© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Case report
Disseminated Cunninghamella bertholletiae infection with spinal epidural abscess in a kidney transplant patient: case report and literature review O. Navanukroh, A. Jitmuang, M. Chayakulkeeree, P. Ngamskulrungroj. Disseminated Cunninghamella bertholletiae infection with spinal epidural abscess in a kidney transplant patient: case report and literature review. Transpl Infect Dis 2014: 16: 658–665. All rights reserved Abstract: Cunninghamella bertholletiae is a rare cause of invasive mucormycosis. We report the case of a 42-year-old Thai woman who suffered from disseminated C. bertholletiae infection. The patient developed dry cough, sharp shooting pain in the left buttock referred to the left leg, and fever 1 month after undergoing deceased-donor kidney transplantation. Radiographic studies exhibited multiple pulmonary cavities, osteomyelitis of the sacral spine, epidural abscess along the lumbrosacral spine, and paravertebral soft tissue involvement. Surgical debridement of the epidural abscess concurrent with prolonged intravenous administration of amphotericin B resulted in a good outcome.
O. Navanukroh1, A. Jitmuang1, M. Chayakulkeeree1, P. Ngamskulrungroj2 1
Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand, 2 Department of Microbiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand Key words: Cunninghamella bertholletiae; mucormycosis; kidney transplant Correspondence to: Anupop Jitmuang, MD, Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, 2 Prannok Road, Bangkok Noi, Bangkok 10700, Thailand Tel: 66 2 419 7783 Fax: 66 2 419 7783 E-mail: [email protected]
Received 14 November 2013, revised 27 January 2014, accepted for publication 13 March 2014 DOI: 10.1111/tid.12251 Transpl Infect Dis 2014: 16: 658–665
Mucormycosis is a highly invasive fungal infection caused by fungi in the recently proposed subphylum Mucoromycotina and order Mucorales (1). The fungi in the order include several species, including Rhizopus species, Mucor species, Rhizomucor species, Absidia species (reclassified as Lichtheimia species), Apophysomyces species, Saksenaea species, Cunninghamella species, Cokeromyces species, and Syncephalastrum species. The 3 most common species that cause angioinvasive disease are Rhizopus species, Absidia species, and Mucor species, while the other species are rarely reported to cause diseases in humans (2). Human mucormycosis by Cunninghamella species is rare, and typically causes invasive disease in the immunocompromised patient. Herein, we report a case of disseminated Cunninghamella bertholletiae infection
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with multiple lung cavities and spinal epidural abscess of the lumbrosacral spine.
Case report A 42-year-old Thai woman with chronic kidney disease had been receiving regular hemodialysis for 10 years. On December 30, 2012, she was admitted to Siriraj Hospital, Bangkok, Thailand, and underwent deceaseddonor kidney transplantation. The donor was a previously healthy 39-year-old woman who suffered a car accident with severe head injury. The anti-cytomegalovirus immunoglobulin-G of both donor and recipient were positive, whereas other screening tests and chest radiography were normal. The patient was prescribed a
Navanukroh et al: Disseminated Cunninghamella bertholletiae infection
combination of immunosuppressive agents, methylprednisolone, tacrolimus, prednisolone, and mycophenolate mofetil, for primary prevention of graft rejection, and co-trimoxazole for prophylaxis of Pneumocystis jirovecii pneumonia, respectively. However, renal function deteriorated, and serum creatinine level rose from 4.96 to 8.95 mg/dL within 4 days post kidney transplantation. Kidney biopsy identified acute tubular necrosis and antibody-mediated glomerulitis, which were consistent with acute graft rejection. Therefore, to treat the acute graft rejection, total plasma exchange, intravenous immunoglobulin, rituximab, and anti-thymocyte globulin were administered. Her renal function recovered after the intensive immunosuppressive regimen. Eventually, serum creatinine level went down to 1.33 mg/dL, and the patient was discharged with a maintenance oral immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and prednisolone). Seven days after discharge, the patient was readmitted to the hospital with a presentation of dry cough for 5 days and continuous sharp shooting pain in the left buttock. The pain radiated to the posterior aspect of her left leg, and was worse when bending her left knee. One day before the re-admission, she developed progressive pain in the left lower limb with fever and pleurisy of the right side of her chest. Physical examination revealed body temperature of 38.6°C, pulse rate of 120/min, respiratory rate of 20/ min, and blood pressure of 120/90 mmHg. Coarse crackles and rhonchi in the right lower lung field were heard. Neurological examination identified hyperalgesia on the posterior side of the left leg, hypoesthesia on plantar and dorsolateral side of the left foot, and left ankle hyporeflexia. Complete blood count revealed hemoglobin 8.8 g/ dL, hematocrit 28%, white blood cell count 16,300/mm3 with polymorphonuclear (PMN) cells 94%, and platelet count 508,000/mm3. Blood urea nitrogen and creatinine level were 36 and 1.31 mg/dL, respectively. Chest radiography demonstrated a huge cavity with smooth borders in the right lung, while computed tomography of the chest identified 2 thick-walled cavities 1.2 9 1.4 cm and 2.8 9 3.1 cm diameter in size, at the right upper lung and right middle lung, respectively. The chest radiography also revealed a large complex thick-walled cavity 4.5 9 5.3 cm in diameter at the superior segment of the right lower lung, as shown in Figure 1. Magnetic resonance imaging of her lumbosacral spine showed osteomyelitis of S1 vertebral body and left alar of the sacrum, left S1 neuritis, epidural abscess along L4 to S1 vertebral level, and abnormal enhancement of adjacent left presacral and left paravertebral soft tissues, as shown in Figure 2.
