1 23
European Journal of Clinical
Microbiology & Infectious Diseases
ISSN 0934-9723
Eur J Clin Microbiol Infect Dis
DOI 10.1007/s10096-017-3113-6
Acute hantavirus infection presenting as
haemolytic-uraemic syndrome (HUS): the
importance of early clinical diagnosis
J.Clement, A.P.K.Lee,
G.A.Verpooten, L.Laenen, V.Vergote,
H.De Samblanx, Z.N.Berneman,
M.Van Ranst & P.Maes
1 23
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ORIGINAL ARTICLE
Acute hantavirus infection presenting as haemolytic-uraemic
syndrome (HUS): the importance of early clinical diagnosis
J. Clement
1,2
& A. P. K. Lee
3
& G. A. Verpooten
3
& L. Laenen
1,2
& V. Ve r g o t e
1,2
&
H. De Samblanx
4
& Z. N. Berneman
4
& M. Van Ranst
1,2
& P. Maes
1,2
Received: 11 September 2017 / Accepted: 11 September 2017
#
Springer-Verlag GmbH Germany 2017
Abstract The European prototype of hantavirus, Puumala
virus (PUUV), isolated from a common wild rodent, the bank
vole (Myodes glareolus), causes nephropathia epidemica
(NE). NE can perfectly mimic haemolytic-uraemic syndrome
(HUS), progressing from an aspecific flu-like syndrome to
acute kidney injury with thrombocytopaenia, and presenting
with some signs of haemolytic anaemia and/or coagulopathy.
Moreover, both NE and HUS can occur in local outbreaks. We
report an isolated case of NE, initially referred for plasmaphe-
resis for suspected HUS, although signs of overt haemolysis
were lacking. Early suspicion of hantavirus infection, later
confirmed by serology and reverse transcription polymerase
chain reaction (RT-PCR), prevented subsequent excessive
treatment modalities.
Introduction
Despite the increasing incidence of rodent-borne hantavirus
infections (approximately 10,000 cases/year in West Europe
[1]), Puumala hantavi rus (PUUV)-induced n ephropa thia
epidemica (NE) and other forms of so-called haemorrhagic
fever with renal syndrome (HFRS), are still heavily
underdiagnosed in Europe and in the Americas, probably
due to insufficient medical awareness and because of the mul-
tiple diagnostic pitfalls. HFRS and its milder variant NE can
mimic other non-tropical infectious illnesses, such as leptospi-
rosis [2, 3] and haemolytic-uraemic syndrome (HUS), which,
moreover, can all present in local outbreaks, mostly in sum-
mertime [4, 5]. Misdiagnosis and subsequent invasive treat-
ment for HUS was reported previously [4]. According to a
German multi-clinic study, NE cases can end up hospitalised
in 12 different clinical departments, and undergo several un-
necessary diagnostic procedures [6]. In the here described case
of a flu-like syndrome followed by acute kidney injury (AKI)
and thrombocytopaenia, prior contact with bank voles, evoked
during anamnesis by the consulted nephrologist, was practi-
cally diagnostic from the start.
Case report
A 58-year-old Belgian male patient developed a flu-like syn-
drome with respiratory and gastrointestinal complaints. Three
days post onset of symptoms (POS), his fever reached 40 °C,
accompanied by shivers, diaphoresis and oliguria. A progres-
sive decline of renal function with thrombocytopaenia
prompted referral to the Antwerp University Hospital,
Belgium, on day 10 POS for suspected HUS. The patient
mentioned nausea, epigastric pain, diarrhoea and food intoler-
ance since day 4 POS, plus dry coughing with mild dyspnoea
since day 5 POS. There were no relevant medical antecedents
or chronic medication. He smoked a package of tobacco every
3 days. No medication had been taken, except acetaminophen,
when in pain. The patient had a horse-breeding farm. When
asked about potential contact with rodents, he admitted having
* J. Clement
jan.clement@uzleuven.be
1
National Reference Laboratory for Hantavirus Infections, University
Hospitals Leuven, Leuven, Belgium
2
Rega Institute for Medical Research, Department of Microbiology
and Immunology, KU Leuven, Leuven, Belgium
3
Department of Nephrology, Antwerp University Hospital,
Edegem, Belgium
4
Department of Haematology, Antwerp University Hospital,
Edegem, Belgium
Eur J Clin Microbiol Infect Dis
DOI 10.1007/s10096-017-3113-6
Author's personal copy
cleane d a nest of bank voles 3 weeks before the onset of
symptoms.
