mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Case report
Successful management of hepatic mucormycosis in an acute lymphoblastic leukaemia patient: a case report and review of the literature Gulen Tuysuz1, Nihal Ozdemir1, Osman Faruk Senyuz2, Senol Emre2, Serda Kantarcioglu3, _ Ibrahim Adaletli4, Nuray Kepil5, C ß igdem Tutuncu6 and Tiraje Celkan1 1 Pediatric Hematology Oncology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 2Pediatric Surgery Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 3Microbiology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 4 Radiology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 5Pathology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey and 6Anesthesiology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
Summary
We present a case of hepatic mucormycosis in a 9-year-old boy with acute lymphoblastic leukaemia. Despite long-term use of combined liposomal amphotericin B and posaconazole therapy, the lesion persisted and could only be treated by surgical excision. After surgery, antifungal treatment was continued with posaconazole. On follow-up, the patient had two episodes of ascending cholangitis which were responsive to intravenous antibiotics. He is doing well at the moment in remission for 2.5 years. Mucormycosis was long regarded as a fatal infection with poor prognosis. With early medical and surgical management, survival rates increase. Isolated hepatic mucormycosis is rare and only seven cases were reported in the literature up to now. We wanted to emphasise the role of early surgery in patients with hepatic mucormycosis in view of the literature.
Key words: Hepatic mucormycosis, ALL, posaconazole.
Introduction Mucormycosis, also named as zygomycosis, refers to several diseases caused by infection with fungi in the order of Mucorales.1 This saprophytic fungus has low virulence potential in the human host. Disease in humans mainly occurs in people who have risk factors.2,3 The vast majority of invasive paediatric cases have a fatal outcome, mortality rates range from 70% to 100% in disseminated cases.4 This shows both the difficulty in making an early diagnosis and the poor activity of conventional antifungal agents against € €ltesi Correspondence: G. Tuysuz, _Istanbul Universitesi Cerrahpasßa Tıp Faku Yerlesßkesi Cerrahpasßa-Fatih, _Istanbul 34098, Turkey. Tel.: +90 505 315 96 67. Fax: +90 216 338 45 37. E-mail: [email protected] Submitted for publication 28 November 2013 Revised 17 January 2014 Accepted for publication 16 February 2014
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
Mucorales. Here, we present a case of hepatic mucormycosis in an acute lymphoblastic leukaemia (ALL) patient treated successfully with antifungal therapy and surgery.
Case report A 9-year-old boy was referred to our clinic with enlarged cervical lymph nodes and was diagnosed with ALL. He was classified as moderate risk group according to the BFM-2000 protocol and chemotherapy was initiated. After induction therapy, disease was in complete remission. On the 60th day of the chemotherapy (during phase 1b of induction therapy) the patient developed febrile neutropenia and abdominal pain. Physical examination was normal except for mild upper right abdominal tenderness. Blood count showed neutropenia [absolute neutrophil count (ANC): 100 mm 3] and thrombocytopenia. After obtaining samples for cultures, antibiotic treatment with ceftazidime and amikacin was
doi:10.1111/myc.12184
G. Tuysuz et al.
initiated. Ultrasound of the abdomen was normal; the fever disappeared in 24 h after initiation of antibiotics and the pain vanished. There was no growth in cultures. Fever was under control but antibiotic therapy was continued due to prolonged neutropenia. Fifteen days after the first fever attack, while the patient was still neutropenic (ANC: 0 mm 3), he again developed fever and abdominal pain. Cultures were reobtained. Antibacterial therapy was changed to imipenem/cilastatin and empirical liposomal amphotericin B (LAMB) (3 mg kg 1 day 1; qd) was started due to breakthrough fever. Ultrasonography of the liver showed an irregular lesion of 4 cm in diameter. Serum galactomannan antigen was positive three times. Computerised tomography (CT) of abdomen, thorax and sinuses were performed. Paranasal sinus CT was normal, however, thorax CT demonstrated a solid nodular lesion surrounded by a halo sign at the upper lobe posterior segment of the right lung compatible with fungal infection (Fig. 1). Voriconazole was added with an initial diagnosis of pulmonary aspergillosis. Abdominal magnetic resonance imaging (MRI) scan showed an irregular hypo dense lesion, 4 cm in diameter at the intersection of right–left lobe. Due to the compression of the mass, intrahepatic bile ducts were dilated (Fig. 2). On the 4th day of voriconazole therapy, the patient developed hypotension and oedema. He was diagnosed as capillary leak syndrome due to voriconazole and antifungal drug was switched to posaconazole (200 mg per dose; tid). To identify the type of the fungus, ultrasound-guided fine-needle aspiration biopsy of hepatic lesion was performed. No fungus was detected on direct microscopy.
