Pulmonary Rhizopus infection in a diabetic renal transplant recipient

Clin Transplantation 2000: 14: 8–10 Printed in Ireland. All rights reser6ed

Case Report

Pulmonary Rhizopus infection in a diabetic renal transplant recipient Demirag A, Elkhammas EA, Henry ML, Davies EA, Pelletier RP, Bumgardner GL, Dorner B, Ferguson RM. Pulmonary Rhizopus infection in a diabetic renal transplant recipient. Clin Transplantation 2000: 14: 8 – 10. © Munksgaard, 2000 Abstract: Infectious complications after renal transplantation remain a major cause of morbidity and mortality. Mucormycosis is a rare infection in renal transplant recipients; however, mortality is exceedingly high. Risk factors predisposing to this disease include prolonged neutropenia, diabetes, and patients who are immunosuppressed (Singh N, Gayowski T, Singh J, Yu LV. Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report and review of zygomycosis in solid-organ transplant recipients, Clin Infect Dis 1995: 20: 617). Lifethreatening infections can occur, as this fungus has the propensity to invade blood vessel endothelium, resulting in hematological dissemination. We report a case of cavitary Rhizopus lung infection, 2 months after renal transplantation, where the patient was treated successfully with Amphotericin B and surgical resection of the lesions with preservation of his allograft function. In this era of intensified immunosuppression, we may see an increased incidence of mucormycosis in transplant population. Invasive diagnostic work-up is mandatory in case of suspicion; Amphotericin B and, in selected cases, surgical resection are the mainstays of therapy.

Mucormycosis is an opportunistic infection, which most commonly affects immunosuppressed individuals and patients with hematological diseases and diabetes, or diseases such as those reviewed in (1) and (2). Its incidence in kidney transplant patients is not known. The pathogen itself is ubiquitous and is generally found in decaying food, soil, or manure (1). It generally enters the body through the gastrointestinal tract, but can also enter through the respiratory system or skin lesions. Rhizopus, Mucoi, and Absidia are the most frequently recovered pathogens (1). The pathogen is notorious for vessel endothelium invasion, which can lead to disseminated infection, which carries an extremely high mortality and morbidity rate (2, 3). It is, therefore, extremely important to establish a diagnosis early, so that effective treatment can be instituted. Treatment consists of both surgical extirpation, where possible, along with Amphotericin B. Here, we present a case of a diabetic patient 8

A Demirag, EA Elkhammas, ML Henry, EA Davies, RP Pelletier, GL Bumgardner, B Dorner and RM Ferguson The Ohio State University College of Medicine, Department of Surgery, Columbus, OH 43210, USA

Key words: fungal infection – kidney transplantation – mucormycosis Corresponding author: Elmahdi A Elkhammas, The Ohio State University, 345 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA Accepted for publication 15 July 1999

who acquired pulmonary mucormycosis after receiving a cadaveric renal transplant allograft. Case report

A 52-yr-old African–American male, with end stage renal disease secondary to insulin-dependent diabetes mellitus (IDDM), underwent successful cadaveric renal transplantation. His post-operative course was uneventful and he went home on postoperative day 4. The patient’s immunosuppression consisted of induction with Solu-Medrol 1000 mg, followed by a prednisone taper of 2 mg/kg, Neoral 7.5 mg/kg per day and Rabamycin derivative (RADB) study drug (blinded for mycophenolate use). He returned 2 months after surgery with complaints of a 3-week productive cough with brown colored sputum, right chest pain with inspiration, and right sided abdominal pain. On examination, the patient was noted to have decreased breath sounds on the right chest with egophany.

