1
Characterisation of inflammatory response, coagulation, and
2
radiological findings in acute Katayama syndrome: a report of
3
three cases at the Medical University of Vienna, Austria
4
5
Heimo Lagler1, Cihan Ay2, Fredrik Waneck3, Rainer Gattringer4, Wolfgang Graninger1,
6
Michael Ramharter1,5*
7
8
1
9
Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
Department of Medicine I, Division of Infectious Diseases and Tropical Medicine,
10
2
11
University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
12
3
13
Cardiovascular and Interventional Radiology, Medical University of Vienna, Währinger
14
Gürtel 18-20, 1090 Vienna, Austria
15
4
16
Fadingerstrasse 1, 4020 Linz, Austria
17
5
18
Germany
19
*
20
Email addresses:
Department of Medicine I, Division of Haematology and Haemostasiology, Medical
Departement of Biomedical Imaging and Image-guided Therapy, Division of
Institute of Hygiene, Microbiology and Tropical Medicine, Elisabethinen Hospital Linz,
Institut für Tropenmedizin, University of Tübingen, Wilhelmstraße 27, 72074 Tübingen,
Corresponding author
21
HL: heimo.lagler@meduniwien.ac.at
22
CA: cihan.ay@meduniwien.ac.at
23
FW: fredrik.waneck@meduniwien.ac.at
24
RG: rainer.gattringer@elisabethinen.or.at
25
WG: wolfgang.graninger@meduniwien.ac.at
26
MR: michael.ramharter@meduniwien.ac.at
-1-
1
Abstract
2
Background
3
Katayama fever is an acute clinical condition characterised by high fever, dry cough and
4
general malaise occurring during early Schistosoma spp. infection. It is predominantly
5
reported in travellers from non-endemic regions. Whereas the immunological response to
6
schistosoma infection is well characterised, alterations in markers of inflammation and
7
coagulation in response to this intravascular helminth infection are poorly understood.
8
Methods
9
Here we report the clinical, laboratory and radiological characteristics of three returning
10
travellers suffering from Katayama syndrome. Markers of inflammation and coagulation were
11
assessed repeatedly during follow up to characterise the host’s response to this acute
12
helminthic infection. Radiographic findings were correlated to the clinical and laboratory
13
markers.
14
Results
15
Clinical symptoms were suggestive for a highly inflammatory response including high fevers
16
above 39°C, cough, and general malaise. Classical inflammation markers including blood
17
sedimentation rate, C-reactive protein, and serum amyloid A were only moderately elevated.
18
Marked eosinophilia (33 – 42% of white blood cells) was recorded and persisted despite anti-
19
inflammatory and anthelminthic treatment for up to 32 weeks. Analysis of blood coagulation
20
markers indicated substantial activation of blood coagulation reflected by elevated D-dimer
21
(0.57 – 1.17 µg/ml) and high thrombin generation potential (peak thrombin activity: 311 –
22
384 nM). One patient showed particularly high levels of microparticle-associated tissue factor
23
activity at initial presentation (1.644 pg/ml). Corresponding to the elevated markers of
-2-
1
inflammation, multiple opacities in liver and lungs were demonstrated in computed
2
tomography in one patient.
3
Conclusions
4
The characterization of the inflammatory response, blood coagulation parameters and
5
radiological findings in parenchymatous organs adds to our current understanding of
6
Katayama syndrome and serves as a starting point for further systematic investigations of the
7
pathophysiology of this acute helminthic infection.
8
Keywords
9
Schistosomiasis, Katayama, inflammation, coagulation, radiology, Africa
-3-
1
Background
2
Schistosomiasis is a debilitating chronic infection by trematode worms of the genus
3
Schistosoma. Rural regions in the tropics are most affected leading to a global disease burden
4
of 3-70 million disability-adjusted life years lost [1]. Humans become infected during
5
freshwater exposure by larval stages which are shed from the snail intermediate host.
