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Radiology of Infectious Diseases 6 (2019) 47e53
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Research Article

CT and MRI features of fungal liver infection in children

Cui-ping Guo a,*,1, Qun Lao a,1, Fei Liu b, Hai-peng Pan a, Ning Han a, Xiao-gen Pan a
a
Radiology Department of Hangzhou Children's Hospital, Hangzhou, 310014, China
b
Department of Medicine of Hangzhou Children's Hospital, Hangzhou, 310014, China

Received 3 August 2018; revised 18 February 2019; accepted 11 March 2019

Available online 3 April 2019

Abstract

Objective: To investigate the imaging features of fungal liver infection in pediatric patients.
Materials and methods: CT and MRI findings of fungal liver infection were retrospectively analyzed in nine pediatric patients. There were six
males and three females, patients’ age ranged from 7 months to 9 years with an average of 4.1 years.
Results: Of the nine patients, one had a solitary lesion and eight had multiple lesions. According to the criteria based on the European
Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC-MSG) guidelines for clinical research. Multiphasic CT
and MRI examinations in the liver with fungal infection were performed and there were three types of imaging patterns. Type Ⅰ, "target-ring sign"
phenomenon. The lesion showed uneven low or iso density on plain CT scan, uneven iso-T1 or long T1 and long T2 signal on MRI scan, and
uneven annular enhancement on three-phases enhanced CT and MRI scan. Type Ⅱ, Delayed enhancement. The lesion showed low or iso-density
on plain CT scan, in arterial phase and portal phase, and iso-density in delayed phase. Type Ⅲ, Delayed ring-like-enhancement. The lesion
showed low or iso-density on plain CT scan, in arterial phase and portal phase, and ring-like enhancement in delayed phase. In arterial phase, the
liver parenchyma around the lesion showed transient abnormal, hyperperfusion in seven patients. Usually the lesion did not affect the hepatic
blood vessels which were seen in the enhanced scan. After antifungal therapy, the lesion decreased in size or even completely disappeared.
Conclusion: The findings of fungal liver infection on CT and MRI exhibited some specific imaging patterns, which could be helpful for early
diagnosis and treatment guidance.
© 2019 Beijing You’an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: Children; Liver; Fungal infection; Tomography; X-ray computed; Magnetic resonance imaging

Invasive fungal infection is a well-known complication in
patients who are undergoing lethal diseases, during the past
few decades, there has been a dramatic increase in the fre-
quency of fungal liver infections in pediatric patients. Various
factors have been suggested as contributors to the increased
susceptibility of these infections in this patient population,
these factors include intensive chemotherapy protocols for
* Corresponding author. Graduated From Southern Medical University,
Major for Medical Imaging and Nuclear Medicine, 1984-11, China.
E-mail addresses: 291483372@qq.com (C.-p. Guo), hzlaoqun@163.com
(Q. Lao).
Peer review under responsibility of Beijing You'an Hospital affiliated to
Capital Medical University.
1
Co first authors.
leukemia, liver transplantation, the use of prophylactic
antibiotics, bone marrow transplantation, prolonged antibiotic
therapy and immunosuppressive therapy [1e6]. Current
diagnostic methods lack sensitivity and specificity, a definitive
diagnosis of fungal infection remains challenging, because
patients with fungal infections generally have no specific
symptoms, the clinical assay system is time consuming, and
the findings in biopsy specimen cultures or tests are often
negative for fungi, which results in delayed treatment and
increased mortality. Therefore, prompt recognition of fungal
infection and initiation of appropriate treatment are crucial in
order to control the infection, decreasing the morbidity and
mortality. Imaging examinations play a vital role in the diag-
nosis and follow-up of hepatosplenic fungal infections. In
routine clinical practice, ultrasonography (US), computed