Figure 1 Thorax computerised tomography of patient. A solid
nodular lesion surrounded by a halo sign at the upper lobe posterior segment of the right lung.
514
Figure 2 Axial T2 weighted MRI of abdomen. MRI shows an
irregular hypo dense lesion, 4 cm in diameter at the intersection of right–left lobe.
Attempts to identify the species by culture also failed. One day after the aspiration, the patient developed signs and symptoms of cholestasis including icterus, elevated alkaline phosphatase, gamma-glutamyl transferase and direct bilirubin levels. Control ultrasound revealed a haematoma surrounding the lesion as a complication of the procedure. The patient was treated symptomatically and cholestasis decreased gradually with the resorption of haematoma. The patient was stable, had no fever, free of neutropenia and thrombocytopenia 15 days after the initiation of dual antifungal therapy. Therefore, chemotherapy was resumed after 60 days of interval. Despite the long-term use of combined antifungal therapy (for 72 days) the lesion on the liver did not involute on follow-up imaging with ultrasonography and abdominal CT (Fig. 3). The affected lobe of the liver and bile system was excised with the fungus ball (Fig. 4). The operation ended with insertion of a drainage tube. Necrosis and broad, rectangular branching hyphae were detected on histopathology of the specimen (Fig. 5). Direct microscopical examination of Giemsa stained imprinted tissue slides revealed abundant broad coenocytic hyphae typical of mucormycotic agents. Hyphae were irregularly branched, pleomorphic, with irregular, non-parallel contours and stained eosinophilic. The infection was identified as a mucormycosis based on typical hyphal morphology seen in tissue material and documented by photomicrographs (Fig. 6). The fungus did not grow on culture of operation material. The antifungal treatment was continued with posaconazole during reinduction chemotherapy.
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
Mucormycosis in a child with ALL
Figure 3 Control abdominal computerised tomography (CT).
Figure 5 Pathologic examination of lesion. Periodic acid–Schiff staining of the lesion showed irregularly branched fungal hyphae.
Non-contrast abdominal CT shows persistence of the lesion.
Figure 4 Surgery of the lesion. In operation, lesion on liver was
identified with ultrasonography. With the help of a cautery, parenchyma was deepened and surgeon reached to the anterior capsule of cavity. A small hole was dug at anterior capsule; there was bile leak into the cavity and fungus ball was colorised with bile juice. The hole was enlarged than fungus ball totally excised in a spherical shape. Because of a wide internal biliary fistula from the right main bile duct to the basement of fungus ball cavity, the procedure ended up with insertion of a large Pezzer catheter into the cavity and a drainage procedure (choledochoduodenostomy plus cholecystectomy). Figure 6 Direct microscopical examination of imprinted tissue
Drainage tube was removed 24 days after the operation. Ultrasound and CT of abdomen performed after surgery were unremarkable for any fungal infection. Lesion on lung parenchyma involuted on control thorax CT and totally resolved on the 6th month of antifungal therapy. The patient is in complete remission with no evidence of fungal infection for 2, 5 years now. On
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
slides. Giemsa staining of imprinted tissue slides showed abundant, broad coenocytic, irregularly branched, pleomorphic, eosinophilic stained hyphae.
follow-up, the patient had two episodes of ascending cholangitis which were responsive to intravenous antibiotics.