6
Cercariae penetrate the intact skin and commence the developmental cycle in the human host
7
developing into adult worms in the liver. Mating and migrating to the venous blood vessels of
8
the urogenital tract (S. haematobium) or the intestinum (S. mansoni, intercalatum, japonicum,
9
mekongi) in the human host, the adult worms and the deposed eggs ultimately lead to a variety
10
of chronic pathologies including haematuria, haematochezia, liver fibrosis, bladder cancer,
11
and chronic inflammation of the urogenital tract [2].
12
13
An acute clinical syndrome including high fever, cough and general malaise has been
14
described foremost in travellers from non endemic regions exposed to schistosoma infection.
15
This clinical condition commences 3-8 weeks after exposure and is termed “Katayama fever”
16
or “Katayama syndrome” [3]. The clinical symptoms of Katayama syndrome are mediated by
17
a hypersensitivity reaction to the intravascular helminth pathogens. Clinical symptoms
18
gradually abide even without specific anthelmintic treatment and are substituted by the
19
chronic granulomatous inflammation causing the vast majority of morbidity.
20
21
Katayama fever is an acute inflammatory reaction of the host. Whereas several studies have
22
investigated the immunological characterisation caused by the intravascularly residing worms
23
in animal models and the human host, little is known about the inflammatory response in
24
human patients characterized by inflammation markers and respective radiological signs of
25
inflammation [4]. Intriguingly, no data describing the consequences of intravascular helminth
-4-
1
migration on the activation of the tightly controlled blood coagulation system in acute
2
Katayama syndrome have been published so far. Here we report the clinical course,
3
radiological findings, and observed alterations in markers of inflammation and blood
4
coagulation in three returning travellers suffering from acute Katayama syndrome.
-5-
1
Methods
2
Patients were initially consulted at three distinct hospitals in Eastern Austria. Two patients
3
were subsequently hospitalized at the Division of Infectious Diseases and Tropical Medicine
4
at the Medical University of Vienna, and the third patient was hospitalized at a referral
5
hospital in the province of Upper Austria. Written informed consent was obtained from
6
patients for the provision of additional blood samples for the analysis of coagulation
7
parameters besides routine blood draws and for the authorization to analyse clinical data.
8
Radiological evaluation of patients was performed at the hospitals of primary consultation.
9
The evaluation of D-dimer levels, the in-vitro thrombin generation potential and the analysis
10
of the microparticle-associated tissue factor (MP-TF) activity was performed at the Medical
11
University of Vienna using previously validated assays [5, 6]. Markers of inflammation were
12
assessed using internally and externally quality controlled standard methodology. Data were
13
captured in an electronic database and were depicted using descriptive statistics. Due to the
14
small sample size, original data were reported and non-parametric summary measures were
15
depicted as appropriate.
-6-
1
Results
2
Clinical characterisation of patients and radiographic findings
3
Two female and one male Austrian citizen aged 19 to 21 years presented at hospitals in
4
Eastern Austria due to abrupt onset of general malaise, high fever and a productive cough. All
5
patients returned from a four week travel to the Republic of Tanzania three weeks prior to the
6
onset of symptoms. The journey consisted of work in a developmental aid programme in a
7
rural community, a game park visit and freshwater exposure in Lake Malawi. Patients were
8
treated empirically by the attending physicians of the initial health care institution with broad
9
spectrum beta-lactam antibiotic treatment for suspicion of pneumonia. Repeated radiologic
10
examinations were performed and the two female patients were subsequently transferred to
11
the inpatient ward of the Department of Infectious Diseases at the Medical University of
12
Vienna due to progressive clinical deterioration. The third patient - a young male Austrian
13
citizen – was hospitalized at a referral hospital in the province of Upper Austria.
14
15
The clinical diagnosis of acute Katayama syndrome was established based on the available
16
patient history, laboratory parameters and radiographic findings. Anti-inflammatory treatment
17
with corticosteroids and concomitant anthelminthic treatment with praziquantel was
18
administered. Patients showed rapid clinical recovery to this treatment and were discharged
19
within 5 days. Malaria and systemic bacterial or fungal infections were excluded by
20
repeatedly negative thick blood smears and multiple blood cultures. Clinical follow up visits
21
were performed over a six month period. Schistosoma specific antibody titres – initially
22
negative during the acute phase of infection – later converted to a positive result in all three
23
patients and confirmed the initial clinical diagnosis. No egg excretion was detected during
24
follow up in any of the patients. A second cycle of praziquantel treatment was administered 3
-7-
1
months after initial presentation to target previously immature stages, which are less
2
susceptible to praziquantel.