https://doi.org/10.1016/j.jrid.2019.03.001
2352-6211/© 2019 Beijing You’an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
48 C.-p. Guo et al. / Radiology of Infectious Diseases 6 (2019) 47e53
tomography (CT) and magnetic resonance imaging (MRI)
are frequently utilized. To our knowledge, the studies on the
performance of US, CT and MRI in the detection of fungal
liver infection have been limited, concentrating mainly on
findings during arterial phase and/or portal venous phase
[6e10]. Thus, the purpose of this study was to retrospectively
assess multiphasic (plain scan, arterial phase, portal venous
phase and delayed phase) CT and MRI of the liver for the
depiction of hepatic fungal infection, and for the first time,
delayed phase on CT and MRI was used for the evaluation of
hepatic fungal infection.
1. Materials and methods
1.1. General material
This study was to retrospectively evaluate the performance
of multiphasic CT and MRI in hepatic fungal infections, the
diagnostic criteria of fungal infection in this study was based
on the European Organization for Research and Treatment of
Cancer and Mycoses Study Group (EORTC-MSG) guidelines
for clinical research [6], the data of patients with proved
or probable fungal infection, as well as a final diagnosis, a
clinical diagnosis and intended diagnosis were included [6,11].
Multiphasic hepatic CT and MRI examinations were collected
in nine patients who fulfilled the criteria. All the patients were
unresponsive to broad spectrum antibiotics, were clinically
suspected of having hepatic fungal infection, and the antifungal
drugs had active effect which showed improvement on follow-
up CT and/or MRI after the administration of antifungal ther-
apy. There were six male patients and three female patients,
whose age ranged from 7 months to 9 years old with an average
of 4.1 years. Four patients had acute lymphocytic leukemia,
and two with acute myeloid leukemia. The clinical manifes-
tations were fever, skin bleeding, gingival bleeding, ochriasis
etc. Prophylactic antibiotics were used to prevent infection in
six patients during intensive chemotherapy. One patient was
infected with oral candida. One patient developed central
nervous system symptoms during the disease process, and head
MRI examination was abnormal. Fungal liver infection
occurred in one patient subsequent to fungal pneumonia and
fungal septicemia, this patient had lower extremity subcu-
taneous induration and femoral and tibial lesions which
Data of patients
Case Gender Age Cilinical diagnosis Lesion sites
1 female 9Y AML Liver spleen
2 man 3Y8M ALL Liver
Lung
Skin bone
3 female 3Y ALL Liver
Lung
4 man 1Y ALL Liver
improved after antifungal therapy. In these patients, five
patients had pulmonary fungal infection, two patients had
spleen infection, and one patient had kidney infection simul-
taneously. All patients were treated with antifungal therapy
(voriconazole, posaconazole and amphotericin B) for one to
four months. Lesions decreased in the size and number in three
patients and disappeared in another three patients at follow-up
CT and/or MRI following the administration of antifungal
therapy. Seven patients underwent CT examination, and two
patients underwent MRI examination. Multiple laboratory tests
of plasma 1-3-b-D glucan (<10 pg/ml is normal) showed
negative results, and only one patient had positive results.
1.2. Instrumenttation and methods
Children who can not cooperate were examined after
sedation. CT scans were obtained by using GE helical CT
system with the following parameters:100 kV, application of
automatic tube current modulation techniques. The scans were
reconstructed at collimations of 5 mm with 50% overlap. With
use of a power injector, nonionic intravenous contrast material
(iohexol） was administered at a dose of 1.5e2 ml/kg of body
weight at a rate of 1.0e3.0 ml/s, with 20-30S delay for the
arterial phase, 60-70S delay for the portal venous phase, and
120-180S delay for the delayed phase. The plan CT scan and
three-phase dynamic enhanced scan of the liver were per-
formed by using the same imaging parameters. MRI scans
were performed on 1.5 T MRI (Siemens Medical Systems),
using body coil, spin echo sequence for T1WI, T2WI trans-
action and coronary scanning, thickness 3e5 mm. With use of
Gd-DTPA (gadolinium-diethylenetriamine pentaacetic acid) at
a dose of 0.1e0.2 ml/kg, T1WI dynamic enhanced scan was
administered by using the same imaging parameters.
The scans obtained during all phases of the examination
were reviewed on picture archiving and communication sys-
tem workstation (PACS). The technical parameters used and
patient identifiers were hidden from the reviewers at the time
of analysis. The radiologists were allowed to choose the
window width and window level for each phase, as they saw
fit. The scan images were randomized and presented to a panel
of two experienced radiologists with more than 20 years of
experience reading abdominal CT and MRI images, the
interpretative decisions were made in consensus.
Course of treatment Antifungal therapy effect
Two months The lesions disappeared.
The lesions disappeared.
Three months The lesions disappeared.
The lesions disappeared.
The lesions disappeared.
The lesions absorbed.
Two months The lesions absorbed significantly.
The lesions absorbed significantly.
Two months The lesions absorbed significantly.
(continued on next page)
 C.-p. Guo et al. / Radiology of Infectious Diseases 6 (2019) 47e53 49

