Mucormycosis in renal transplant recipients: review of 174 reported cases

Our goal was to discover the demographic characteristics, the underlying conditions, the site and pattern of infection, microbiologic and histopathologic findings, management and outcomes in RT patients with mucormycosis by review published cases. The literature search was limited to case or case series of mucormycosis in RT patients reported in English language. The PubMed database was searched for all mucormycosis case until December 2015 using the following key words: renal transplant, renal transplantation, kidney transplant, kidney transplantation, zygomycosis, mucormycosis, phycomycosis, Absidia (Mycocladus), Apophysomyces, Cokeromyces, Cunninghamella, Mucor, Rhizopus, Rhizomucor, Saksenaea, and Syncephalastrum.

From each case, we extracted publication year, sex and age of patients, primary underlying condition, duration from transplantation to disease onset, allograft rejection events and the primary site of infection at time of diagnosis, fungal culture, histopathology, antifungal therapy, surgical therapy and outcomes.

The association between potential risk factors and mortality were performed by using univariate analyses. Logistic regression analysis was used for multivariate analysis of variables found to be significant with univariate analysis. The variables were considered for inclusion in a multivariate model if they have a p < 0.20 on univariate analysis. Values of 2-tailed p < 0.05 were considered statistically significant. All statistical analyses were performed using the Statistics Package for Social Science (SPSS) version 17.0.

The demographic characteristics and underlying clinical conditions of the RT recipients with mucormycosis are summarized in Table 1. The average age of the 174 patients was 45.9 years (range, 11–70 years), with male representing the majority (76%). The most common underlying diseases was diabetes mellitus (43.1%). Nine of them were type 1 diabetes, 6 were type 2 diabetes, and 10 were post-transplant diabetes. In 50 of them the diabetes type was not described. The overall mortality of patients with diabetes mellitus was 33.3%. Other underlying conditions including surgery, dental extraction, HIV infection, malignancy, trauma, and deferoxamine therapy. Of note, thirty (25.1%) patients had no special medical history apart from RT. The median time duration from RT to establishing the diagnosis of mucormycosis was 2.5 months (range, 2 days-20 years).

According to the clinical presentation and anatomic localization, there were 7 major clinical forms of mucormycosis infection: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) graft kidney (6) disseminated, and (7) other uncommon sites (Table 2). Disseminated infection was defined as infection at 2 noncontiguous sites. The types of infection by site at the time of diagnosis in our review were shown in Table 2. Overall, rhinocerebral mucormycosis is the most common form (33.3%), followed by pulmonary (25.9%), disseminated (14.4%), transplanted kidney (11.5%), cutaneous (7.5%), gastrointestinal (5.7%), peritoneal (1.1%) and artery stent (0.6%). The mortality of mucormycosis in RT recipients was varied with the site of infection: 76% of patients with disseminated mucormycosis, 42.2% with pulmonary infection, and 55.6% with renal graft infection (Table 2).

Signs that suggest graft kidney mucormycosis were nonspecific, including fever, abdominal pain, oliguria, and graft dysfunction. However, absence of this findings should not exclude the possibility of mucormycosis. Fever was variable and may be absent in up to half of cases. There was only one case accompany with urinary leak before graft infection.

There were two cases of peritoneal dialysis-associated zygomycete peritonitis after renal transplantation. The patients have nonspecial symptoms, including abdominal pain and cloudy dialysis effluent. Tenckoff dialysis catheter were removed in the two zygomycete peritonitis patients and converted to maintain hemodialysis.

Our study finds that there was a rising incidence of mucormycosis in RT recipients in the past 5 decades (Fig. 1). The majority cases documented by culture were reported since the 2000s. This could be caused by the advances in diagnostic techniques.

All patients were confirmed as mucormycosis by histological examination and/or fungal culture. Histological examination was performed in 160 cases. 149 (85.6%) of which revealed typical hyphae. Of the 174 cases, 77 (44.3%) were diagnosed by both histopathology and culture, 25(14.4%) by culture only, 72 (41.4%) by histopathology only (Table 1). In 88 patients pathogenic zygomyectes were identified to species level (Table 3). The most frequent pathogen was Rhizopus species (59.1%), followed by Mucor species (13.6%) and Cunninghamella species (8.0%).

Most cases of mucormycosis in RT recipients (76%) were male. Infection with Mycocladus (100%), Apophysomyces elegans (80.0%), Mucor (90.9%) and Rhizopus rhizopodiformis (100%) was highly associated with male gender (Table 4, Fig. 2).

The treatment strategies included antifungal therapy, surgery, and reduction of immunosuppression (Table 5). One hundred and twenty-one (69.5%) patients received both antifungals and surgery therapy. The survival rate of this group patients (70.2%) was much higher than those who received either antifungal therapy alone (32.4%) or surgery alone (36.4%) (p < 0.001). Of the 174 cases reviewed, 155 (89%) received antifungal chemotherapy (Table 5). The survival rate of patients received deoxycholate amphotericin B (37/78, 47.4%), liposomal amphotericin B (47/64, 73.4%) and posaconazole (12/13, 92.3%) therapy was higher than those receiving other antifungals (4/19, 21.1%) or no treatment (0/8, 0%), (p < 0.001) (Table 6). The overall survivals in patients receiving posaconazole and lipid amphoterincin B were higher than that receiving deoxycholate formulation (92.3% and 73.4% vs 47.4%) (Table 4).