3
4
Chest X-ray was performed in all patients but did not show pathological alterations.
5
Abdominal ultrasound was performed and a slightly enlarged spleen was documented in one
6
case (14.4 cm diameter). Thoracic and abdominal computed tomography was performed at the
7
hospital of initial presentation due to the clinical diagnosis of systemic inflammatory response
8
syndrome in one patient. Multiple opacities in both lungs measuring up to 9 mm were
9
discovered (Figure 1). In addition, multiple hypodense foci were observed in the hepatic
10
parenchyma (Figure 2). These radiological findings were described as alterations resembling
11
metastatic abscesses of septic or malignant origin.
12
13
Characterisation of inflammatory response and blood coagulation parameters
14
Clinical and laboratory markers of inflammation were repeatedly assessed during follow up of
15
patients (Table 1.) All individuals experienced high fevers above 39°C at initial presentation.
16
Classical markers of inflammation including C-reactive protein (CRP; 6 – 23 mg/l), serum
17
amyloid A (SAA; 52 – 67 mg/l), and blood sedimentation rate (BSR; 27/36 – 82/110 mm/h)
18
were moderately elevated. Correspondingly, total leukocyte count was elevated and marked
19
eosinophilia ranging between 33 - 42% of white blood cells was detected in all patients.
20
Inflammation markers returned to normal levels rapidly after initiation of anti-inflammatory
21
treatment with corticosteroids. However, eosinophilia only gradually declined and persisted
22
for up to 32 weeks after initiation of treatment. Elevated lactate dehydrogenase (LDH) levels
23
were demonstrated in one patient with a particularly pronounced inflammatory response (391
24
U/l).
25
-8-
1
Blood coagulation parameters were assessed in the two female patients (Table 2). Here, D-
2
dimer levels were elevated at presentation indicating activation of haemostasis and
3
fibrinolysis (1.2 and 0.6 µg/ml, respectively) and fibrinogen levels were slightly increased
4
(477 - 517 mg/l). The thrombin generation potential was increased at presentation as reflected
5
by a higher peak thrombin generation (384 and 311 nM, respectively) compared to follow up
6
measures. In one patient the peak thrombin generation was increased at the end of follow-up
7
without evidence for disease activity. Finally, the MP-TF activity was markedly raised in one
8
patient up to 1.644 pg/ml before gradually declining to 0.03 pg/ml.
-9-
1
Discussion
2
Acute Katayama fever is thought to be mediated by a systemic hypersensitivity reaction to
3
migrating parasites and circulating immune complexes at the onset of egg production [4]. This
4
immune response causes an inflammatory reaction leading to the classical clinical symptoms.
5
The clinical presentation of the reported cases was indicative for such an acute and highly
6
inflammatory response. Patients showed high fevers above 39°C and were manifestly
7
incapacitated by the clinical disease course. Contrary to these findings, however, classical
8
inflammation markers including CRP and BSR were only modestly elevated. At the same
9
time eosinophilia – a hallmark of invasive helminthic infections – was markedly elevated.
10
Interestingly, eosinophilia persisted for more than six months prior to normalisation indicating
11
prolonged exposure to helminthic antigen stimulation. This finding may be explained by the
12
fact that praziquantel – although administered in our patients already during acute infection –
13
has little activity against early developmental stages of schistosomal worms and complete
14
cure from all intravascular worms was therefore achieved only after re-administration of
15
praziquantel during the follow up period [7].
