Postgraduate Medical Journal (1988) 64, 82-84 Postgrad Med J: first published as 10.1136/pgmj.64.747.82 on 1 January 1988. Downloaded from

Disseminated mucormycosis due to Cunninghamella bertholletiae in a liver transplant recipient

G.R. Nimmo, R.F. Whiting and R.W. Strong Departments of Clinical Microbiology, Intensive Care and Surgery, Princess Alexandra Hospital, Brisbane, Australia.

Summary: Disseminated mucormycosis occurred in a 19 year old female following orthotopic liver transplantation for fulminant Wilson's disease. The causative organism Cunninghamella bertholletiae has previously been described in ten clinical cases, but never before in this setting.

Introduction Mucormycosis is a recognized complication in due mainly to the severe coagulopathy and portal patients who are acidotic or who have hypertension. compromised cellular immune defences due to At operation the patient had 3 litres of ascites, a primary disease or immunosuppressive therapy. It is nodular liver weighing 1810 grams and evidence of being increasingly described as an infective severe portal hypertension with numerous varices. complication of organ transplantation.'12 At the Histology of the removed liver showed micro- same time species only rarely identified as causal nodular cirrhosis. The hepatic copper content was agents in the past are being reported with greater 28,200 mol/kg dry weight (normal range 400-1700)copyright. frequency.1 This report of a case of disseminated confirming the diagnosis of Wilson's disease. infection due to Cunninghamella bertholletiae is the Immunosuppressive therapy consisted of cyclo- first reported in a liver transplant and illustrates the sporin A 4mg/kg/day intravenously and methyl- difficulties encountered in the diagnosis and prednisolone 50mg four times daily intravenously, treatment of this condition. reducing to 20mg four times daily by 16th post- operative day. The post-operative course was Case report complicated by oliguric renal failure which responded to fluids, low dose dopamine and A 19 year old female was admitted deeply frusemide. Bile production by the transplanted liver http://pmj.bmj.com/ jaundiced and encephalopathic. She had a two week was poor but liver enzymes and prothrombin time history of upper abdominal pain, progressive returned to normal limits by the end of the first anaemia and deepening jaundice. A diagnosis of week. fulminant Wilson's disease was made and it was Chest radiographs initially showed bilateral decided that liver transplantation was the only pulmonary oedema. This had largely cleared by the potentially effective method of treatment. Major third day leaving a residual area of consolidation at the right lung base. Diagnoses considered included clinical problems were acute hepatic failure with on October 2, 2021 by guest. Protected encephalopathy, severe coagulopathy, severe intra- infection, aspiration and septic embolism. Sputum vascular haemolysis and impending renal failure. microscopy revealed Gram negative rods and Gram She was treated with charcoal haemoperfusion, positive cocci. The leukocyte count was at the blood and component therapy and on the fourth upper limit of normal with a relative neutrophilia. day following admission underwent orthotopic liver The patient was afebrile and was begun on transplantation. The procedure took 13 hours to tobramycin 200mg twice daily and flucloxacillin 1 g perform and blood loss was approximately 51 units six hourly. Some clearing of the consolidation was noted on the following day's radiograph. Sputum Correspondence: G.R. Nimmo, M.B., B.S., M.Sc., culture grew a heavy growth of Enterobacter sp. F.R.C.P.A., Department of Clinical Microbiology, and scanty Streptococcus faecalis. Princess Alexandra Hospital, Woolloongabba 4102, Both hepatic function and the patient's general Australia condition showed a definite improvement by day 6 Accepted: 8 July 1987 and an unsuccessful attempt to wean her from © The Fellowship of Postgraduate Medicine, 1988 CLINICAL REPORTS. 83 Postgrad Med J: first published as 10.1136/pgmj.64.747.82 on 1 January 1988. Downloaded from mechanical ventilation was made on day 7. She Mucorales of the class Zygomycotina. It is became febrile on the following day and chest characterized by rapid tissue spread with vascular radiographs showed worsening of consolidation at invasion. The mode of infection would appear to be the right lung base and new consolidation at the by inhalation of spores in the case of the rhino- left base. Amoxicillin 1g four hourly and metro- cerebral and pulmonary forms, while direct nidazole 500mg eight hourly were added to her inoculation is thought to account for primary therapy. Aspergillus fumigatus was isolated from a subcutaneous infections. In vitro studies by Waldorf sputum culture taken on day 9 and amphotericin B and co-workers3 have shown that defective broncho- was commenced as fungal infection was considered alveolar macrophage function allows spore probable. germination to occur in diabetic and cortisone An open lung biopsy was performed on day 11. treated mice. Dissemination from a primary The biopsy consisted of a wedge of the left lower pulmonary focus is not uncommon. lobe as the advent of consolidation in this area had Infection due to organisms of the genus Cunning- coincided with the onset of fever and general hamella is uncommon and only ten cases have been deterioration. Stains and cultures were performed previously reported.5 6 Pulmonary involvement was to exclude Pneumocystis carinii, fungi, noted in six cases, of which four had disseminated mycobacteria, Legionella sp. and other bacteria and disease. All the patients had an underlying disease all proved negative. The histological appearance likely to compromise immune defences and seven was consistent with adult respiratory distress had received steroid therapy. Our case certainly syndrome and, although no specific cause was conforms to this pattern. It is, however, the first obvious, aspiration was felt to be a likely case reported in a liver transplant recipient and antecedent. only the second case of mucormycosis in this The patient remained febrile and antifungal setting. The previous case would appear to have therapy was ceased while antibacterial therapy was been diagnosed histologically as no mycological continued with the substitution of vancomycin for details were recorded.7 flucloxacillin. After some initial clearing of In the past there has been some confusion in the consolidation on day 12, radiographic appearances literature regarding the classification of clinical continued to worsen as did her general clinical state isolates of Cunninghamella. In their study of the copyright. until the patient died on day 17 post-transplant. mating behaviour of Cunninghamella spp., At autopsy fungal infection was found in all Weitzman and Crist established that Cunninghamella lobes of both lungs, with dissemination to the bertholletiae, and not Cunninghamella elegans, is the mediastinum, left ventricle, brain, thymus and species causing human infection.8 In their thyroid. The histological appearance was of broad subsequent physiological and morphological studies hyphae with relatively few septae and haphazard thermotolerance proved to be the key differential branching. Fungal invasion of vessel walls was a feature.9 Cunninghamella elegans does not grow at noticeable feature. Multiple post-mortem specimens 400C. from the lungs and mediastinum grew a grey-white The difficulty of ante-mortem diagnosis of http://pmj.bmj.com/ cotton wool-like fungus. Growth was evident at 24 mucormycosis has been noted previously.10 Five of hours on Sabouraud dextrose agar incubated at the ten cases of Cunninghamella infection in the 25°C and 37°C and was luxuriant after 72 hours. literature were diagnosed post-mortem. Biopsy of On subculture, growth also occurred at 42°C but involved tissue would appear to be the most was less marked. Hyphae of 7 to 11 im diameter promising diagnostic approach although it was were smooth and hyaline with infrequent septae unsuccessful in this case. The area of the left lobe