515
516
3.5
5
2
50
58
2
3
4
5
6
F
M
F
M
F
F
M
Gender
Immunocompromised (recipient of liver transplantation for 2 times due to fulminant hepatitis A infection) Immunocompromised (recipient of kidney transplantation, type 2 diabetes mellitus, end stage renal disease) Immunocompromised (BMT recipient, diabetes mellitus, chronic hepatitis B infection) Immunocompromised (recipient of orthopaedic liver transplantation)
Immunocompetent (accompanied by hepatitis A infection)
Immunocompetent
Immunocompromised (BMT recipient due to MDS) intake of naturopathic medicine
Predisposing conditions
Right hypochondriac pain and fever
Abdominal pain for 4 months
Palpable mass at epigastrium
Abdominal haemorrhage (24 h after 2nd liver transplantation)
Abdominal pain, intermittent fever, palpable 5 9 5 cm mass at epigastrium and enlarged liver 4 cm below costal margin Jaundice, loss of consciousness, enlarged liver 8 cm below costal margin
Right upper quadrant pain
Clinical presentation
Localised left-sided 4.9 9 2.8 9 5.2 cm sub diaphragmatic abscess on liver at abdominal CT Hepatic abscess 5.3 9 5.1 cm in liver at abdominal CT
Necrotic left hepatic lobe of liver at abdominal CT
No data
No data
Inhomogeneous mass occupying left lobe of liver at abdominal CT
Three, circumscribed low attenuation lesion on liver at abdominal CT
Liver involvement
Fungal culture positive for mucor species from liver abscess aspiration specimen Tissue invasion of specific hyphae for mucormycosis
Fungal culture positive for mucor species from hepatic lobectomy specimen
Postmortem liver specimen; necrotic debris and hyphae specific for mucormycosis Post mortem liver specimen; necrosis and hyphae specific for mucormycosis
Fungal growth of mucormycosis from fine-needle aspiration of specimen Open liver biopsy; hyphae specific of mucormycosis
Diagnostic confirmation of mucormycosis
Lesions disappeared
Patient stable
Died due to septic shock caused by Klebsiella pneumonia and Staphylococcus aureus
Catheter placement LAMB+ micafungin Left lateral hepatic segmentectomy Percutaneous drainage of abscess LAMB+ polymyxin
Died on post-op 10th day due to disseminated mucormycosis and septic shock
Developed progressive liver failure and died at 12th day of retransplantation
Deteriorated fast and died on 8th day of hospitalisation
The child was good 6 months later leaving the hospital
Hepatic lesions unchanged but patient was free of symptoms
Survey
Went under left hepatic lobectomy
No specific treatment for fungus
No specific treatment for fungus
Family refused the therapy
ABLC and percutaneous drainage of abscess
Treatment
14
13
12
11
10
9
8
Reference
M, male; F, female; BMT, bone marrow transplantation; MDS, myelodysplastic syndrome; ABLC, amphotericin B lipid complex; LAMB, liposomal amphotericin B; CT, computerised tomography.
23
39
1
7
Age (years)
Patient no.
Table 1 The review of previous patients with isolated hepatic involvement.