Pulmonary Rhizopus infection

tinued on conventional Amphotericin B at home with a total cumulative dose of 1.1 g, and returned to the hospital 10 days later with a rising creatinine. The baseline creatinine was 1.2 mg/dL; it increased to 3.4 mg/dL during therapy with conventional Amphotericin B. The patient was switched to the lipophilic form of amphotericin B at a lower dose (3.2 mg/kg per day) for 6 weeks on a total of 6 g, and a kidney biopsy was obtained. The biopsy returned as interstitial inflammation, and his creatinine gradually declined from a high of 3.4 mg/dL to 1.4 mg/dL. While in the hospital, the patient underwent resection of his right upper lung lobe. Tissue cultures showed Rhizopus and methicillin resistant staphylococcus epidermidis. Fig. 1. Chest roentgenogram showing a right upper lobe lesion approximately 8.5 cm in size and a right lower lobe lesion 4 cm in size.

Chest X-ray revealed cavitary lesions in the right upper and lower lobes measuring 8.5 and 4 cm in diameter, respectively (Fig. 1). A chest computerized tomography (CT) was obtained, which revealed a large cavitary mass in the right upper lobe measuring 6.5 cm in diameter with bronchial and pleural invasion (Fig. 2). A second, smaller, right middle lobe mass was identified along with a right lower lobe mass, which also involved the pleura. Both head and abdominal CT scans were normal with no evidence of extra-pulmonary involvement. The patient was admitted to the hospital and underwent immediate bronchoscopy. He was started on conventional Amphotericin B therapy (1 mg/kg per day) empirically, and his immunosuppressive therapy was discontinued except for his prednisone. Bronchioalveolar lavage cultures returned positive for Rhizopus species. The patient was con-

Fig. 2. Computed tomography scan of the chest revealing a cavitary mass in the right upper lobe measuring 6.5 cm in diameter.

Discussion

Rhizopus is the most commonly isolated zygomycosis in solid-organ transplant recipients. Rhizopus arrhizus was the most common pathogenic species that was seen in 50% of transplant recipients. With zygomycosis, Rhizopus rhizopodiformis was the second most common organism (1). The incidence of zygomycosis complicating, solid-organ transplantation, ranged from 1 to 9% (1). The median time to the onset of the infection was 60 days after transplantation (range, 5 d to 8 yr); 80% of the cases occurred within 6 months of transplantation (1). Overall, 76% of the transplant recipients had diabetes or had received augmented immunosuppression, mainly in the form of corticosteroids for prevention of rejection, before zygomycotic infection occurred (1–6). Our patient received immunosuppression therapy with Neoral, prednisone and RADB study drug. This patient was diabetic, but has not had any rejection episodes. The most common form of the disease is the rhinocerebral form (57%), followed by pulmonary, cutaneous, and disseminated forms (13%), renal form (2%), and gastrointestinal (2%) (1). The mortality for patients who received antifungal therapy and/or who underwent surgery was 50% for those who had rhinocerebral zygomycosis, none for those who had pulmonary and cutaneous zygomycosis, and 100% for those who had of disseminated zygomycosis (4). The underlying mechanisms predisposing a patient to mucormycosis infections appears to be neutropenia, impaired phagocytosis, or acidosis (1–6). Immunosuppressive medications predispose a patient to opportunistic infections (2, 5, 6). Corticosteroids have multiple effects upon the immune system including inhibition of alveolar macrophage’s ability to ingest spores of mucormy9

Demirag et al.