16
17
Acute Katayama syndrome is a systemic state of inflammation and distinct radiographic
18
abnormalities of the lungs have been described in acute Katayama syndrome in a few case
19
reports [8-10] including patchy pulmonary infiltrates in chest X-ray [11]. Single or multiple
20
pulmonary nodules with ground-glass halos were reported in standard X-ray or in computed
21
tomography [12]. However, radiological alterations in other parenchymatous organs have
22
been less well described. Computed tomography in one of our patients showed radiographic
23
alterations of the lung interstitium concordant with previous reports. In addition, multiple
24
hypodense foci of comparable appearance were demonstrated in liver parenchyma indicating
25
a generalized inflammatory response during acute Katayama syndrome both in lung and liver
- 10 -
1
tissue (Figure 1 and 2). This finding supports the hypothesis of a systemic inflammatory
2
response as opposed to a localized immune response in the lungs as the cause for the
3
respective radiological alterations. Whereas these findings are intriguing information from a
4
scientific point of view, the authors are convinced that computed tomography should not be
5
considered as a standard diagnostic examination for patients with suspected Katayama
6
syndrome. CT-examinations lack pathognomonic features for this disease and risks of
7
exposure to radiation most likely outweigh the diagnostic benefit in Katayama syndrome.
8
9
Detailed analysis of the blood coagulation system including D-dimer, which indicates an
10
activation of haemostasis and fibrinolysis, the thrombin generation potential, a global in-vitro
11
assay indicating an individual´s coagulation potential, and measurement of the MP-TF
12
activity, which reflect a prothrombotic state, showed considerable variability in acute
13
schistosomiasis. From a theoretical point of view, one may speculate that intravascular
14
migration of helminths may result in activation of the blood coagulation system despite the
15
absence of clinical consequences including thrombosis and thrombophlebitis. Concordantly,
16
this activation was demonstrated by increased levels of D-dimer, a high peak thrombin and a
17
marked increase of the MP-TF activity in one patient. This was less evident in a second
18
patient, which may be explained by either lower response in this patient or the fact that the
19
peak in alterations may have been missed due to the referral from another hospital. Despite
20
the intravascular localization of schistosomal worms and the pronounced activation of the
21
blood coagulation system, clinical complications such as thrombotic events are not commonly
22
reported in the context of acute schistosomiasis. A better understanding of the underlying
23
mechanisms for this puzzling discordance of clinical disease and laboratory findings may
24
prove particularly fruitful to improve our knowledge of the complex interplay between
25
helminth pathogens and the host’s response.
- 11 -
1
Conclusion
2
The characterization of the inflammatory response, activation of the blood coagulation system
3
and description of corresponding radiographic findings in our patients may provide helpful
4
information for the diagnostic workup of future patients with acute febrile conditions
5
returning from the tropics. Based on these first preliminary findings, a further systematic
6
evaluation of the impact of intravascular helminth infection on blood coagulation and the
7
inflammatory response may be considered a particularly rewarding endeavour.
8
- 12 -
1
Abbreviations
2
MP-TF, microparticle-associated tissue factor; CRP, C-reactive protein; SAA, serum
3
amyloid A; BSR, blood sedimentation rate; LDH, lactate dehydrogenase; CT, computed
4
tomography; max, maximum; PCT, Procalcitonin.
5
Competing interests
6
The authors declare that they have no competing interests.
7
Authors' contributions
8
HL, RG, MR collected, assembled and analyzed the data. CA analyzed, supervised and
9
interpreted all blood coagulation parameters. FA supervised and interpreted all CT scan
10
findings. HL, WG and MR contributed to the study design, interpretation of data, writing
11
and revision of the article. All authors read and approved the final manuscript.
12
Acknowledgements
13
This study was supported by a grant from the independent Karl Landsteiner Gesellschaft, Austria.
14
15
References
16
1.
schistosomiasis. Chronic illness 2008, 4(1):65-79.
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18
19
King CH, Dangerfield-Cha M: The unacknowledged impact of chronic
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Gryseels B, Polman K, Clerinx J, Kestens L: Human schistosomiasis. Lancet
2006, 368(9541):1106-1118.
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3
4.
Ross AG, Vickers D, Olds GR, Shah SM, McManus DP: Katayama syndrome.
The Lancet infectious diseases 2007, 7(3):218-224.