A
B
Fig. 1. Radiological findings illustrate (A) a huge, well-defined border cavity (white arrow) at the right lower lobe on chest x-ray, and (B) 2 thick-walled cavities (black arrow) at right middle lobe and right lower lobe, including a single nodule (arrow head) on computed tomography scan.
From the radiological findings, the presumptive diagnosis was multiple lung abscesses, S1 vertebral osteomyelitis, and lumbrosacral epidural abscess. An empirical antibiotics treatment for invasive bacterial and fungal infections was prescribed with intravenous imipenem-cilastatin 2 g/day and amphotericin B deoxycholate 40 mg/day. Bronchoscopy and bronchoalveolar lavage (BAL) were performed; galactomannan index from the BAL fluid was 0.71. Transbronchial lung biopsy was also undertaken; the pathological findings showed acute
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A
Fig. 2. Magnetic resonance imaging of the lumbosacral spine shows abnormal epidural fluid collection with rim enhancement (arrow head) along L4-S1 levels and gadolinium enhancement of S1 vertebral body (arrow).
and chronic inflammation with focal foreign body granulomatous reaction and degenerated fungal hyphae. On the twelfth day of the hospitalization, decompressive laminectomy of L4 and S1 vertebra was carried out and 5 mL of yellowish pus was obtained from the epidural abscess. Pathological sections discovered degenerated fungal hyphae. Both fungal cultures from BAL fluid and pus from the abscess rapidly grew cottony colonies of gray-to-white non-septate mold, which were morphologically consistent with Cunninghamella species. Polymerase chain reaction and sequencing of the internal transcribed spacer regions of ribosomal DNA were performed and identified Cunninghamella bertholletiae. Therefore, imipenem-cilastatin was discontinued, while antifungal therapy was switched to 5 mg/ kg/day (200 mg/day) of liposomal amphotericin B (LAMB) intravenously owing to deterioration of renal function after receiving the conventional amphotericin B. The patient was hospitalized for 50 days, and then she was transferred to a provincial hospital for continuation of the LAMB infusion. After a 3-month course of LAMB, her symptoms were gradually improved, and serum creatinine level ranged between 1.3 and 1.5 mg/dL. She had no remaining chest symptoms. Her weakness and numbness of the lower extremities were improved. As the minimum inhibi-
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B
Fig. 3. Radiographic follow-up of the chest shows (A) disappearance of the cavitary lesion on plain radiography, and (B) the reduced cavitary lesions on computed tomography scan (arrow).
tory concentration (MIC) of posaconazole of the isolates was 0.25 lg/mL, the patient received oral posaconazole 800 mg/day as maintenance therapy. After she took posaconazole for 1 week, she developed a pruritic rash and discontinued antifungal treatment. Nonetheless, her overall condition has remained stable. Radiographic follow-up of the chest showed disappearance of the cavitary lesion on plain radiography, and computed tomography scan exhibited smaller size of cavitary lesions, as shown in Figure 3.
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Discussion and literature review Cunninghamella species are saprophytic, ubiquitous fungi found in soil, sewage, air, water, and vegetation, especially in tropical and subtropical zones. The genus Cunninghamella contains 7 species, of which C. bertholletiae, Cunninghamella elegans, and Cunninghamella echinulata are the most common. To our knowledge, C. bertholletiae is the only species that has been reported to be a human pathogen. It was primarily isolated from Brazilian soil samples by Stadel in 1911 and was first reported to cause an infection in a human in 1958. Cunninghamella species are characterized by white-togray colonies that grow rapidly at room temperature to 45°C in 24–48 h on Sabouraud dextrose agar. The mycelium is 0.5–2 cm tall and varies in color from gray or white to yellow. The morphology is pleomorphic depending on the culture media. Microscopically, hyphae appear to be non-septate or sparsely septate with broad, branching, and erect sporangiophores. The sporangiophores terminate in swollen vesicles covered by short stalked sporangioles. Sporangioles are round-tooval shape (3, 4). It uncommonly grows in hemoculture. Thus, definite diagnosis of invasive mold infection usually requires evidence of tissue invasion from a histopathology specimen and identification of species. Fungal tissue culture is necessary for susceptibility testing. Nevertheless, culture results are often negative, despite fungal hyphae being seen in pathological specimens. For speciation, conventional carbohydrate utilization is a very intricate and time-consuming technique for species identification. Rickerts et al. (5) discovered that detection of fungal DNA from tissue specimens by polymerase chain reaction can improve the diagnosis of aspergillosis and mucormycosis. To identify Cunninghamella species, the variable sequence of internal transcribed spacer regions has a great value for species differentiation (6). C. bertholletiae infection is a rare cause of invasive mucormycosis and has a strong predilection to affect immunocompromised patients. Previously reported cases were described and >98% of patients had immunodeficiency states: leukemia (7–10), solid organ transplantation (9, 11–14), bone marrow transplantation (15, 16), diabetes mellitus (17), non-malignant hematologic disease (18–20), deferoxamine-based therapy (21), AIDS (22), cirrhosis (23), and immunosuppressive therapy. Only 2 cases were reported in immunocompetent patients (24, 25). Inhalation of fungal spores that contaminate the environment has been speculated to be a major source