(continued )
Case Gender Age Cilinical diagnosis Lesion sites Course of treatment Antifungal therapy effect
5 man 2Y ALL Liver Four months The lesions disappeared.
Lung cerebral The lesions absorbed significantly.
infarction
6 man 5Y3M ALL Liver Three months The lesions disappeared.
Lung The lesions disappeared.
7 female 3Y9M AML Liver One month The lesions absorbed significantly.
8 man 8Y7M ALL Liver Two months The lesions disappeared.
Lung The lesions disappeared.
9 man 7m ALL Liver One month The lesions absorbed significantly.
Spleen The lesions absorbed significantly
Kidney The lesions disappeared.
Oral candidiasis The lesions absorbed significantly

2. Results
Among the nine cases, there was one with a solitary lesion
(Fig. 1) and eight with multiple lesions (Figs. 2e6). The size
of the lesions varied, there was no specific pattern of distri-
bution, and all lesions showed a round contour with 3e34 mm
diameters.
According to the criteria of multiphasic CT and MRI ex-
aminations in the liver with fungal infection, three patterns of
the lesions were found.
Type Ⅰ, "target-ring sign" phenomenon. On plain CT scan,
the lesion showed uneven low or iso-density with lower density
in the central of lesion as well as at the outer edge of the lesion,
which presented a "target-ring sign" (Fig. 1a). On enhanced
scan, the lesion showed ring-like inhomogeneous enhance-
mentdlow density in the center of lesiond (target-ring sign)
in arterial phase, in portal phase as well as in delayed phase
(Figs. 1bed, 2). Low density at the outer edge of the lesions
can be seen in arterial phase (Figs. 1b and 2), some faded away
in portal phase and some faded away in delayed phase
(Fig. 1d). The degree of enhancement of the lesion was higher
than normal liver parenchyma in triphasic enhancement scan
(Figs. 1bed, 2). The liver parenchyma around the lesion
showed transient abnormal, hyperperfusion in arterial phase,
and faded away in portal phase (Figs. 1b and c, 2).
On MRI scan, the lesions showed uneven isointense or
hypointense signal on T1WI (Fig. 3a) and hyperintense signal
on T2WI (Fig. 3b), lower signal on T1WI and higher signal on
T2WI in center of the lesion, which presented as "target-ring
sign" (Fig. 3a and b). On dynamic enhanced scans, lesion
showed annular inhomogeneous enhancement, hypointense
signal in the center of lesions, which presented the feature of
"target-ring sign" in arterial phase, in portal phase as well as in
delayed phase (Fig. 3cee). The ring-like lower signal at the
outer edge of the lesions could be seen in arterial phase
(Fig. 3c), some faded away in portal phase and some faded

Fig. 1. Type Ⅰ, three years eight months old male. On plain scan (Fig. 1a), the lesion shows uneven low density which presents a "target ring sign". The lesion shows
ring-like inhomogeneous enhancement, low density in the center, which presented a "target ring sign" in arterial phase (Fig. 1b), in portal phase (Fig. 1c) as well as
delayed phase (Fig. 1d). After treatment of three months duration, the lesion is resolved (Fig. 1 e).
50 C.-p. Guo et al. / Radiology of Infectious Diseases 6 (2019) 47e53

delayed phase (Figs. 5e6). The lesion presented mild enhance-

ment or no enhancement during arterial phase and portal phase.
In arterial phase, the liver parenchyma around the lesion
showed transient abnormality, hypertransfusion in seven
patients (Figs. 1b, 2 and 3c,6b,6f). Usually the lesion did not
affect the hepatic blood vessels which were seen in the
enhanced scan (Figs. 2 and 4d). After antifungal therapy, the
lesion decreased in size or even completely disappeared
(Figs. 1e, 3f and 4e,6f).

