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First case report of isolated penile mucormycosis in a liver transplantation recipient
International Journal of Infectious Diseases 29 (2014) 208–210
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Case Report
First case report of isolated penile mucormycosis in a liver transplantation recipient Ming-chun Lai 1, Wei Zhang 1, Zhe Yang, Wu Zhang, K.G. Owusu-Ansah, Song-feng Yu, Lei Geng, Hai-yang Xie, Lin Zhou, Shu-sen Zheng * Division of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
A R T I C L E I N F O
Article history: Received 1 September 2014 Received in revised form 23 September 2014 Accepted 25 September 2014 Corresponding Editor: Eskild Petersen, Aarhus, Denmark Keywords: Penile mucormycosis Transplantation Surgical intervention Early diagnosis
S U M M A R Y
Mucormycosis is a rare but potentially lethal complication of liver transplantation. Most reported cases have involved rhinocerebral, pulmonary, gastrointestinal, or disseminated forms. We present herein the case of a 61-year-old male patient with hepatocellular carcinoma who developed isolated penile mucormycosis after orthotopic liver transplantation. Such a case has not been reported in the literature to date. Early diagnosis and timely surgical intervention combined with comprehensive treatment are the key factors for improving the survival rate in patients with mucormycosis. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).
1. Introduction
2. Case report
Mucormycosis is an extremely rare, but potentially lifethreatening fungal infection, which occurs in 0.4% to 16.0% of solid organ transplantation (SOT) recipients and results in high mortality rates.1 It is caused by species of the order Mucorales, and those most often implicated include Rhizopus, Rhizomucor, Cunninghamella, and Mucor. An increasing number of transplantassociated mucormycosis cases have been reported over recent decades. Despite aggressive surgical debridement and appropriate antifungal treatment, the mortality remains high and virtually unchanged since the 1960s.2 Mucormycosis can manifest with different clinical presentations, particularly in SOT recipients, among whom the most common type of infection is paranasal sinus (39%), followed by pulmonary (24%), cutaneous (19%), cerebral (9%), and gastrointestinal (7%) forms; other miscellaneous forms are extremely rare.3 We describe the first case of penile mucormycosis, occurring following liver transplantation in a patient with hepatocellular carcinoma. He was treated successfully with surgical debridement, antifungal therapy, and temporary withdrawal of immunosuppressants.
A-61-year-old male patient underwent a deceased donor liver transplantation for a small hepatocellular carcinoma in a background of chronic hepatitis B-related cirrhosis. During the waiting period, he underwent trans-arterial chemoembolization treatment once to prevent tumor progression. The surgery was uneventful, and the graft perfusion was normal. A bigeminy immunosuppressive regimen (methylprednisolone, mycophenolate mofetil) with antiCD25 induction therapy (basiliximab) was administered, and fluconazole was given for antifungal prophylaxis. Postoperatively, the patient developed impaired liver function and acute renal failure; hence tacrolimus was suspended until the serum creatinine level was below 1.24 mg/dl. In light of these problems, he received artificial liver support therapy and continuous renal replacement therapy (CRRT). After treatment, the liver function recovered rapidly. Twenty days post liver transplantation, the patient’s urinary volume increased continuously and kidney function gradually improved; no further CRRT was required. Surprisingly, 35 days after the operation, some deep ulcers with irregular margins appeared at the coronary sulcus and the bottom of his penis. However, within days, the ulcerous lesions had noticeably increased in size and his glans penis became necrotic and flecked with black spots (Figure 1a). He had a high fever but no pain or difficulty in urination. Thus, we suspected an invasive fungal or bacterial infection of the penis. Subsequently, a biopsy
* Corresponding author. Tel.: +86 571 87236570; fax: +86 571 87236466. E-mail address: [email protected] (S.-s. Zheng). 1 These authors contributed to this work equally.
http://dx.doi.org/10.1016/j.ijid.2014.09.017 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
M.- Lai et al. / International Journal of Infectious Diseases 29 (2014) 208–210
209
Figure 1. The patient was diagnosed with isolated penile mucormycosis and underwent surgical debridement, penectomy, and cystostomy. (a) Some deep ulcers and black spots on the penis before the operation. (b) Cytological examination revealed tangles of large non-septated fungal hyphae consistent with mucormycosis (400). (c) Postoperation. (d) Histology examination showed several fungal hyphae (hematoxylin–eosin staining, 400).
