results show thrombocytopenia, leukocytopenia and alterations in coagulation markers (e.g. prolonged partial thrombo-plastin time) (Molinas et al. 1989). The increased bleed-ing tendency is thought to be related to both impaired primary hemostasis (thrombocytopenia and impaired platelet function) and secondary hemostasis (Enria and Pinheiro 2000; Kunz 2009). In AHF a prothrombotic phenotype is seen with elevated procoagulant markers (D-dimer), thrombin-antithrombin complexes (TAT) and thrombin fragment 1 and 2 (F1+F2). A raise in serum PAI-1 indicates inhibition of fibrinolysis in severe cases (Heller et al. 1995). The role of vascular endothelium dysfunction in SAHF has been studied in vitro. The up-regulation of ICAM-1 and VCAM-1 expression on Junin-virus-infected endothelial cells, the increased production of nitric oxide and prostaglandin PGI

2 and the reduced

production of coagulation factors (e.g. von Willebrand factor) are shown in vitro (Kunz 2009).

Early diagnosis in SAHF is possible by RT-PCR as patients show viraemia for 5–10 days after the first symptoms. Molecular detection has proven to be sensitive in the early phase of AHF (a sensitivity of 98% and a specificity of 76%) (Lozano et al. 1995). The gold-standard test is a proven seroconversion by ELISA or IFA using paired sera. Antibodies against the highly conserved

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nucleocapsid proteins (NP) of New-World arenaviruses are commonly used for virus detection because the SAHF viruses occur very locally. However, this cross reactivity could be a limitation in diagnosing a returning traveler who visited multiple SAHF endemic areas.

TreatmentDuring the first 8 days of the disease AHF can be treated with immune plasma containing high titers of neutralizing antibodies (Enria et al. 2008). Also, Ribavirin can be effective in AHF as in the other SAHF (Enria and Maiztegui 1994; McKee, Jr. et al. 1988; Charrel and de Lamballerie 2003). Further treatment should consist of supportive care regarding blood loss in hemorrhagic events and adequate handling of neurological complications such as seizures. An effective live-attenuated vaccine is available for AHF (Maiztegui et al. 1998).

Co-infectionsThe rodent-borne hemorrhagic fevers share several characteristics including areas of endemicity, trans-mission pathways and the majority of their clinical symptoms. Therefore, the possibility of coinfection with multiple rodent-borne pathogens can’t be excluded in differential diagnostics. However, reports on such co-infections are very rare.Three reports from Croatia describe double infections with both Leptospira and a hantavirus in humans (Kudesia et al. 1988; Markotic et al. 2002; Tadin et al. 2012). Interestingly both pathogens have been isolated from the same reservoir rodent, namely Apodemus flavicollis (Dobrava-Belgrade and Leptospira) and from a Myodes glareolus in Croatia (Puumala and Leptospira) (Cvetko et al. 2006; Tadin et al. 2012). Co-infecitons between other rodent-borne hemorrhagic fever pathogens have not been reported. There are also reports describing co- and multi-infections with Leptospira and other pathogens such as dengue virus, malaria parasites, hepatitis A and E virus, Orientia tsutsugamushi, Toxoplasma gon-dii, Babesia and Francisella tularensis in humans and/or non-human reservoir species (Lu and Tseng 2005; Jittapalapong et al. 2009; Behera et al. 2010; Alves et al. 2011; Gurjar et al. 2011; Duncan et al. 2012; Singh et al. 2012; Tadin et al. 2012).The possibility of mul-tiple pathogens in one patient can be both of clinical and diagnostic importance. Case reports showed more severe disease in co-infected patients and sometimes the occurrence of a coinfection warrants changes in treatment (Gurjar et al. 2011; Wei et al. 2011). Co-infections between hanta and Lassa viruses have not been reported. However outbreaks of these viral diseases have poorly been investigated for the occur-rence of co-infections. While in the Guinean forests of West Africa, an ecological very diverse region reaching from Guinea and Sierra Leone eastward to Cameroon,

serological evidence is present for both Lassa virus infections as infections with the Sangassou hantavirus (SANV) (Klempa et al. 2010).

Concluding remarks

The rodent-borne hemorrhagic fever pathogens belong to an important group of zoonotic diseases causing severe disease all over the world. Since the diseases described in this review share many common clinical symptoms and laboratory markers, and to some extent show an overlap in their geographic distribution, accu-rate diagnosis depends on the availability of sensitive and specific testing and high level clinical practice. Rodent control, proper education aimed at avoiding contacts with rodents or rodent excreta and the devel-opment of vaccines can decrease infection rates, such as in AHF. However, for these preventive measures to be effective, thorough knowledge of the pathogens, and particularly their specific rodent hosts, is necessary. Changes in climate and human behaviur (particularly land use) are predictors for the distribution of cases or outbreaks of rodent-borne pathogens outside their current areas of endemicity (Viel et al. 2010). The chal-lenge lies in the timely recognition of the disease, fol-lowed by adequate risk management. Knowledge of the clinical picture, epidemiology (including rodent ecol-ogy) and pathogenesis of these diseases are vital if we are to decrease morbidity and mortality (Abela-Ridder et al. 2010). Proper knowledge of their epidemiology facilitates the choice of adequate diagnostics for the right pathogen.

Acknowledgements

The authors would like to thank Michiel Gravesteijn and Lonneke Kiel for their help with the figures. Furthermore we would like to acknowledge the contribution of the Spread global health initiative facilitating the collabora-tive work between different workgroups working in the infectious diseases field. This study was partially funded by EU grant FP7-261504 EDENext and is catalogued by the EDENext Steering Committee as EDENext 011 (http://www.edenext.eu). The contents of this publication are the sole responsibility of the authors and do not neces-sarily reflect the views of the European Commission.

Declaration of Interest

The authors report no declarations of interest.

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