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CT and MRI features of fungal liver infection in children
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ScienceDirect Radiology of Infectious Diseases 6 (2019) 47e53 www.elsevier.com/locate/jrid
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 b
Radiology Department of Hangzhou Children's Hospital, Hangzhou, 310014, China 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 frequency 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: [email protected] (C.-p. Guo), [email protected] (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 diagnosis 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/).
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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.
improved after antifungal therapy. In these patients, five patients had pulmonary fungal infection, two patients had spleen infection, and one patient had kidney infection simultaneously. 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. Materials and methods 1.2. Instrumenttation 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 followup CT and/or MRI after the administration of antifungal therapy. 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 manifestations 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 subcutaneous induration and femoral and tibial lesions which
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 performed 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 transaction 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 system 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.
Data of patients Case
Gender
Age
Cilinical diagnosis
Lesion sites
Course of treatment
Antifungal therapy effect
1
female
9Y
AML
Liver spleen
Two months
2
man
3Y8M
ALL
Liver Lung Skin bone
Three months
3
female
3Y
ALL
Two months
4
man
1Y
ALL
Liver Lung Liver
The The The The The The The The The
Two months
lesions lesions lesions lesions lesions lesions lesions lesions lesions
disappeared. disappeared. disappeared. disappeared. disappeared. absorbed. absorbed significantly. absorbed significantly. 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
Four months
The lesions disappeared. The lesions absorbed significantly.
6
man
5Y3M
ALL
Three months
7 8
female man
3Y9M 8Y7M
AML ALL
9
man
7m
ALL
Liver Lung cerebral infarction Liver Lung Liver Liver Lung Liver Spleen Kidney Oral candidiasis
The The The The The The The The The
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 distribution, and all lesions showed a round contour with 3e34 mm diameters. According to the criteria of multiphasic CT and MRI examinations 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 enhancementdlow 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
One month Two months One month
lesions lesions lesions lesions lesions lesions lesions lesions lesions
disappeared. disappeared. absorbed significantly. disappeared. disappeared. absorbed significantly. absorbed significantly disappeared. absorbed significantly
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).
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C.-p. Guo et al. / Radiology of Infectious Diseases 6 (2019) 47e53
delayed phase (Figs. 5e6). The lesion presented mild enhancement 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
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
Obviously, fungal infection is a major and potentially fatal complication in patients with liver transplantation, hematopoietic 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 immunosuppressive 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 malignancies, 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
51
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 laboratory 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 followup 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.
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]
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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 parenchymal 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 lesions 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, imaging 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 bacterial 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 patients, 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] Gru¨nebaum M, Ziv N, Kaplinsky C, Kornreich L, Horev G, Mor C. Liver candidiasis. The various sonographic patterns in the immunocompromised 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 patients with acute leukemia using magnetic resonance imaging. Acta Haematol 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 Nosocomiol 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.
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[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.
H O S T E D BY
ScienceDirect Radiology of Infectious Diseases 6 (2019) 47e53 www.elsevier.com/locate/jrid
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 b
Radiology Department of Hangzhou Children's Hospital, Hangzhou, 310014, China 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 frequency 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: [email protected] (C.-p. Guo), [email protected] (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 diagnosis 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/).
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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.
improved after antifungal therapy. In these patients, five patients had pulmonary fungal infection, two patients had spleen infection, and one patient had kidney infection simultaneously. 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. Materials and methods 1.2. Instrumenttation 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 followup CT and/or MRI after the administration of antifungal therapy. 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 manifestations 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 subcutaneous induration and femoral and tibial lesions which
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 performed 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 transaction 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 system 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.
Data of patients Case
Gender
Age
Cilinical diagnosis
Lesion sites
Course of treatment
Antifungal therapy effect
1
female
9Y
AML
Liver spleen
Two months
2
man
3Y8M
ALL
Liver Lung Skin bone
Three months
3
female
3Y
ALL
Two months
4
man
1Y
ALL
Liver Lung Liver
The The The The The The The The The
Two months
lesions lesions lesions lesions lesions lesions lesions lesions lesions
disappeared. disappeared. disappeared. disappeared. disappeared. absorbed. absorbed significantly. absorbed significantly. 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
Four months
The lesions disappeared. The lesions absorbed significantly.
6
man
5Y3M
ALL
Three months
7 8
female man
3Y9M 8Y7M
AML ALL
9
man
7m
ALL
Liver Lung cerebral infarction Liver Lung Liver Liver Lung Liver Spleen Kidney Oral candidiasis
The The The The The The The The The
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 distribution, and all lesions showed a round contour with 3e34 mm diameters. According to the criteria of multiphasic CT and MRI examinations 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 enhancementdlow 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
One month Two months One month
lesions lesions lesions lesions lesions lesions lesions lesions lesions
disappeared. disappeared. absorbed significantly. disappeared. disappeared. absorbed significantly. absorbed significantly disappeared. absorbed significantly
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).
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delayed phase (Figs. 5e6). The lesion presented mild enhancement 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
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
Obviously, fungal infection is a major and potentially fatal complication in patients with liver transplantation, hematopoietic 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 immunosuppressive 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 malignancies, 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).
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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 laboratory 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 followup 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.
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]
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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 parenchymal 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 lesions 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, imaging 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 bacterial 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 patients, 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] Gru¨nebaum M, Ziv N, Kaplinsky C, Kornreich L, Horev G, Mor C. Liver candidiasis. The various sonographic patterns in the immunocompromised 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 patients with acute leukemia using magnetic resonance imaging. Acta Haematol 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 Nosocomiol 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.
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[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.