was performed and cytological examination revealed tangles of broad, ribbon-like, and aseptate hyphae, suggesting mucormycosis (Figure 1b). As a result, immunosuppressive treatment was temporarily suspended. Concerned about the rapid progression and high mortality of this mold infection, surgical debridement was performed immediately. During the operation, we found that the infection had disseminated from the urethra and corpus cavernosum to the penile root. The patient underwent a penectomy and cystostomy (Figure 1c). Postoperatively, histopathological evaluation also showed several fungal hyphae consistent with penile mucormycosis in a background of necrotic tissue (Figure 1d). Antifungal treatment was initiated with intravenous liposomal amphotericin B (3 mg/kg/day) for 5 weeks and this was switched to oral posaconazole at a dose of 800 mg/day for another 7 weeks. During this period, the patient also struggled with pulmonary and abdominal infections, as well as poor wound healing. Therefore, as well as the parenteral antibiotics, vacuum-sealing drainage (VSD) was employed, which required him to stay in bed for more than a month. Of note, the liposomal amphotericin B regimen was lower than the standard starting doses of 5 mg/kg/day because of his relatively poor kidney function. Fortunately, the patient was able to tolerate the long course of antifungal therapy; kidney function and that of the grafted liver remained stable after this infectious episode. The mucormycosis was completely controlled, as seen by normalization of infection parameters (leukocyte count and C-reactive protein). Three months later, he was readmitted and underwent a urethroplasty. During the surgery, an additional biopsy was performed to confirm the success of the antifungal treatment. 3. Discussion Mucormycosis in liver transplantation recipients is an extremely rare, but life-threatening fungal infection, frequently associated with impaired immune states. With the emergence of new antifungal therapies, immunomodulation regimens, and combined
treatment, the survival rate of patients with invasive fungal infections has improved significantly.3 This situation is, however, different for mucormycosis. Although remarkable progress has also been made in recent decades, the overall mortality of patients with mucormycosis remains high because of relative delays in diagnosis. Indeed, a delay in diagnosis of this type of infection of more than 5 days can even be associated with a two-fold increase in mortality.4 According to a recent multicenter TRANSNET study, the 12-month cumulative incidence of mucormycosis was 0.16% in liver transplantation recipients, with a mortality rate of approximately 40%, which appears to far exceed that of all other invasive mold infections.2 Mucormycosis generally affects patients with known predisposing conditions, such as organ transplantation, uncontrolled diabetes mellitus, neutropenia, cancer, etc.3 We could identify several risk factors for the penile mucormycosis in this patient: he had hepatocellular carcinoma, was post liver transplantation, had acute renal insufficiency after surgery, and was taking immunosuppressants and steroids. The pathogenic mechanisms of mucormycosis are not yet fully understood, unlike those of other fungi. The hallmark of Mucorales is angioinvasion leading to thrombosis of the invaded vessels, which can cause tissue necrosis and prevent antifungal drugs (amphotericin B) from reaching the site of infection.2 Therefore, timely surgical debridement is crucial in some cases and has been reported to be an independent prognostic factor of successful therapy in SOT patients with mucormycosis. In terms of antifungal therapy, liposomal amphotericin B has shown better tissue penetration and safety than amphotericin B deoxycholate. The use of liposomal amphotericin B has been associated with a better prognosis in SOT recipients with Mucoraceae infections, and it is considered as the first-line treatment.2,4 However, the efficacy of monotherapy is always limited and given the high mortality of mucormycosis, once infection is established, or the clinical suspicion is high, surgical intervention combined with liposomal amphotericin B and/or posaconazole is recommended.5 In our case, the diagnosis of penile mucormycosis was established early and
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M.- Lai et al. / International Journal of Infectious Diseases 29 (2014) 208–210
this was treated with prompt and effective combined therapies, which helped in the rapid control of the infection; the patient eventually recovered. In conclusion, we have presented the first report of isolated penile mucormycosis occurring in a liver-transplant patient that was treated successfully with surgery and antifungal therapy. This case emphasizes the importance of clinical findings and biopsy as effective methods for the early diagnosis of this infection. Mucormycosis in unusual locations is extremely rare, but it is important to maintain a suspicion for this infection in high-risk patients, as this is key to early diagnosis and treatment. Acknowledgements Our work was supported by the National S&T Major Project (No. 2012ZX10002017) and National Natural Science Foundation of China (No. 81302074, 81101840).
Conflict of interest: The authors declare that they have no conflict of interest. References 1. Neofytos D, Treadway S, Ostrander D, Alonso CD, Dierberg KL, Nussenblatt V, et al. Epidemiology, outcomes, and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience. Transpl Infect Dis 2013;15:233–42. 2. Lanternier F, Sun HY, Ribaud P, Singh N, Kontoyiannis DP, Lortholary O. Mucormycosis in organ and stem cell transplant recipients. Clin Infect Dis 2012;54: 1629–36. 3. Singh N, Wagener MM, Cacciarelli TV, Levitsky J. Antifungal management practices in liver transplant recipients. Am J Transplant 2008;8:426–31. 4. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008;47:503–9. 5. Chakrabarti A, Das A, Sharma A, Panda N, Das S, Gupta KL, et al. Ten years’ experience in zygomycosis at a tertiary care centre in India. J Infect 2001;42: 261–6.