of transmission. Macrophages and neutrophils prevent fungal invasion by phagocytosis and oxidative killing of spores, whereas these cells in immunocompromised patient fail to suppress the germination of spores and are unable to kill the fungal element effectively (26). As a result, disorders of those cells, such as neutropenia, diabetic ketoacidosis, or immunosuppressive therapy, are a pivotal contributing factor of angioinvasion (27). Moreover, fungi in the order Mucorales can utilize host iron or iron compounds in chelating agents, such as deferoxamine and desferrioxamine, to augment their growth, so patients who have excessive iron level or are receiving the chelating agents also are at increased risk of severe infection (28). As in our reported case, the important risk factor was a previous combination of immunosuppressive treatments to prevent acute graft rejection. In terms of environmental factors, a cluster of C. bertholletiae pulmonary infection in immunocompromised patients might be related to hospital construction (9). Although the reported case developed disseminated infection within 1 week after discharge, invasive mucormycosis has not been strongly correlated with the hospital environment in our institute. Like other infections by fungi in the order Mucorales, clinical characteristics of Cunninghamella infection are not specific. Moreover, the clinical infection may resemble other opportunistic infections such as tuberculosis, nocardiosis, and cryptococcosis, which should be considered in the differential diagnosis. Because inhalation is a main portal of entry, the vast majority of these infections manifest as pulmonary disease, disseminated infection secondary to pulmonary disease, and rhino-orbito-cerebral infection. Unusual manifestations of C. bertholletiae infection have also been reported, such as cutaneous or osteoarticular infections following percutaneous inoculation and peritonitis following continuous ambulatory peritoneal dialysis (17, 22, 29). From case series, approximately 70% of disseminated disease occurred in patients with underlying hematologic diseases and were diagnosed postmortem (3). The lung was the most affected organ of infection, and other foci of dissemination were heart and/or pericardium, spleen, brain, kidney, liver, gastrointestinal tract, skin, etc. Our case initially presented with respiratory symptoms and subsequently developed dissemination to vertebra and lumbrosacral epidural space. Pulmonary angioinvasion is a significant pathological finding from this infection; however, few patients with disseminated infection and pulmonary involvement developed hemoptysis. Typically, central nervous system infection commonly presented with brain abscesses or stroke, due to adjacent fungal rhinosinusitis (30, 31).
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Table 1 illustrates C. bertholletiae infection in solid organ transplantation, including the present case (9, 11–14, 32, 33). Most infections occurred in kidney transplant recipients, with onset of infection appearing between 17 days to 12 months after transplantation. Two previous cases, along with our present case, developed invasive infection early post transplantation. However, the authors could not prove whether these infections were associated with transplantation procedure contamination or donor-organ infection. Clinical presentations varied from localized infection to multifocal infection. Most patients succumbed because of delayed diagnosis and treatment. In Roden et al. (34), who previously reviewed 929 reported case of mucormycosis, the 3 most common species were Rhizopus species (47%), Mucor species (18%), and C. bertholletiae (7%), respectively. C. bertholletiae infection mostly affected males and caused pulmonary infection. In addition to disseminated Mucorales infection, C. bertholletiae significantly had a 2.8fold risk of mortality compared to Rhizopus species (4). Several mechanisms from in vitro and in vivo studies hypothesized about why C. bertholletiae infection had more fatal outcomes, especially in neutropenic hosts, than other Mucorales. C. bertholletiae showed more resistance to human PMN-induced damage than Rhizopus species. It could also decrease interleukin-8 production and induced enhanced production of tumor necrosis factor-a, which diminished chemotaxis of PMN and caused inflammatory reaction, consecutively. In addition, the rapid rate of sporangiospore germination and increased hyphal growth at physiological temperature may correlate with the virulence of this organism (35, 36). Invasive fungal infection usually has a fatal outcome and high mortality rate, especially among immunocompromised patients. Once the infection is clinically suspected, an empirical treatment with broad-spectrum antifungal agents is mandatory while waiting for definite diagnosis. In vitro studies demonstrated terbinafine and posaconazole had lower MICs against C. bertholletiae, i.e., 0.03–0.25 lg/mL and 0.06–1 lg/mL, respectively, while MIC of amphotericin B was varied and ranged from 0.25 to 4 lg/mL. Voriconazole, itraconazole, caspofungin, and 5-flucytosine showed higher MIC levels, i.e., 0.5 to >16 lg/mL, 0.125 to >64 lg/mL, 4 to >16 lg/mL, and 32 to >64 lg/mL, respectively (37–39). Amphotericin B deoxycholate is considered as a standard antifungal treatment for mucormycosis, but the efficacy is limited by its potentially renal toxicity. Lipid formulations of amphotericin B can be used with higher dose in case of nephrotoxicity. However, because the optimal dose and duration of these agents is still