Examination at admission (day 10 POS) withheld stable
haemodynamics, a blood pressure of 113/92 mmHg, a pulse
of 96/min and fever of 39 °C. Minor lung crepitations were
heard. Abdominal examination was normal. Peripheral oede-
ma was absent.
Initial blood anomalies comprised a mild coagulopathy
(Table 1). Peripheral blood smear revealed a mild but mislead-
ing presence (0.8%) of schistocytes (Fig. 1a), neutrophilia and
4% of immunoblasts (Fig. 1b, c). Arterial sampling at admis-
sion yielded a pH of 7.40 , de saturation with a pO
2
of
64 mmHg and hypocapnia with a pCO
2
of 31 mmHg. Urine
sediment showed mild microscopic haematuria and discrete
pyuria. However, nephrotic-range proteinuria of 14 g/L was
found on day 10 POS, while 24-h urine collection on day 11
POS yielded only 3.2 g. Chest radiograph and renal ultrasound
were normal. Bone marrow examination showed
normocellularity with active trilinear haematopoiesis and an
elevated amount of immunoblasts (Fig. 1d), compatible with
reactive plasmacytosis.
While platelets were spontaneously recovering after one
day of hospitalisation, renal function showed a maximal de-
crease to an eGFR of 20 mL/min/1.73 m
2
on day 13 POS.
Given the new clinical suspicion of a hantavirus infection, the
only therapy consisted of optimising fluid balance and routine
supporting care.
Recuperation of the kidney function occurred spontaneous-
ly on day 15 POS and the patient was discharged from hospital
two days later. After 6 weeks, a complete renal recovery, with-
out any proteinuria, was confirmed during follow-up. PUUV
ELISA IgM on admission (day 10 POS) appeared strongly
positive with optical density (OD) 2.78 (normal < 0.80), while
IgG was already slightly positive (OD 0.86, normal < 0.80).
Of interest, while reverse transcription polymerase chain reac-
tion (RT-PCR) on the acute serum sample on admission (day
10 POS) was already negative, repeated RT-PCR with subse-
quent sequencing on a hyperacute (7 days POS) serum sam-
ple, still available upon request via the general practitioner
(GP), disclosed PUUV RNA, thus confirming the diagnosis
[3, 7](Fig.2).
Discussion
This patient was referred for suspected diarrhoea-associated
(D+) Btypical HUS^ because of AKI, concomitant with
thrombocytopaenia, schistocytes, raised lactic dehydrogenase
(LDH) and coagulopathy, after an episode of gastrointestinal
complaints. However, haemolytic anaemia, characteristic for
D+ HUS, was absent. Moreover, instead of the expected low-
ering of haptoglobin, a rather elevated level of this haemolysis
indicator was found, and instead of anaemia, an initially slight-
ly raised haemoglobin and haematocrit (Table 1) was present
on admission, the latter indicating haemoconcentration and re-
duction of the intravascular volume, secondary to endothelial
hyperpermeability [3, 8–10]. This temporary Bcapillary leak^ is
common to all hantavirus infections, and is far more pro-
nounced than in the endothelial dysfunction, also linked to
HUS. Extravasation of exudate, extremely rich in proteins, to
third spaces can result in substantial weight gain, without no-
ticeable peripheral Bclassic^ oedema, e.g. in the lower limbs,
Table 1 Blood results on
admission or 10 days after the
onset of symptoms. Mild
coagulopathy was suggested by
decreased levels of antithrombin
activity, protein C and protein S,
together with thrombocytopaenia
and slightly elevated level of
schistocytes and D-dimers
Parameter Result (reference value) Parameter Result (reference value)
Creatinine (mg/dL) 2.06 (0.62–1.10) PT (%) 83 (70–120)
eGFR (mL/min/1.73 m
2
) 33 (> 90) APTT (s) 36 (30–42)
Sodium (mmol/L) 131 (136–145) Fibrinogen (mg/dL) 466 (200–400)
Chloride (mmol/L) 98 (98–107) D-dimers (ng/dL) 4.399 (< 500)
Urea (mg/dL) 67 (13–43) Lupus anticoagulans Positive
a
(negative)
Thrombocytes (×10E9/L) 50 (140–440) Cardiolipin IgG/M Negative (negative)
Haemoglobin (g/dL) 17.6 (13–17) APC resistance (ratio) 3.26 (> 2.1)
Haematocrit (%) 50.5 (40–50) Protein C (%) 64 (70–130)
Schistocytes (%) 0.8% (< 0.5%) Protein S (%) 38 (70–130)
Haptoglobin (mg/dL) 244 (30–200) Antithrombin (%) 69 (80–120)
Leucocytes (×10E9/L) 15 (4.3–10.0) Direct Coombs test Positive
a
(negative)
Leucocyte differential (%) Neutrophils: 77 (40–75)
Immunoblasts: 4 (0–2)
LDH (U/L) 323 (84–246)
CRP (mg/dL) 6.4 (< 0.30) Albumin (g/dL) 2.5 (3.5–5.2)
ANA Negative (negative) ANCA
a
Positive, 1/20 (negative)
Results higher or lower than the norm, indicated in parentheses, are marked in bold
a
Not reproducible/negative after a few days
Eur J Clin Microbiol Infect Dis
Author's personal copy
but is illustrated in this case by frank hypoalbuminaemia
(Table 1). Finally, flu-like symptoms with high fever prior to
admission are not suggestive for D+ HUS.