G. Tuysuz et al.
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
Mucormycosis in a child with ALL
Discussion Mucormycosis is a rare fungal infection occurring mainly in immunocompromised patients.5,6 Solid organ transplant recipients, immunosuppressive drug and prolonged corticosteroids receivers, patients with malignancies, poorly controlled diabetes mellitus, malnutrition and chronic illness are at high risk for mucormycosis. Deferoxamine chelation therapy with iron overload is also a predisposing factor for the disease.1,7 The most common sites of infection include rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, renal and central nervous system. Hepatic infection is rarely reported and usually occurs with gastrointestinal or pulmonary involvement and also disseminated disease.2 We reviewed the PubMed database for cases with isolated hepatic mucormycosis and found seven cases (Table 1). Three of these cases were children and the rest four were adults. Five of the cases were immunocompromised and the two were immunocompetent. One of the immunocompetent patients (patient 3) had fulminant hepatitis A infection. Most of the patients (patient no: 3, 4, 5, 6) died due to disease progression. Two of the patients who died were children (patient no: 3, 4). There are no data about liver scanning of these patients and disease was diagnosed at autopsy material. These patients did not receive any treatment for fungal infection. The other two adult patients who died were under treatment and were lost due to disease progression despite all the attempts including catheter replacement, combined antifungal therapy (patient no: 6) and lobectomy of the affected liver (patient no: 5). The two survivors of the disease (patient no: 1, 7) had undergone percutaneous drainage of the abscess and received antifungal treatment with LAMB and LAMB+ polymyxin respectively. A 3.5-year-old immunocompetent boy (patient no: 2) survived despite cessation of antifungal treatment by the family and found to be normal 6 months later. Successful treatment of mucormycosis involves reversal of underlying factors, surgical debridement of the lesion and concomitant early administration of antifungal agents. The first-line drug of choice is liposomal amphotericin B.15 Posaconazole is an alternative drug and recommended at prophylaxis and salvage therapy. The preferred posaconazole dosage for paediatric patients has not been defined.16 We applied a dosage of 200 mg orally three times per daily with an informed consent from the family. In the haematological immunocompromised patients, suspicion is crucial for the diagnosis of mucormycosis infection since early management can reduce morbidity
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
and mortality. Mucormycosis was long regarded as a fatal infection with poor prognosis. In review of paediatric zygomycosis by Zaoutis et al. [17], cerebral, gastrointestinal and disseminated zygomycosis were associated with a mortality rate of 100%, 100% and 88% respectively. With early medical and surgical management, survival rates are now thought to exceed 70%.18 In our case, surgery was performed with delay, on 72th day of combined antifungal therapy, relating to concerns about wound healing in immunocompromised patients. Earlier surgical operations should be considered if there is no radiologic improvement 4–5 weeks of full antifungal therapy despite neutrophil recovery because these patients are under risk of death or disseminated disease. The differential diagnosis of focal lesions in liver in patients with ALL should include mucormycosis, other fungal, bacterial and parasitic infections, leukaemia deposits, cholangitis and sarcoidosis. Hepatic mucormycosis was successfully treated with combined antifungal therapy and early surgery in our patient. There are not enough data on the use of combined antifungal treatment in mucormycosis infection. The management of patients with hepatic lesions unresponsive to antibiotic/antifungal treatment should include surgery. The prognosis is better with early surgery. In conclusion, isolated hepatic mucormycosis is rare disease and early surgery is crucial in patients unresponsive to antifungal therapy.
Conflict of interest The authors declare no conflict of interest.
References 1 2
3 4
5
6 7
8
Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev 2000; 13: 236–301. Mooney J, Wagner A. Mucormycosis of the gastrointestinal tract in children: report of a case and review of the literature. Pediatr Infect Dis 1993; 12: 872–6. Paya CV. Fungal infections in solid organ transplantation. Clin Infect Dis 1993; 16: 677–88. Yeung CK, Cheng VC, Lie AK, Yuen KY. Invasive disease due to Mucorales: a case report and review of the literature. Hong Kong Med J 2001; 7: 180–8. Ingram CW, Sennesh J, Cooper JN, Perfect JR. Disseminated zygomycosis: report of four cases and review. Rev Infect Dis 1989; 11: 741– 54. Harril WC, Stewart MG, Lee AG, Cernoch P. Chronic rhinocerebral mucormycosis. Laryngoscope 1996; 106: 1292. Barber an J. Recommendations for the treatment of invasive fungal infection caused by filamentous fungi in the hematological patient. Rev Esp Quimioter 2011; 24: 263–70. Oliver MR, Van Voorhis WC, Boeckh M, Mattson D, Bowden RA. Hepatic mucormycosis in a bone marrow transplant recipient who ingested naturopathic medicine. Clin Infect Dis 1996; 22: 521–4.