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unknown, some experts recommended the therapy should be continued for at least 6–8 weeks (2). Although terbinafine showed a good in vitro efficacy against C. bertholletiae, its pharmacokinetics has restricted the clinical application of this drug. From 2 clinical studies (40, 41), posaconazole 800 mg per day was used as salvage therapy for mucormycosis in patients who were intolerant or refractory to standard antifungal treatment. The average duration of posaconazole ranged between 30 to 292 days, and the overall response rate (complete and partial response) ranged between 60% and 79% (40, 41). However, clinical studies of antifungal treatment for C. bertholletiae are scarce, and only 33% of patients who received antifungal drugs survived. In addition to the antifungal treatments, surgical resection of infected lesions increased survival rate among invasive fungal infections (34); 57% of patients who suffered from C. bertholletiae infection recovered after undergoing surgical debridement, while 11% of patients recovered by receiving antifungal therapy alone (3). Nevertheless, surgical intervention was limited by patients’ underlying conditions, multiple foci of infection, delayed diagnosis, and the clinical instability of the patient. Other modalities have been studied as adjunctive therapies for invasive mucormycosis, such as hyperbaric oxygen therapy (42, 43) and immunotherapy. In a previous study, interferon gamma and granulocytemacrophage colony-stimulating factor could augment zygomycetes hyphal damage by PMN (44). Further experimental studies should be conducted to prove the efficacy and safety of this immunotherapy. Treatment of coexisting conditions, such as hyperglycemia, ketoacidosis, neutropenia, and discontinuation of iron chelating agent or immunosuppressive drugs, are also warranted for this infection.
Conclusion C. bertholletiae is an emerging opportunistic mold that causes invasive and fatal disease in the immunosuppressed population. Successful treatment requires high clinical awareness, accurate diagnosis from specimen culture, and prompt effective antifungal treatment, including surgical treatment.
Acknowledgement: Thanks: We express our sincere thanks to the staff of department of pathology, Norasate Samarnthai, MD, and Pornsuk Cheunsuchon, MD, of Siriraj Hospital,
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Present report
8 (2013)
42/F
52/M
16/F
54/M
48/F
61/F
19/F
40/M
Age in years/ Gender
Kidney
Kidney
Liver, pancreas, intestine
Kidney
Kidney
Kidney
Liver
Kidney
Transplanted organ
PMP, MP, P, TL, MMF, IVIG, RTX, ATG
None
TL, MMF, P, SL, MP
TL, CS
PMP, OKT3, TL, MMF, P
PMP, MP, TL, MMF, BLX
CSA, MP
MP, P, AZA
Immunosuppressive agents
8
N/A
N/A
N/A
N/A
N/A
1
7
Duration of symptoms (days)
30
N/A
365
150
105
180
17
30
Onset post transplantation (days)
Fever, dry cough, radicular pain
Fever, vomiting, abdominal pain
Painful cellulitis on right thigh, extending to groin
Skin nodule
Pneumonia, cellulitis, hemorrhagic stroke
Respiratory distress
Fever, ARDS
Fever, chest pain, shortness of breath
Presenting symptoms
Lung, vertebra, epidural space
Peritoneum
Skin
Skin
Lung, skin, brain, endocardium
Lung
Lung, brain, thymus, thyroid, mediastinum
Heart, lung, kidney, liver, GI tract, spleen, lymph node
Organ involvement
LAMB, debridement
Remove catheter, IP FCZ, oral ITZ
LAMB then oral PCZ, I&D
ITZ, excision
None
LAMB, 5-FC
ABD
None
Treatment
Improved
Survived
Survived
Survived
Dead
Dead
Dead
Dead
Outcome
Transplant Infectious Disease 2014: 16: 658–665
Table 1
M, male; MP, methylprednisolone; P, prednisolone; AZA, azathioprine; GI, gastrointestinal; F, female; CSA, cyclosporine; ARDS, acute respiratory distress syndrome; ABD, amphotercin B deoxycholate; PMP, plasmapheresis; TL, tacrolimus; MMF, mycophenolate mofetil; BLX, basiliximab; N/A, not available; LAMB, liposomal amphotericin B; 5-FC, 5 flucytosine; OKT3, murine monoclonal antibody; CS, corticosteroid; SL, sirolimus;. IP, intraperitoneal; FCZ, fluconazole; I&D, incision and drainage; ITZ, itraconazole; PCZ, posaconazole; IVIG, intravenous immunoglobulin; RTX, rituximab; ATG, anti-thymocyte globulin.
Bhutada (33)
4 (2002)
7 (2012)
Zhang (14)
3 (1998)
AshkenaziHoffnung (32)
Rickerts (9)
2 (1987)
Quinio (13)
Nimmo (12)
1 (1983)
6 (2010)
Kolbeck (11)
Case (year)
5 (2004)
First author (Ref.)
Summary of reported cases of Cunninghamella bertholletiae infection in solid organ transplant
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Mahidol University, Thailand for providing considerable information about the patient.