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Case Report
First case report of isolated penile mucormycosis in a liver transplantation recipient Ming-chun Lai 1, Wei Zhang 1, Zhe Yang, Wu Zhang, K.G. Owusu-Ansah, Song-feng Yu, Lei Geng, Hai-yang Xie, Lin Zhou, Shu-sen Zheng * Division of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
A R T I C L E I N F O
Article history: Received 1 September 2014 Received in revised form 23 September 2014 Accepted 25 September 2014 Corresponding Editor: Eskild Petersen, Aarhus, Denmark Keywords: Penile mucormycosis Transplantation Surgical intervention Early diagnosis
S U M M A R Y
Mucormycosis is a rare but potentially lethal complication of liver transplantation. Most reported cases have involved rhinocerebral, pulmonary, gastrointestinal, or disseminated forms. We present herein the case of a 61-year-old male patient with hepatocellular carcinoma who developed isolated penile mucormycosis after orthotopic liver transplantation. Such a case has not been reported in the literature to date. Early diagnosis and timely surgical intervention combined with comprehensive treatment are the key factors for improving the survival rate in patients with mucormycosis. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).
1. Introduction
2. Case report
Mucormycosis is an extremely rare, but potentially lifethreatening fungal infection, which occurs in 0.4% to 16.0% of solid organ transplantation (SOT) recipients and results in high mortality rates.1 It is caused by species of the order Mucorales, and those most often implicated include Rhizopus, Rhizomucor, Cunninghamella, and Mucor. An increasing number of transplantassociated mucormycosis cases have been reported over recent decades. Despite aggressive surgical debridement and appropriate antifungal treatment, the mortality remains high and virtually unchanged since the 1960s.2 Mucormycosis can manifest with different clinical presentations, particularly in SOT recipients, among whom the most common type of infection is paranasal sinus (39%), followed by pulmonary (24%), cutaneous (19%), cerebral (9%), and gastrointestinal (7%) forms; other miscellaneous forms are extremely rare.3 We describe the first case of penile mucormycosis, occurring following liver transplantation in a patient with hepatocellular carcinoma. He was treated successfully with surgical debridement, antifungal therapy, and temporary withdrawal of immunosuppressants.
A-61-year-old male patient underwent a deceased donor liver transplantation for a small hepatocellular carcinoma in a background of chronic hepatitis B-related cirrhosis. During the waiting period, he underwent trans-arterial chemoembolization treatment once to prevent tumor progression. The surgery was uneventful, and the graft perfusion was normal. A bigeminy immunosuppressive regimen (methylprednisolone, mycophenolate mofetil) with antiCD25 induction therapy (basiliximab) was administered, and fluconazole was given for antifungal prophylaxis. Postoperatively, the patient developed impaired liver function and acute renal failure; hence tacrolimus was suspended until the serum creatinine level was below 1.24 mg/dl. In light of these problems, he received artificial liver support therapy and continuous renal replacement therapy (CRRT). After treatment, the liver function recovered rapidly. Twenty days post liver transplantation, the patient’s urinary volume increased continuously and kidney function gradually improved; no further CRRT was required. Surprisingly, 35 days after the operation, some deep ulcers with irregular margins appeared at the coronary sulcus and the bottom of his penis. However, within days, the ulcerous lesions had noticeably increased in size and his glans penis became necrotic and flecked with black spots (Figure 1a). He had a high fever but no pain or difficulty in urination. Thus, we suspected an invasive fungal or bacterial infection of the penis. Subsequently, a biopsy
* Corresponding author. Tel.: +86 571 87236570; fax: +86 571 87236466. E-mail address: [email protected] (S.-s. Zheng). 1 These authors contributed to this work equally.
http://dx.doi.org/10.1016/j.ijid.2014.09.017 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
M.- Lai et al. / International Journal of Infectious Diseases 29 (2014) 208–210
209
Figure 1. The patient was diagnosed with isolated penile mucormycosis and underwent surgical debridement, penectomy, and cystostomy. (a) Some deep ulcers and black spots on the penis before the operation. (b) Cytological examination revealed tangles of large non-septated fungal hyphae consistent with mucormycosis (400). (c) Postoperation. (d) Histology examination showed several fungal hyphae (hematoxylin–eosin staining, 400).