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5
Doherty JF, Moody AH, Wright SG: Katayama fever: an acute manifestation
5.
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8(4):759-765.
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6.
Thaler J, Ay C, Mackman N, Bertina RM, Kaider A, Marosi C, Key NS, Barcel
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DA, Scheithauer W, Kornek G et al: Microparticle-associated tissue factor
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JTH 2012, 10(7):1363-1370.
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Esbroeck M, Vervoort T, Van Gompel A, Van den Ende J: Imported Katayama
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fever: clinical and biological features at presentation and during treatment.
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The Journal of infection 2006, 52(5):339-345.
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computed tomography (CT) findings. The American journal of tropical
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[Acute pulmonary schistosomiasis: correlation between the high-resolution
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Katz N, Rocha RS, Rezende DF, Neves J: Pulmonary manifestations in the
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10
11
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1
Tables
2
Table 1 - Clinical and laboratory markers of inflammation at initial presentation
3
and during follow up
4
Parameter
Patient
Baseline
Week 1
Week 2
Week 6
Week 11
Week 32
Temperature
A
max 39.0
<37
<37
<37
<37
<37
(°C)
B
max 39.6
<37
<37
<37
<37
<37
C
max 39.3
<37
<37
<37
<37
<37
BSR
A
55/82
-
31/60
7/22
12/22
12/20
(mm)
B
82/110
-
64/102
12/28
14/31
15/31
C
27/36
25/30
-
-
-
-
CRP
A
6
3
0.7
0.3
0.4
0.2
(<10 mg/l)
B
23
10
6
1
1
2
C
23
11
-
-
-
-
PCT
A
0.13
-
-
-
-
-
(<0.5 ng/ml)
B
0.17
-
-
-
-
-
C
-
-
-
-
-
-
SAA
A
52
32
-
-
-
-
(<5 mg/l)
B
67
31
-
-
-
-
C
-
-
-
-
-
-
LDH
A
192
173
206
189
149
157
(<247 U/l)
B
391
237
275
204
180
183
C
200
202
-
-
-
-
Leukocyte
A
5.9
8.5
2
5.4
4.7
5.2
count
B
16.1
17.1
14.2
6.7
6.5
7.6
(4-10 G/l)
C
12.7
11.9
-
-
-
-
Eosinophile
A
2
3.1
1.2
0.4
0.3
0.2
count
B
6.7
7.2
5.8
0.8
0.7
0.2
(0-0.4 G/l)
C
4.5
4
-
-
-
-
Eosinophile
A
33
36
15.1
7.4
6.0
3.8
relative
B
42
42
41
12
16
2.6
(0-4%)
C
35
33.5
-
-
-
-
5
6
max: maximum; BSR: blood sedimentation rat after one hour/after two hours; CRP: C-
7
reactive protein; PCT: procalcitonin; SAA: serum amyloid A; LDH: lactate
8
dehydrogenase.
- 16 -
1
Table 2 - Parameters of coagulation cascade at initial presentation and during
2
follow up
3
Parameter
Patient
Baseline
Week 1
Week 6
D-dimer
A
0.57
0.06
0.28
(<0.5 µg/ml)*
B
1.17
1.21
0.46
Finbrinogen
A
477
443
331
302
312
(180-390 mg/dl)
B
517
369
307
281
341
Peak thrombin
A
311
-
190.2
168.8
121.5
generation (nM)
B
384.4
-
201.6
236.5
506.1
MP-TF activity
A
0.0916
-
0.0467
0
0.85
(pg/ml)
B
1.644
-
1.101
0.115
0.033
4
5
* this cut-off indicates non-increased or negative D-dimer values.
6
MP-FT = microparticle-associated tissue factor
7
- 17 -
Week 11
Week 32
1
Figures
2
Figure 1 - Radiographic findings of lung computed tomography during Katayama
3
syndrome (axial (A) and coronal (B) reconstruction).
4
5
Figure 2 - Radiographic findings of abdominal computed tomography during
6
Katayama syndrome (axial (A) and coronal (B) reconstruction).
- 18 -