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Case report
Disseminated Cunninghamella bertholletiae infection with spinal epidural abscess in a kidney transplant patient: case report and literature review O. Navanukroh, A. Jitmuang, M. Chayakulkeeree, P. Ngamskulrungroj. Disseminated Cunninghamella bertholletiae infection with spinal epidural abscess in a kidney transplant patient: case report and literature review. Transpl Infect Dis 2014: 16: 658–665. All rights reserved Abstract: Cunninghamella bertholletiae is a rare cause of invasive mucormycosis. We report the case of a 42-year-old Thai woman who suffered from disseminated C. bertholletiae infection. The patient developed dry cough, sharp shooting pain in the left buttock referred to the left leg, and fever 1 month after undergoing deceased-donor kidney transplantation. Radiographic studies exhibited multiple pulmonary cavities, osteomyelitis of the sacral spine, epidural abscess along the lumbrosacral spine, and paravertebral soft tissue involvement. Surgical debridement of the epidural abscess concurrent with prolonged intravenous administration of amphotericin B resulted in a good outcome.
O. Navanukroh1, A. Jitmuang1, M. Chayakulkeeree1, P. Ngamskulrungroj2 1
Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand, 2 Department of Microbiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand Key words: Cunninghamella bertholletiae; mucormycosis; kidney transplant Correspondence to: Anupop Jitmuang, MD, Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, 2 Prannok Road, Bangkok Noi, Bangkok 10700, Thailand Tel: 66 2 419 7783 Fax: 66 2 419 7783 E-mail: [email protected]
Received 14 November 2013, revised 27 January 2014, accepted for publication 13 March 2014 DOI: 10.1111/tid.12251 Transpl Infect Dis 2014: 16: 658–665
Mucormycosis is a highly invasive fungal infection caused by fungi in the recently proposed subphylum Mucoromycotina and order Mucorales (1). The fungi in the order include several species, including Rhizopus species, Mucor species, Rhizomucor species, Absidia species (reclassified as Lichtheimia species), Apophysomyces species, Saksenaea species, Cunninghamella species, Cokeromyces species, and Syncephalastrum species. The 3 most common species that cause angioinvasive disease are Rhizopus species, Absidia species, and Mucor species, while the other species are rarely reported to cause diseases in humans (2). Human mucormycosis by Cunninghamella species is rare, and typically causes invasive disease in the immunocompromised patient. Herein, we report a case of disseminated Cunninghamella bertholletiae infection
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with multiple lung cavities and spinal epidural abscess of the lumbrosacral spine.
Case report A 42-year-old Thai woman with chronic kidney disease had been receiving regular hemodialysis for 10 years. On December 30, 2012, she was admitted to Siriraj Hospital, Bangkok, Thailand, and underwent deceaseddonor kidney transplantation. The donor was a previously healthy 39-year-old woman who suffered a car accident with severe head injury. The anti-cytomegalovirus immunoglobulin-G of both donor and recipient were positive, whereas other screening tests and chest radiography were normal. The patient was prescribed a
Navanukroh et al: Disseminated Cunninghamella bertholletiae infection
combination of immunosuppressive agents, methylprednisolone, tacrolimus, prednisolone, and mycophenolate mofetil, for primary prevention of graft rejection, and co-trimoxazole for prophylaxis of Pneumocystis jirovecii pneumonia, respectively. However, renal function deteriorated, and serum creatinine level rose from 4.96 to 8.95 mg/dL within 4 days post kidney transplantation. Kidney biopsy identified acute tubular necrosis and antibody-mediated glomerulitis, which were consistent with acute graft rejection. Therefore, to treat the acute graft rejection, total plasma exchange, intravenous immunoglobulin, rituximab, and anti-thymocyte globulin were administered. Her renal function recovered after the intensive immunosuppressive regimen. Eventually, serum creatinine level went down to 1.33 mg/dL, and the patient was discharged with a maintenance oral immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and prednisolone). Seven days after discharge, the patient was readmitted to the hospital with a presentation of dry cough for 5 days and continuous sharp shooting pain in the left buttock. The pain radiated to the posterior aspect of her left leg, and was worse when bending her left knee. One day before the re-admission, she developed progressive pain in the left lower limb with fever and pleurisy of the right side of her chest. Physical examination revealed body temperature of 38.6°C, pulse rate of 120/min, respiratory rate of 20/ min, and blood pressure of 120/90 mmHg. Coarse crackles and rhonchi in the right lower lung field were heard. Neurological examination identified hyperalgesia on the posterior side of the left leg, hypoesthesia on plantar and dorsolateral side of the left foot, and left ankle hyporeflexia. Complete blood count revealed hemoglobin 8.8 g/ dL, hematocrit 28%, white blood cell count 16,300/mm3 with polymorphonuclear (PMN) cells 94%, and platelet count 508,000/mm3. Blood urea nitrogen and creatinine level were 36 and 1.31 mg/dL, respectively. Chest radiography demonstrated a huge cavity with smooth borders in the right lung, while computed tomography of the chest identified 2 thick-walled cavities 1.2 9 1.4 cm and 2.8 9 3.1 cm diameter in size, at the right upper lung and right middle lung, respectively. The chest radiography also revealed a large complex thick-walled cavity 4.5 9 5.3 cm in diameter at the superior segment of the right lower lung, as shown in Figure 1. Magnetic resonance imaging of her lumbosacral spine showed osteomyelitis of S1 vertebral body and left alar of the sacrum, left S1 neuritis, epidural abscess along L4 to S1 vertebral level, and abnormal enhancement of adjacent left presacral and left paravertebral soft tissues, as shown in Figure 2.