cosis (1, 2, 5, 6). Azathioprine and mycophenolate cause a dose-dependent bone marrow suppression and leukopenia (1, 2). However, cyclosporine affects the IL-2 pathway for T-lymphocyte proliferation, but does not appear to affect either the alternate complement pathway or neutrophil function, which are essential for fungal protection (2). However, infection is more common in patients undergoing multiple drug regimens for immunosuppression (1, 2, 4). Therefore, decreasing the immunosuppressive medications of transplant patients in the face of life-threatening fungal infections is judicious medical practice. Other predisposing factors include hematological diseases, diabetes mellitus (especially diabetic ketoacidosis), renal failure, recent operation, and solid-organ tumor (3). Diagnosis remains difficult and a high index of suspicion is necessary. The most common symptoms of pulmonary mucormycosis are fever, cough, bloody sputum, dyspnea, and chest pain (7). Some patients are asymptomatic. Because of the propensity of Zygomycetes to invade vascular structures, massive hemoptysis and major airway obstruction leading to death have been described on several occasions (2). Pulmonary mucormycosis was typically manifested in immunocompromised or diabetic patients by consolidation on chest radiographs; cavitation was observed in 40% of patients (7). Besides this, abnormalities observed on chest radiographs included lobar or multilobar consolidation, solitary or multiple masses, and solitary or multiple nodules (7). Intracavitary masses were also seen in chest X-ray. Associated radiographic findings include hilar or mediastinal adenopathy and unilateral or bilateral pleural effusion (7). Abdominal CT revealed significant unsuspected abnormalities in 26% of patients, for example, splenic or renal involvement (7). Mucormycosis can mimic routine bacterial infection, which presents in a similar fashion. Compounding this difficulty is that many patients have a secondary bacterial infection, which delays diagnosis of the underlying pathogen as treatment with standard antibacterials commences (2 – 7). Until recently, bacterial samples were homogenized in the laboratory, which is lethal to mucor species making culture almost impossible (2 – 7). Lastly, diagnosis is difficult using traditional sputum samples. The diagnosis usually requires invasive techniques such as bronchioalveolar lavage, open lung biopsy, percutaneous transthoracic needle biopsy, or empyema drainage (2 – 7).

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The primary treatment of pulmonary mucormycosis is with antifungal therapy and surgical extirpation where possible (2–6). The mortality associated with medical treatment alone has been reported to be as high as 68% whereas the mortality associated with surgical therapy with or without antifungal treatment has been 11% (3). The most common causes of death were fungal sepsis and respiratory insufficiency, with hemoptysis and bacterial sepsis being less frequent (2–6). In our patient, initial treatment consisted of conventional Amphotericin B, which lead to a rising creatinine because of the nephrotoxic effects. Initiation of the lipophilic form at a lower dose resulted in a quick recovery of renal function. In this patient Amphotericin B alone failed to a measurable improvement clinically or radiologically, and he underwent a right upper lobectomy with wedge resections of smaller lesions within the right middle and lower lobes. As well as the antifungal therapy, the abscess cavity must be drained surgically. When compared with conventional Amphotericin B, liposomal Amphotericin B has less nephrotoxicty and greater tissue diffusion capacity, but it is more expensive (2, 4). In conclusion, successful therapy for mucormycosis, in solid-organ transplant recipients, depends on early diagnosis. Immediate surgical resection or debridement is often a necessary adjunct to antifungal therapy for these transplant recipients. References 1. SINGH N, GAYOWSKI T, SINGH J, YU LV. Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report and review of zygomycosis in solid-organ transplant recipients. Clin Infect Dis 1995: 20: 617. 2. LATIF S, SAFFARIAN N, BELLOVICH K, PROVENZANO R. Pulmonary mucormycosis in diabetic renal allograft recipients. Am J Kidney Dis 1997: 29 (3): 461. 3. TEDDER M, SPRAT JA, ANSTADT MP, HEGDE SS, TEDDER SD, LOWE JE. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg 1994: 57: 1044. 4. TEMECK BK, VENZON DJ, MOSKALU CA, PASS HI. Thoracotomy for pulmonary mycosis in nonHIV-immunosuppressed patients. Ann Thorac Surg 1994: 58: 333. 5. MUHM M, ZUCKERMANN A, PROKESCH R, PAMMER J, HIESMAYR M, HAIDER W. Early onset of pulmonary mucormycosis with pulmonary vein thrombosis in a heart transplant recipient. Transplantation Oct 1996: 62 (8): 1185. 6. KFOURY AG, SMITH JC, FARHOUD HH, TERREROS DA, STRINGHAM JC, TAYLOR DO, REN LUND DG. Adjuvant intrapleural Amphotericin B therapy for pulmonary mucormycosis in a cardiac allograft recipient. Clin Transplant Dec 1997: 11 (6): 608. 7. MCADAMS HP, ROSADO DE CHRISTENSON M, STROLLO DC, PATZ EF JR. Pulmonary mucormycosis: radiologic findings in 32 cases. AJR Jun 1997: 168 (6): 1541.