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12 13 14
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Al-Asiri RH, Van Dijken PJ, Mahmood MA, Al-Shahed MS, Rossi ML, Osoba AO. Isolated hepatic mucormycosis in an immunocompetent child. Am J Gastroenterol 1996; 91: 606–7. €ren Z, Kanra G. Hepatic mucoErdem G, Ca glar M, Ceyhan M, Akcßo rmycosis in a child with fulminant hepatic failure. Turk J Pediatr 1996; 38: 511–4. Marc o del Pont J, De Cicco L, Gallo G, Llera J, De Santibanez E, D’agostino D. Hepatic arterial thrombosis due to Mucor species in a child following orthotopic liver transplantation. Transpl Infect Dis 2000; 2: 33–35. Mekeel KL, Hemming AW, Reed AI et al. Hepatic mucormycosis in a renal transplant recipient. Transplantation 2005; 79: 1636. Su H, Thompson GR 3rd, Cohen SH. Hepatic mucormycosis with abscess formation. Diagn Microbiol Infect Dis 2012; 73: 192–4. Abboud CS, Bergamasco MD, Baıa CE et al. Case report of hepatic mucormycosis after liver transplantation: successful treatment with
15
16
17
18
liposomal amphotericin B followed by posaconazole sequential therapy. Transplant Proc 2012; 44: 2501–2. Spellberg B, Walsh TJ, Kontoyiannis DP et al. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009; 48: 1743. Cesaro S, Milano GM, Aversa F. Retrospective survey on the off-label use of posaconazole in pediatric hematology patients. Eur J Clin Microbiol Infect Dis 2011; 30: 595–6. Zaoutis TE, Roilides E, Chiou CC et al. Zygomycosis in children: a systematic review and analysis of reported cases. Pediatr Infect Dis J 2007; 26: 723–7. Roden MM, Zaoutis TE, Buchanan WL et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41: 634–53.
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Case report
Successful management of hepatic mucormycosis in an acute lymphoblastic leukaemia patient: a case report and review of the literature Gulen Tuysuz1, Nihal Ozdemir1, Osman Faruk Senyuz2, Senol Emre2, Serda Kantarcioglu3, _ Ibrahim Adaletli4, Nuray Kepil5, C ß igdem Tutuncu6 and Tiraje Celkan1 1 Pediatric Hematology Oncology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 2Pediatric Surgery Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 3Microbiology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 4 Radiology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 5Pathology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey and 6Anesthesiology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
Summary
We present a case of hepatic mucormycosis in a 9-year-old boy with acute lymphoblastic leukaemia. Despite long-term use of combined liposomal amphotericin B and posaconazole therapy, the lesion persisted and could only be treated by surgical excision. After surgery, antifungal treatment was continued with posaconazole. On follow-up, the patient had two episodes of ascending cholangitis which were responsive to intravenous antibiotics. He is doing well at the moment in remission for 2.5 years. Mucormycosis was long regarded as a fatal infection with poor prognosis. With early medical and surgical management, survival rates increase. Isolated hepatic mucormycosis is rare and only seven cases were reported in the literature up to now. We wanted to emphasise the role of early surgery in patients with hepatic mucormycosis in view of the literature.
Key words: Hepatic mucormycosis, ALL, posaconazole.
Introduction Mucormycosis, also named as zygomycosis, refers to several diseases caused by infection with fungi in the order of Mucorales.1 This saprophytic fungus has low virulence potential in the human host. Disease in humans mainly occurs in people who have risk factors.2,3 The vast majority of invasive paediatric cases have a fatal outcome, mortality rates range from 70% to 100% in disseminated cases.4 This shows both the difficulty in making an early diagnosis and the poor activity of conventional antifungal agents against € €ltesi Correspondence: G. Tuysuz, _Istanbul Universitesi Cerrahpasßa Tıp Faku Yerlesßkesi Cerrahpasßa-Fatih, _Istanbul 34098, Turkey. Tel.: +90 505 315 96 67. Fax: +90 216 338 45 37. E-mail: [email protected] Submitted for publication 28 November 2013 Revised 17 January 2014 Accepted for publication 16 February 2014
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
Mucorales. Here, we present a case of hepatic mucormycosis in an acute lymphoblastic leukaemia (ALL) patient treated successfully with antifungal therapy and surgery.