A
B
Fig. 1. Radiological findings illustrate (A) a huge, well-defined border cavity (white arrow) at the right lower lobe on chest x-ray, and (B) 2 thick-walled cavities (black arrow) at right middle lobe and right lower lobe, including a single nodule (arrow head) on computed tomography scan.
From the radiological findings, the presumptive diagnosis was multiple lung abscesses, S1 vertebral osteomyelitis, and lumbrosacral epidural abscess. An empirical antibiotics treatment for invasive bacterial and fungal infections was prescribed with intravenous imipenem-cilastatin 2 g/day and amphotericin B deoxycholate 40 mg/day. Bronchoscopy and bronchoalveolar lavage (BAL) were performed; galactomannan index from the BAL fluid was 0.71. Transbronchial lung biopsy was also undertaken; the pathological findings showed acute
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A
Fig. 2. Magnetic resonance imaging of the lumbosacral spine shows abnormal epidural fluid collection with rim enhancement (arrow head) along L4-S1 levels and gadolinium enhancement of S1 vertebral body (arrow).
and chronic inflammation with focal foreign body granulomatous reaction and degenerated fungal hyphae. On the twelfth day of the hospitalization, decompressive laminectomy of L4 and S1 vertebra was carried out and 5 mL of yellowish pus was obtained from the epidural abscess. Pathological sections discovered degenerated fungal hyphae. Both fungal cultures from BAL fluid and pus from the abscess rapidly grew cottony colonies of gray-to-white non-septate mold, which were morphologically consistent with Cunninghamella species. Polymerase chain reaction and sequencing of the internal transcribed spacer regions of ribosomal DNA were performed and identified Cunninghamella bertholletiae. Therefore, imipenem-cilastatin was discontinued, while antifungal therapy was switched to 5 mg/ kg/day (200 mg/day) of liposomal amphotericin B (LAMB) intravenously owing to deterioration of renal function after receiving the conventional amphotericin B. The patient was hospitalized for 50 days, and then she was transferred to a provincial hospital for continuation of the LAMB infusion. After a 3-month course of LAMB, her symptoms were gradually improved, and serum creatinine level ranged between 1.3 and 1.5 mg/dL. She had no remaining chest symptoms. Her weakness and numbness of the lower extremities were improved. As the minimum inhibi-
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B
Fig. 3. Radiographic follow-up of the chest shows (A) disappearance of the cavitary lesion on plain radiography, and (B) the reduced cavitary lesions on computed tomography scan (arrow).
tory concentration (MIC) of posaconazole of the isolates was 0.25 lg/mL, the patient received oral posaconazole 800 mg/day as maintenance therapy. After she took posaconazole for 1 week, she developed a pruritic rash and discontinued antifungal treatment. Nonetheless, her overall condition has remained stable. Radiographic follow-up of the chest showed disappearance of the cavitary lesion on plain radiography, and computed tomography scan exhibited smaller size of cavitary lesions, as shown in Figure 3.
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Discussion and literature review Cunninghamella species are saprophytic, ubiquitous fungi found in soil, sewage, air, water, and vegetation, especially in tropical and subtropical zones. The genus Cunninghamella contains 7 species, of which C. bertholletiae, Cunninghamella elegans, and Cunninghamella echinulata are the most common. To our knowledge, C. bertholletiae is the only species that has been reported to be a human pathogen. It was primarily isolated from Brazilian soil samples by Stadel in 1911 and was first reported to cause an infection in a human in 1958. Cunninghamella species are characterized by white-togray colonies that grow rapidly at room temperature to 45°C in 24–48 h on Sabouraud dextrose agar. The mycelium is 0.5–2 cm tall and varies in color from gray or white to yellow. The morphology is pleomorphic depending on the culture media. Microscopically, hyphae appear to be non-septate or sparsely septate with broad, branching, and erect sporangiophores. The sporangiophores terminate in swollen vesicles covered by short stalked sporangioles. Sporangioles are round-tooval shape (3, 4). It uncommonly grows in hemoculture. Thus, definite diagnosis of invasive mold infection usually requires evidence of tissue invasion from a histopathology specimen and identification of species. Fungal tissue culture is necessary for susceptibility testing. Nevertheless, culture results are often negative, despite fungal hyphae being seen in pathological specimens. For speciation, conventional carbohydrate utilization is a very intricate and time-consuming technique for species identification. Rickerts et al. (5) discovered that detection of fungal DNA from tissue specimens by polymerase chain reaction can improve the diagnosis of aspergillosis and mucormycosis. To identify Cunninghamella species, the variable sequence of internal transcribed spacer regions has a great value for species differentiation (6). C. bertholletiae infection is a rare cause of invasive mucormycosis and has a strong predilection to affect immunocompromised patients. Previously reported cases were described and >98% of patients had immunodeficiency states: leukemia (7–10), solid organ transplantation (9, 11–14), bone marrow transplantation (15, 16), diabetes mellitus (17), non-malignant hematologic disease (18–20), deferoxamine-based therapy (21), AIDS (22), cirrhosis (23), and immunosuppressive therapy. Only 2 cases were reported in immunocompetent patients (24, 25). Inhalation of fungal spores that contaminate the environment has been speculated to be a major source