3. Discussion

Obviously, fungal infection is a major and potentially fatal

Fig. 2. Type Ⅰ, three years old female, lesions show "target-ring sign" in arterial
phase, the liver parenchyma around the lesions shows transient abnormality,
hypertransfusion. Blood vessel can be seen at the edge of the lesion.
away in delayed phase (Fig. 3d and e). The signal of
enhancement part of lesion was higher than normal liver
parenchyma in three enhanced phases (Fig. 3cee). The liver
parenchyma around the lesion showed transient abnormality,
hypertransfusion in arterial phase, and faded away in portal
phase (Fig. 3c and d).
Type Ⅱ, delayed enhancement. The lesion showed low or
iso-density on plain CT scan, as well as in arterial phase and
portal phase, and iso-density in delayed phase (Fig. 4). The
lesion presented mild enhancement or no enhancement during
arterial phase and portal phase.
Type Ⅲ, delayed ring-like-enhancement. The lesion showed
low or iso-density on plain CT scan, as well as in arterial phase
and portal phase, and ring-like-enhancement which presented
higher density compared with normal liver parenchyma in
complication in patients with liver transplantation, hemato-
poietic stem cell transplantation, hematologic malignancies or
granulocytopenia [1e11]. The incidence of fungal infections
in marrow transplant patients varies from 10% to 25%, in the
first year after liver transplantation is 40% [2,3].Pathogens of
fungal infection include Candida, Aspergillus, Cryptococcus
neoformans, and Histoplasma capsulatum et al. [4]. Patients
with fungal infections generally have no specific symptoms,
the risk for fungal infection is related to the use of immuno-
suppressive agents, broad-spectrum antibiotics, prophylactic
antibiotics, intensive chemotherapy protocols for leukemia.
Invasive fungal infection is an opportunistic infection, the
common target organs are lungs, liver and spleen.
There has been a dramatic increase in the frequency of
invasive fungal infections in patients with hematologic ma-
lignancies, especially, those being treated with intensive
chemotherapy protocols for acute leukemia. Disseminated
fungal disease can occur in 3%e29% of leukemia patients
[12]. Hepatic fungal infection can occur in different periods of
leukemia, according to literature reports, it often occurs in the