Case report A 9-year-old boy was referred to our clinic with enlarged cervical lymph nodes and was diagnosed with ALL. He was classified as moderate risk group according to the BFM-2000 protocol and chemotherapy was initiated. After induction therapy, disease was in complete remission. On the 60th day of the chemotherapy (during phase 1b of induction therapy) the patient developed febrile neutropenia and abdominal pain. Physical examination was normal except for mild upper right abdominal tenderness. Blood count showed neutropenia [absolute neutrophil count (ANC): 100 mm 3] and thrombocytopenia. After obtaining samples for cultures, antibiotic treatment with ceftazidime and amikacin was
doi:10.1111/myc.12184
G. Tuysuz et al.
initiated. Ultrasound of the abdomen was normal; the fever disappeared in 24 h after initiation of antibiotics and the pain vanished. There was no growth in cultures. Fever was under control but antibiotic therapy was continued due to prolonged neutropenia. Fifteen days after the first fever attack, while the patient was still neutropenic (ANC: 0 mm 3), he again developed fever and abdominal pain. Cultures were reobtained. Antibacterial therapy was changed to imipenem/cilastatin and empirical liposomal amphotericin B (LAMB) (3 mg kg 1 day 1; qd) was started due to breakthrough fever. Ultrasonography of the liver showed an irregular lesion of 4 cm in diameter. Serum galactomannan antigen was positive three times. Computerised tomography (CT) of abdomen, thorax and sinuses were performed. Paranasal sinus CT was normal, however, thorax CT demonstrated a solid nodular lesion surrounded by a halo sign at the upper lobe posterior segment of the right lung compatible with fungal infection (Fig. 1). Voriconazole was added with an initial diagnosis of pulmonary aspergillosis. Abdominal magnetic resonance imaging (MRI) scan showed an irregular hypo dense lesion, 4 cm in diameter at the intersection of right–left lobe. Due to the compression of the mass, intrahepatic bile ducts were dilated (Fig. 2). On the 4th day of voriconazole therapy, the patient developed hypotension and oedema. He was diagnosed as capillary leak syndrome due to voriconazole and antifungal drug was switched to posaconazole (200 mg per dose; tid). To identify the type of the fungus, ultrasound-guided fine-needle aspiration biopsy of hepatic lesion was performed. No fungus was detected on direct microscopy.
Figure 1 Thorax computerised tomography of patient. A solid
nodular lesion surrounded by a halo sign at the upper lobe posterior segment of the right lung.
514
Figure 2 Axial T2 weighted MRI of abdomen. MRI shows an
irregular hypo dense lesion, 4 cm in diameter at the intersection of right–left lobe.
Attempts to identify the species by culture also failed. One day after the aspiration, the patient developed signs and symptoms of cholestasis including icterus, elevated alkaline phosphatase, gamma-glutamyl transferase and direct bilirubin levels. Control ultrasound revealed a haematoma surrounding the lesion as a complication of the procedure. The patient was treated symptomatically and cholestasis decreased gradually with the resorption of haematoma. The patient was stable, had no fever, free of neutropenia and thrombocytopenia 15 days after the initiation of dual antifungal therapy. Therefore, chemotherapy was resumed after 60 days of interval. Despite the long-term use of combined antifungal therapy (for 72 days) the lesion on the liver did not involute on follow-up imaging with ultrasonography and abdominal CT (Fig. 3). The affected lobe of the liver and bile system was excised with the fungus ball (Fig. 4). The operation ended with insertion of a drainage tube. Necrosis and broad, rectangular branching hyphae were detected on histopathology of the specimen (Fig. 5). Direct microscopical examination of Giemsa stained imprinted tissue slides revealed abundant broad coenocytic hyphae typical of mucormycotic agents. Hyphae were irregularly branched, pleomorphic, with irregular, non-parallel contours and stained eosinophilic. The infection was identified as a mucormycosis based on typical hyphal morphology seen in tissue material and documented by photomicrographs (Fig. 6). The fungus did not grow on culture of operation material. The antifungal treatment was continued with posaconazole during reinduction chemotherapy.
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
Mucormycosis in a child with ALL
Figure 3 Control abdominal computerised tomography (CT).