of transmission. Macrophages and neutrophils prevent fungal invasion by phagocytosis and oxidative killing of spores, whereas these cells in immunocompromised patient fail to suppress the germination of spores and are unable to kill the fungal element effectively (26). As a result, disorders of those cells, such as neutropenia, diabetic ketoacidosis, or immunosuppressive therapy, are a pivotal contributing factor of angioinvasion (27). Moreover, fungi in the order Mucorales can utilize host iron or iron compounds in chelating agents, such as deferoxamine and desferrioxamine, to augment their growth, so patients who have excessive iron level or are receiving the chelating agents also are at increased risk of severe infection (28). As in our reported case, the important risk factor was a previous combination of immunosuppressive treatments to prevent acute graft rejection. In terms of environmental factors, a cluster of C. bertholletiae pulmonary infection in immunocompromised patients might be related to hospital construction (9). Although the reported case developed disseminated infection within 1 week after discharge, invasive mucormycosis has not been strongly correlated with the hospital environment in our institute. Like other infections by fungi in the order Mucorales, clinical characteristics of Cunninghamella infection are not specific. Moreover, the clinical infection may resemble other opportunistic infections such as tuberculosis, nocardiosis, and cryptococcosis, which should be considered in the differential diagnosis. Because inhalation is a main portal of entry, the vast majority of these infections manifest as pulmonary disease, disseminated infection secondary to pulmonary disease, and rhino-orbito-cerebral infection. Unusual manifestations of C. bertholletiae infection have also been reported, such as cutaneous or osteoarticular infections following percutaneous inoculation and peritonitis following continuous ambulatory peritoneal dialysis (17, 22, 29). From case series, approximately 70% of disseminated disease occurred in patients with underlying hematologic diseases and were diagnosed postmortem (3). The lung was the most affected organ of infection, and other foci of dissemination were heart and/or pericardium, spleen, brain, kidney, liver, gastrointestinal tract, skin, etc. Our case initially presented with respiratory symptoms and subsequently developed dissemination to vertebra and lumbrosacral epidural space. Pulmonary angioinvasion is a significant pathological finding from this infection; however, few patients with disseminated infection and pulmonary involvement developed hemoptysis. Typically, central nervous system infection commonly presented with brain abscesses or stroke, due to adjacent fungal rhinosinusitis (30, 31).
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Table 1 illustrates C. bertholletiae infection in solid organ transplantation, including the present case (9, 11–14, 32, 33). Most infections occurred in kidney transplant recipients, with onset of infection appearing between 17 days to 12 months after transplantation. Two previous cases, along with our present case, developed invasive infection early post transplantation. However, the authors could not prove whether these infections were associated with transplantation procedure contamination or donor-organ infection. Clinical presentations varied from localized infection to multifocal infection. Most patients succumbed because of delayed diagnosis and treatment. In Roden et al. (34), who previously reviewed 929 reported case of mucormycosis, the 3 most common species were Rhizopus species (47%), Mucor species (18%), and C. bertholletiae (7%), respectively. C. bertholletiae infection mostly affected males and caused pulmonary infection. In addition to disseminated Mucorales infection, C. bertholletiae significantly had a 2.8fold risk of mortality compared to Rhizopus species (4). Several mechanisms from in vitro and in vivo studies hypothesized about why C. bertholletiae infection had more fatal outcomes, especially in neutropenic hosts, than other Mucorales. C. bertholletiae showed more resistance to human PMN-induced damage than Rhizopus species. It could also decrease interleukin-8 production and induced enhanced production of tumor necrosis factor-a, which diminished chemotaxis of PMN and caused inflammatory reaction, consecutively. In addition, the rapid rate of sporangiospore germination and increased hyphal growth at physiological temperature may correlate with the virulence of this organism (35, 36). Invasive fungal infection usually has a fatal outcome and high mortality rate, especially among immunocompromised patients. Once the infection is clinically suspected, an empirical treatment with broad-spectrum antifungal agents is mandatory while waiting for definite diagnosis. In vitro studies demonstrated terbinafine and posaconazole had lower MICs against C. bertholletiae, i.e., 0.03–0.25 lg/mL and 0.06–1 lg/mL, respectively, while MIC of amphotericin B was varied and ranged from 0.25 to 4 lg/mL. Voriconazole, itraconazole, caspofungin, and 5-flucytosine showed higher MIC levels, i.e., 0.5 to >16 lg/mL, 0.125 to >64 lg/mL, 4 to >16 lg/mL, and 32 to >64 lg/mL, respectively (37–39). Amphotericin B deoxycholate is considered as a standard antifungal treatment for mucormycosis, but the efficacy is limited by its potentially renal toxicity. Lipid formulations of amphotericin B can be used with higher dose in case of nephrotoxicity. However, because the optimal dose and duration of these agents is still