Endothelial dysfunction is postulated as being mediated
amongst other by an Binflammatory cytokine storm^ caused
by hantavirus-specific cytotoxic CD8+ T lymphocytes,
Fig. 1 a Schistocytes in
peripheral blood smear (arrows).
b, c Peripheral immunoblasts
defined as enlarged lymphoid
cells with little, moderate to deep
basophilic cytoplasm, a large
reticular nucleus with uniform
chromatin and variably prominent
nucleoli. d Bone marrow with the
presence of an immunoblast
(lower left), a band neutrophil
(top) and a promyelocyte (right)
AJ277075, Puumala virus BE/Mg/Montbliart/1/1986
AJ277076, Puumala virus BE/Mg/Montbliart/2/1986
AJ277031, Puumala virus BE/Montbliart/23Cg/1996
AJ277030, Puumala virus BE/Thuin/33Cg/1996
AJ277034, Puumala virus BE/Couvin/59Cg/1997
AJ277033, Puumala virus BE/Momignies/55Cg/1996
AJ277032, Puumala virus BE/Momignies/47Cg/1996
Puumala virus BE/Hu/Olmen/1/2012
U22423, Puumala virus BE/Mg/Turnhout/1/1985
DQ016430, Puumala virus Germany/Bavaria/CG33/04
AM695638, Puumala virus France/Mignovillard/CgY02/2005
AF294652, Puumala virus Slovakia/Opina916
AJ888752, Puumala virus Austria/Ernstbrunn/Cg641/1995
GQ339487, Puumala virus Sweden/Munga/Mg16/05
M32750, Puumala virus Russia/CG1820
JN657228, Puumala virus Latvia/Jelgava/Mg149/2008
GU808824, Puumala virus Finland/Kuhmo/X5
GQ339479, Puumala virus Sweden/Moskosel/Mg17/05
U14137, Puumala virus Bosnia/Vranica
NC _005227, Tula virus Czech Republic/Moravia/5302Ma/94
NC_005216, Sin Nombre virus USA/NM/H10
NC_003466, Andes virus Chile/9717869
M14626, Hantaan virus South Korea/76-118
NC_005233, Dobrava-Belgrade virus Greece/Ano-Poroia
KC626089, Seoul virus China/ZT10
50
100
100
99
100
100
85
99
96
100
99
100
71
95
79
54
58
100
0.05
Fig. 2 Phylogenetic tree based on full-length hantavirus S segment (nu-
cleocapsid protein) sequences. The patient lineage is designated as BE/
Hu/Olmen/2012/1. For the Belgian (BE) strains, Puumala virus isolates
from different regions are used. The evolutionary history was inferred
using the neighbour-joining method. The bootstrap consensus tree in-
ferred from 10,000 replicates is taken to represent the evolutionary history
of the taxa analysed. The 450-bp amplicon retrieved from a serum sample
taken 7 days after the onset of symptoms clusters significantly with a
Puumala virus (PUUV) strain (BE/Mg/Turnhout/1/1985, formerly called
CG 13891) isolated already in 1985 out of a bank vole capture d in
Turnhout, north Belgium. Bootstrap values less than 50% are not shown.
GenBank accession numbers are shown in bold. The scale bar represents
the number of base substitutions per site
Eur J Clin Microbiol Infect Dis
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