Fig. 3. TypeⅠ, nine years old female, The lesion shows uneven long T1 (Fig. 3a) and long T2 signal (Fig. 3b) on MRI scan, lower signal on T1WI and higher signal
on T2WI in center of the lesion, which represents a "target ring sign". The lesion shows annular inhomogeneous enhancement, hypointense signal in the center of
lesion, which represents a "target ring sign" in three enhanced phases (Fig. 3cee). After two months of treatment, the lesion has disappeared (Fig. 3f).
 C.-p. Guo et al. / Radiology of Infectious Diseases 6 (2019) 47e53
Fig. 4. Type Ⅱ, two years three months old male, the lesions shows low or iso-density on plain CT scan (Fig. 4a), as well as in arterial phase (Fig. 4b) and portal
phase (Fig. 4c and d), and iso-density in delayed phase (Fig. 4e). Blood vessels can be seen at the center of the lesion (Fig. 4d).
complete remission phase of bone marrow transplant or during
induced remission of leukemia after chemotherapy [13,14].
Early diagnosis and treatment of these infections are crucial in
order to control the infection and decrease the mortality and
morbidity. Furthermore, fungal liver infection lacks signs and
symptoms as diagnostic indicators, the positive rate of labo-
ratory examinations is low, and the early diagnosis can be
challenging, only one case showed positive results of Plasma
1-3-b-D Glucan in this group. Therefore, noninvasive imaging
examinations are of utmost clinical significance for early
diagnosis, treatment and therapeutic effects evaluation of
liver fungal infection, especially for children. If liver fungal
infection was not diagnosed promptly, it would be detrimental
to patients’ condition and could even endanger their life.
Imaging has a momentous role in the diagnosis and follow-
up of patients with hepatic fungal infection. Data reported in
Fig. 5. Type III, male, 1 year old, The lesion showed ring-like enhancement in
delayed phase.
51
the available literature included US, CT and MRI. Overall, CT
and MRI are superior to US in depicting fungal liver infection
and MRI is superior to CT [6,10,15]. In a study, portal venous
phase CT depicted 60% of the lesions, the results indicated,
without the addition of an arterial phase, 31% of the lesions of
fungal liver infection would have been missed, and 32.3% of
the lesions would have been missed with only the portal
venous phase [6]. However, enhanced scan only included
arterial and venous phases in the report by Metser et al., and
our study included plain scan, arterial phase, portal venous
phase and delayed phase on CT and MRI of the liver for the
evaluation of hepatic fungal infection.
According to the performances of multiphasic CT and MRI
examinations in the liver with fungal infection, three types of
patterns regarding the lesions could be found. There were
"target-ring sign" phenomenon (Type Ⅰ) which presented a
"target-ring sign" on multiphase CT and MRI scan, delayed
enhancement (Type Ⅱ) which presented iso-density in delayed
phase, and delayed ring-like enhancement (Type Ⅲ) which
presented ring-like enhancement in delayed phase.
In arterial phase, the liver parenchyma around the lesions
showed transient abnormal hyperperfusion which may be
associated with inflammation, probably owing to associated
hyperemia and portal venous flow stoppage. The nidus of
fungal infection in the liver was walled off by inflammatory
cells, proven by biopsy and autopsy study results [6]. Fungal
infection might lead to arterial congestion which could be
caused by a wide range of peripheral vasculitis. Consequently,
the host response to the inflammatory process affected the
imaging characteristics of inflammatory lesions of the liver.
On CT multiphasic enhancement scan, the detection of
lesions was better in arterial phase than portal phase and plain
scan, the detection rate in arterial phase and portal phase were
100% and 69% respectively [6,16]. Moreover, Li et al. [17]
52 C.-p. Guo et al. / Radiology of Infectious Diseases 6 (2019) 47e53
Fig. 6. Seven months old male, multiple lesions are seen in Liver, spleen and kidney. The lesions show low or iso-density on plain CT scan (Fig. 6a). The lesions
show low or iso-density which represents mild enhancement or no enhancement in arterial phase (Fig. 6b) and portal phase (Fig. 6c). In delayed phase (Fig. 6d),
some lesions show ring-like enhancement (type III), some lesions show iso-density (typeⅡ).
reported that the detection of lesions in the delayed phase of
2 min proved to be better than portal phase and plain scan. It
was interesting to note that type II lesions in our study were of
iso-density in the delayed phase, transient hepatic paren-
chymal enhancement on the periphery of most lesions could
be seen during the arterial phase. These patterns of multiphase
enhancement could indicate fungal infection.
In summary, it is believed that sensitivity of detecting le-