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unknown, some experts recommended the therapy should be continued for at least 6–8 weeks (2). Although terbinafine showed a good in vitro efficacy against C. bertholletiae, its pharmacokinetics has restricted the clinical application of this drug. From 2 clinical studies (40, 41), posaconazole 800 mg per day was used as salvage therapy for mucormycosis in patients who were intolerant or refractory to standard antifungal treatment. The average duration of posaconazole ranged between 30 to 292 days, and the overall response rate (complete and partial response) ranged between 60% and 79% (40, 41). However, clinical studies of antifungal treatment for C. bertholletiae are scarce, and only 33% of patients who received antifungal drugs survived. In addition to the antifungal treatments, surgical resection of infected lesions increased survival rate among invasive fungal infections (34); 57% of patients who suffered from C. bertholletiae infection recovered after undergoing surgical debridement, while 11% of patients recovered by receiving antifungal therapy alone (3). Nevertheless, surgical intervention was limited by patients’ underlying conditions, multiple foci of infection, delayed diagnosis, and the clinical instability of the patient. Other modalities have been studied as adjunctive therapies for invasive mucormycosis, such as hyperbaric oxygen therapy (42, 43) and immunotherapy. In a previous study, interferon gamma and granulocytemacrophage colony-stimulating factor could augment zygomycetes hyphal damage by PMN (44). Further experimental studies should be conducted to prove the efficacy and safety of this immunotherapy. Treatment of coexisting conditions, such as hyperglycemia, ketoacidosis, neutropenia, and discontinuation of iron chelating agent or immunosuppressive drugs, are also warranted for this infection.
Conclusion C. bertholletiae is an emerging opportunistic mold that causes invasive and fatal disease in the immunosuppressed population. Successful treatment requires high clinical awareness, accurate diagnosis from specimen culture, and prompt effective antifungal treatment, including surgical treatment.
Acknowledgement: Thanks: We express our sincere thanks to the staff of department of pathology, Norasate Samarnthai, MD, and Pornsuk Cheunsuchon, MD, of Siriraj Hospital,
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Present report
8 (2013)
42/F
52/M
16/F
54/M
48/F
61/F
19/F
40/M
Age in years/ Gender
Kidney
Kidney
Liver, pancreas, intestine
Kidney
Kidney
Kidney
Liver
Kidney
Transplanted organ
PMP, MP, P, TL, MMF, IVIG, RTX, ATG
None
TL, MMF, P, SL, MP
TL, CS
PMP, OKT3, TL, MMF, P
PMP, MP, TL, MMF, BLX
CSA, MP
MP, P, AZA
Immunosuppressive agents
8
N/A
N/A
N/A
N/A
N/A
1
7
Duration of symptoms (days)
30
N/A
365
150
105
180
17
30
Onset post transplantation (days)
Fever, dry cough, radicular pain
Fever, vomiting, abdominal pain
Painful cellulitis on right thigh, extending to groin
Skin nodule
Pneumonia, cellulitis, hemorrhagic stroke
Respiratory distress
Fever, ARDS
Fever, chest pain, shortness of breath
Presenting symptoms
Lung, vertebra, epidural space
Peritoneum
Skin
Skin
Lung, skin, brain, endocardium
Lung
Lung, brain, thymus, thyroid, mediastinum
Heart, lung, kidney, liver, GI tract, spleen, lymph node
Organ involvement
LAMB, debridement
Remove catheter, IP FCZ, oral ITZ
LAMB then oral PCZ, I&D
ITZ, excision
None
LAMB, 5-FC
ABD
None
Treatment
Improved
Survived
Survived
Survived
Dead
Dead
Dead
Dead
Outcome
Transplant Infectious Disease 2014: 16: 658–665
Table 1
M, male; MP, methylprednisolone; P, prednisolone; AZA, azathioprine; GI, gastrointestinal; F, female; CSA, cyclosporine; ARDS, acute respiratory distress syndrome; ABD, amphotercin B deoxycholate; PMP, plasmapheresis; TL, tacrolimus; MMF, mycophenolate mofetil; BLX, basiliximab; N/A, not available; LAMB, liposomal amphotericin B; 5-FC, 5 flucytosine; OKT3, murine monoclonal antibody; CS, corticosteroid; SL, sirolimus;. IP, intraperitoneal; FCZ, fluconazole; I&D, incision and drainage; ITZ, itraconazole; PCZ, posaconazole; IVIG, intravenous immunoglobulin; RTX, rituximab; ATG, anti-thymocyte globulin.
Bhutada (33)
4 (2002)
7 (2012)
Zhang (14)
3 (1998)
AshkenaziHoffnung (32)
Rickerts (9)
2 (1987)
Quinio (13)
Nimmo (12)
1 (1983)
6 (2010)
Kolbeck (11)
Case (year)
5 (2004)
First author (Ref.)
Summary of reported cases of Cunninghamella bertholletiae infection in solid organ transplant
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Mahidol University, Thailand for providing considerable information about the patient.
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