and branched at acute and right angles. selected for biopsy had shown the most recent on October 2, 2021 by guest. Protected Sporangiophores were vertical with globose to radiological changes, the advent of which had subglobose terminal vesicles bearing spinelike coincided with clinical deterioration. It is phialides. Conidia were spherical to ellipsoidal and disappointing that the tissue biopsied was not measured 7 to 14 tm. Based on these criteria the representative of the infectious process which must fungus was identified as Cunninghamella have been active at the time. Realising the obvious bertholletiae, a zygomycete of the order Mucorales. difficulties encountered in the timely diagnosis of this condition using current techniques, it would seem that alternative strategies may be needed. Discussion Serological diagnosis of the infections warrants further investigation. Yankey & Abraham have Mucormycosis is an acute opportunistic mycosis demonstrated high levels of specific IgA and IgM caused by thermotolerant genera of the order by immunofluorescence in a patient with cranio- 84 CLINICAL REPORTS Postgrad Med J: first published as 10.1136/pgmj.64.747.82 on 1 January 1988. Downloaded from

facial mucormycosis." The antigenic profiles of number of cases recorded. Only two patients have some potentially pathogenic mucoraceous fungi survived so far, but it is worth noting that only have been compared by Hessian & Smith12 who three of the remaining cases were diagnosed ante- concluded that the antigenic characterization of the mortem. Due to the lack of success of the medically significant mucoraceae is feasible. If this diagnostic efforts in our case, a full course of proves to be the case then clinically useful tests for treatment was not given. However, even if the specific antibodies and antigens may be a diagnosis had been made, surgical resection would possibility. not have been possible due to the extensive and The mainstays of therapy for mucormycosis rapidly progressive nature of the disease. It is remain surgical resection and systemic amphotericin doubtful if therapy with amphotericin B alone B. The efficacy of this approach in Cunninghamella would have been curative under these infections remains uncertain due to the small circumstances.

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Yankey, Serological copyright. 4. Rippon, J.W. Mucormycosis. In: Rippon, J.W. (ed) case of fatal craniofacial mucormycosis. Medical Mycology: The Pathogenic Fungi and The Mycopathologia 1983, 82: 105-109. Pathogenic Actinomycetes. W.B. Saunders, 12. Hessian, P.A. & Smith, J.M. Antigenic Philadelphia, 1982, pp 615-640. characterization of some potentially pathogenic 5. Ventura, G.J., Kantarjian, H.M., Anaissie, E., mucoraceous fungi. Sabouraudia 1982, 20: 209-216. Hopfer, R.L. & Fainstein, V. Pneumonia with Cunninghamella species in patients with hematologic malignancies. Cancer 1986, 58: 1534-1536. 6. Sands, J.M., Macher, A.M., Ley, T.J. & Nienhuis, A.W. Disseminated infection caused by Cunninghamella bertholletiae in a patient with beta- http://pmj.bmj.com/ thalassemia. Ann Intern Med 1985, 102: 59-63. on October 2, 2021 by guest. Protected