Figure 5 Pathologic examination of lesion. Periodic acid–Schiff staining of the lesion showed irregularly branched fungal hyphae.
Non-contrast abdominal CT shows persistence of the lesion.
Figure 4 Surgery of the lesion. In operation, lesion on liver was
identified with ultrasonography. With the help of a cautery, parenchyma was deepened and surgeon reached to the anterior capsule of cavity. A small hole was dug at anterior capsule; there was bile leak into the cavity and fungus ball was colorised with bile juice. The hole was enlarged than fungus ball totally excised in a spherical shape. Because of a wide internal biliary fistula from the right main bile duct to the basement of fungus ball cavity, the procedure ended up with insertion of a large Pezzer catheter into the cavity and a drainage procedure (choledochoduodenostomy plus cholecystectomy). Figure 6 Direct microscopical examination of imprinted tissue
Drainage tube was removed 24 days after the operation. Ultrasound and CT of abdomen performed after surgery were unremarkable for any fungal infection. Lesion on lung parenchyma involuted on control thorax CT and totally resolved on the 6th month of antifungal therapy. The patient is in complete remission with no evidence of fungal infection for 2, 5 years now. On
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
slides. Giemsa staining of imprinted tissue slides showed abundant, broad coenocytic, irregularly branched, pleomorphic, eosinophilic stained hyphae.
follow-up, the patient had two episodes of ascending cholangitis which were responsive to intravenous antibiotics.
515
516
3.5
5
2
50
58
2
3
4
5
6
F
M
F
M
F
F
M
Gender
Immunocompromised (recipient of liver transplantation for 2 times due to fulminant hepatitis A infection) Immunocompromised (recipient of kidney transplantation, type 2 diabetes mellitus, end stage renal disease) Immunocompromised (BMT recipient, diabetes mellitus, chronic hepatitis B infection) Immunocompromised (recipient of orthopaedic liver transplantation)
Immunocompetent (accompanied by hepatitis A infection)
Immunocompetent
Immunocompromised (BMT recipient due to MDS) intake of naturopathic medicine
Predisposing conditions
Right hypochondriac pain and fever
Abdominal pain for 4 months
Palpable mass at epigastrium
Abdominal haemorrhage (24 h after 2nd liver transplantation)
Abdominal pain, intermittent fever, palpable 5 9 5 cm mass at epigastrium and enlarged liver 4 cm below costal margin Jaundice, loss of consciousness, enlarged liver 8 cm below costal margin
Right upper quadrant pain
Clinical presentation
Localised left-sided 4.9 9 2.8 9 5.2 cm sub diaphragmatic abscess on liver at abdominal CT Hepatic abscess 5.3 9 5.1 cm in liver at abdominal CT
Necrotic left hepatic lobe of liver at abdominal CT
No data
No data
Inhomogeneous mass occupying left lobe of liver at abdominal CT
Three, circumscribed low attenuation lesion on liver at abdominal CT
Liver involvement
Fungal culture positive for mucor species from liver abscess aspiration specimen Tissue invasion of specific hyphae for mucormycosis
Fungal culture positive for mucor species from hepatic lobectomy specimen
Postmortem liver specimen; necrotic debris and hyphae specific for mucormycosis Post mortem liver specimen; necrosis and hyphae specific for mucormycosis
Fungal growth of mucormycosis from fine-needle aspiration of specimen Open liver biopsy; hyphae specific of mucormycosis
Diagnostic confirmation of mucormycosis
Lesions disappeared
Patient stable
Died due to septic shock caused by Klebsiella pneumonia and Staphylococcus aureus
Catheter placement LAMB+ micafungin Left lateral hepatic segmentectomy Percutaneous drainage of abscess LAMB+ polymyxin
Died on post-op 10th day due to disseminated mucormycosis and septic shock
Developed progressive liver failure and died at 12th day of retransplantation
Deteriorated fast and died on 8th day of hospitalisation
The child was good 6 months later leaving the hospital
Hepatic lesions unchanged but patient was free of symptoms
Survey
Went under left hepatic lobectomy
No specific treatment for fungus
No specific treatment for fungus
Family refused the therapy
ABLC and percutaneous drainage of abscess
Treatment
14
13
12
11
10
9
8
Reference
M, male; F, female; BMT, bone marrow transplantation; MDS, myelodysplastic syndrome; ABLC, amphotericin B lipid complex; LAMB, liposomal amphotericin B; CT, computerised tomography.