was performed and cytological examination revealed tangles of broad, ribbon-like, and aseptate hyphae, suggesting mucormycosis (Figure 1b). As a result, immunosuppressive treatment was temporarily suspended. Concerned about the rapid progression and high mortality of this mold infection, surgical debridement was performed immediately. During the operation, we found that the infection had disseminated from the urethra and corpus cavernosum to the penile root. The patient underwent a penectomy and cystostomy (Figure 1c). Postoperatively, histopathological evaluation also showed several fungal hyphae consistent with penile mucormycosis in a background of necrotic tissue (Figure 1d). Antifungal treatment was initiated with intravenous liposomal amphotericin B (3 mg/kg/day) for 5 weeks and this was switched to oral posaconazole at a dose of 800 mg/day for another 7 weeks. During this period, the patient also struggled with pulmonary and abdominal infections, as well as poor wound healing. Therefore, as well as the parenteral antibiotics, vacuum-sealing drainage (VSD) was employed, which required him to stay in bed for more than a month. Of note, the liposomal amphotericin B regimen was lower than the standard starting doses of 5 mg/kg/day because of his relatively poor kidney function. Fortunately, the patient was able to tolerate the long course of antifungal therapy; kidney function and that of the grafted liver remained stable after this infectious episode. The mucormycosis was completely controlled, as seen by normalization of infection parameters (leukocyte count and C-reactive protein). Three months later, he was readmitted and underwent a urethroplasty. During the surgery, an additional biopsy was performed to confirm the success of the antifungal treatment. 3. Discussion Mucormycosis in liver transplantation recipients is an extremely rare, but life-threatening fungal infection, frequently associated with impaired immune states. With the emergence of new antifungal therapies, immunomodulation regimens, and combined
treatment, the survival rate of patients with invasive fungal infections has improved significantly.3 This situation is, however, different for mucormycosis. Although remarkable progress has also been made in recent decades, the overall mortality of patients with mucormycosis remains high because of relative delays in diagnosis. Indeed, a delay in diagnosis of this type of infection of more than 5 days can even be associated with a two-fold increase in mortality.4 According to a recent multicenter TRANSNET study, the 12-month cumulative incidence of mucormycosis was 0.16% in liver transplantation recipients, with a mortality rate of approximately 40%, which appears to far exceed that of all other invasive mold infections.2 Mucormycosis generally affects patients with known predisposing conditions, such as organ transplantation, uncontrolled diabetes mellitus, neutropenia, cancer, etc.3 We could identify several risk factors for the penile mucormycosis in this patient: he had hepatocellular carcinoma, was post liver transplantation, had acute renal insufficiency after surgery, and was taking immunosuppressants and steroids. The pathogenic mechanisms of mucormycosis are not yet fully understood, unlike those of other fungi. The hallmark of Mucorales is angioinvasion leading to thrombosis of the invaded vessels, which can cause tissue necrosis and prevent antifungal drugs (amphotericin B) from reaching the site of infection.2 Therefore, timely surgical debridement is crucial in some cases and has been reported to be an independent prognostic factor of successful therapy in SOT patients with mucormycosis. In terms of antifungal therapy, liposomal amphotericin B has shown better tissue penetration and safety than amphotericin B deoxycholate. The use of liposomal amphotericin B has been associated with a better prognosis in SOT recipients with Mucoraceae infections, and it is considered as the first-line treatment.2,4 However, the efficacy of monotherapy is always limited and given the high mortality of mucormycosis, once infection is established, or the clinical suspicion is high, surgical intervention combined with liposomal amphotericin B and/or posaconazole is recommended.5 In our case, the diagnosis of penile mucormycosis was established early and
210
M.- Lai et al. / International Journal of Infectious Diseases 29 (2014) 208–210
this was treated with prompt and effective combined therapies, which helped in the rapid control of the infection; the patient eventually recovered. In conclusion, we have presented the first report of isolated penile mucormycosis occurring in a liver-transplant patient that was treated successfully with surgery and antifungal therapy. This case emphasizes the importance of clinical findings and biopsy as effective methods for the early diagnosis of this infection. Mucormycosis in unusual locations is extremely rare, but it is important to maintain a suspicion for this infection in high-risk patients, as this is key to early diagnosis and treatment. Acknowledgements Our work was supported by the National S&T Major Project (No. 2012ZX10002017) and National Natural Science Foundation of China (No. 81302074, 81101840).
Conflict of interest: The authors declare that they have no conflict of interest. References 1. Neofytos D, Treadway S, Ostrander D, Alonso CD, Dierberg KL, Nussenblatt V, et al. Epidemiology, outcomes, and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience. Transpl Infect Dis 2013;15:233–42. 2. Lanternier F, Sun HY, Ribaud P, Singh N, Kontoyiannis DP, Lortholary O. Mucormycosis in organ and stem cell transplant recipients. Clin Infect Dis 2012;54: 1629–36. 3. Singh N, Wagener MM, Cacciarelli TV, Levitsky J. Antifungal management practices in liver transplant recipients. Am J Transplant 2008;8:426–31. 4. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008;47:503–9. 5. Chakrabarti A, Das A, Sharma A, Panda N, Das S, Gupta KL, et al. Ten years’ experience in zygomycosis at a tertiary care centre in India. J Infect 2001;42: 261–6.