sions in patients with fungal infection in the liver was
significantly increased by using plain scan combined with
three-phase enhanced scan. A multiphasic technique was
needed for the assessment of focal liver lesions in patients
suspected of having hepatic fungal infection, which could aid
the radiologist in making a more confident diagnosis. When
broad-spectrum antibiotics failed in the treatment of patients
with liver abnormalities, especially in leukemia patients, im-
aging examinations should play an important role in the early
diagnosis and treatment of these patients, as well as detection
of the therapeutic effect during the course of treatment.
Differential diagnosis: (1) liver infiltration of leukemia, on
plain CT scan, lesion showed low density, ring enhancement on
multiphasic scans was rare, enlargement of liver volume and
multiple organ violations could be seen. (2) Liver metastatic
tumor in children was relatively rare. The "bovine eye sign" was
characteristic on enhanced scan. The necrotic tissue in the
central portion of tumor was irreversible, while the abnormity
in the central portion of hepatic fungal lesion mostly recovered
after antifungal treatment. (3) The obvious symptom of bacte-
rial liver abscess in patients was ardent fever, and edema around
the lesion was commonly seen on imaging examination.
The deficiency of this study was the small number of pa-
tients, which might lead to the loss of some patterns of lesions.
As it has been shown in the literature, obtaining histologic
proof in this patient population could be difficult. However,
the other limitation of this study was still the lack of histologic
proof which prevented us from clearly defining the correlation
between the different morphological structures depicted by
imaging (CT and MRI) and pathology. We intend to perform
another study with more patients in the future.
References
[1] Shao-Cheng L, Xian-Jie S, Lei H, Fang L, Yu-rong L, Ying L, et al.
Diagnosis and treatment of fungal infection after liver transplantation.
Chin J Nosocomiol 2011;124(7):1015e7.
[2] Rossetti F, Brawner DL, Bowden R, Meyer WG, Schoch HG, Fisher L,
et al. Fungal liver infection in marrow transplant recipients: prevalence at
autopsy, predisposing factors, and clinical features. Clin Infect Dis 1995;
20(4):801e11.
[3] Verma A, Wade JJ, Cheeseman P, Samaroo B, Rela M, Heaton ND, et al.
Risk factors for fungal infection in paediatric liver transplant recipients[J].
Pediatr Transplant 2010;9(2):220e5.
[4] Fung JJ. Fungal infection in liver transplantation. Transpl Infect Dis
2010;4(s3):18e23.
[5] Gedik H, Yokus O. Hepatosplenic candidiasis in patient with acute
leukemia. Asian Pac J Trop Dis 2015;5:S175e7.
[6] Metser U, Haider MA, Dill-Macky M, Atri M, Lockwood G, Minden M.
Fungal liver infection in immunocompromised patients: depiction with
multiphasic contrast-enhanced helical CT1. Radiology 2005;235(1):
97e105.
[7] Shirkhoda A, Lopez-Berestein G, Holbert JM, Luna MA. Hepatosplenic
fungal infection: CT and pathologic evaluation after treatment with
liposomal amphotericin B. Radiology 1986;159(2):349e53.
[8] Shirkhoda A. CT findings in hepatosplenic and renal candidiasis.
J Comput Assist Tomogr 1987;11(5):795e8.
[9] Grünebaum M, Ziv N, Kaplinsky C, Kornreich L, Horev G, Mor C. Liver
candidiasis. The various sonographic patterns in the immunocompro-
mised child. Pediatr Radiol 1991;21(7):497e500.
 C.-p. Guo et al. / Radiology of Infectious Diseases 6 (2019) 47e53
[10] Sallah S, Semelka R, Kelekis N, Worawattanakul S, Sallah W. Diagnosis
and monitoring response to treatment of hepatosplenic candidiasis in pa-
tients with acute leukemia using magnetic resonance imaging. Acta Hae-
matol 1998;100(2):77e81.
[11] Shi XJ, Lu SC, He L, Lu F, Liang YR, Luo Y, et al. Diagnosis and
treatment of fungal infection after liver transplantation. Chin J Nosoco-
miol 2011;124(7):1015e7.
[12] Massed A, Sallah S. Chronic disseminated candidiasis in patients with
acute leukemia：emphasis on diagnostic definition and treatment. Leuk
Res 2005;29(5):493e501.
[13] Pagano L, Mele L, Fianchi L, Melillo L, Martino B, D'Antonio D, et al.
Chronic disseminated candidiasis in patients with hematologic malignancies.
Haematologica 2002;87(5):535e41.
53
[14] An Qi, Ji Q, Daihua F, Mingwei J, Shumei X, Chengmin X. Clinical
analysis of invasive fungal disease after chemotherapy in childhood acute
leukemia. J Clin Pediatr 2016;34(1):7e9. 28.
[15] Moore NJ, Pang Y. In: Systemic candidiasis, vol. 23 5. Radiographics A
Review Publication of the Radiological Society of North America Inc;
2003. p. 1287e90.
[16] Yang XF, Guo HY, Zhou LS, Hu XS, Zhu HZ, Li ZP. CT findings of
fungal liver infection in leukemia patients. J Sun Yat-sen Univ (Soc Sci
Ed) 2014;35(5):786e90.
[17] Zhou Y, Li YH, Zhu M, Jiang H, Zou JY. CT evaluation in children with
hepatosplenic and renal fungal infection after chemotherapy. Chin J
Radiol 2005;5(39):517e9.