23
39
1
7
Age (years)
Patient no.
Table 1 The review of previous patients with isolated hepatic involvement.
G. Tuysuz et al.
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
Mucormycosis in a child with ALL
Discussion Mucormycosis is a rare fungal infection occurring mainly in immunocompromised patients.5,6 Solid organ transplant recipients, immunosuppressive drug and prolonged corticosteroids receivers, patients with malignancies, poorly controlled diabetes mellitus, malnutrition and chronic illness are at high risk for mucormycosis. Deferoxamine chelation therapy with iron overload is also a predisposing factor for the disease.1,7 The most common sites of infection include rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, renal and central nervous system. Hepatic infection is rarely reported and usually occurs with gastrointestinal or pulmonary involvement and also disseminated disease.2 We reviewed the PubMed database for cases with isolated hepatic mucormycosis and found seven cases (Table 1). Three of these cases were children and the rest four were adults. Five of the cases were immunocompromised and the two were immunocompetent. One of the immunocompetent patients (patient 3) had fulminant hepatitis A infection. Most of the patients (patient no: 3, 4, 5, 6) died due to disease progression. Two of the patients who died were children (patient no: 3, 4). There are no data about liver scanning of these patients and disease was diagnosed at autopsy material. These patients did not receive any treatment for fungal infection. The other two adult patients who died were under treatment and were lost due to disease progression despite all the attempts including catheter replacement, combined antifungal therapy (patient no: 6) and lobectomy of the affected liver (patient no: 5). The two survivors of the disease (patient no: 1, 7) had undergone percutaneous drainage of the abscess and received antifungal treatment with LAMB and LAMB+ polymyxin respectively. A 3.5-year-old immunocompetent boy (patient no: 2) survived despite cessation of antifungal treatment by the family and found to be normal 6 months later. Successful treatment of mucormycosis involves reversal of underlying factors, surgical debridement of the lesion and concomitant early administration of antifungal agents. The first-line drug of choice is liposomal amphotericin B.15 Posaconazole is an alternative drug and recommended at prophylaxis and salvage therapy. The preferred posaconazole dosage for paediatric patients has not been defined.16 We applied a dosage of 200 mg orally three times per daily with an informed consent from the family. In the haematological immunocompromised patients, suspicion is crucial for the diagnosis of mucormycosis infection since early management can reduce morbidity
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 513–518
and mortality. Mucormycosis was long regarded as a fatal infection with poor prognosis. In review of paediatric zygomycosis by Zaoutis et al. [17], cerebral, gastrointestinal and disseminated zygomycosis were associated with a mortality rate of 100%, 100% and 88% respectively. With early medical and surgical management, survival rates are now thought to exceed 70%.18 In our case, surgery was performed with delay, on 72th day of combined antifungal therapy, relating to concerns about wound healing in immunocompromised patients. Earlier surgical operations should be considered if there is no radiologic improvement 4–5 weeks of full antifungal therapy despite neutrophil recovery because these patients are under risk of death or disseminated disease. The differential diagnosis of focal lesions in liver in patients with ALL should include mucormycosis, other fungal, bacterial and parasitic infections, leukaemia deposits, cholangitis and sarcoidosis. Hepatic mucormycosis was successfully treated with combined antifungal therapy and early surgery in our patient. There are not enough data on the use of combined antifungal treatment in mucormycosis infection. The management of patients with hepatic lesions unresponsive to antibiotic/antifungal treatment should include surgery. The prognosis is better with early surgery. In conclusion, isolated hepatic mucormycosis is rare disease and early surgery is crucial in patients unresponsive to antifungal therapy.
Conflict of interest The authors declare no conflict of interest.
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