Abstract

Clinical manifestations, treatment, and outcomes of cutaneous cryptococcosis in solid organ transplant (SOT) recipients are not fully defined. In a prospective cohort comprising 146 SOT recipients with cryptococcosis, we describe the presentation, antifungal therapy, and outcome of cutaneous cryptococcal disease. Cutaneous cryptococcosis was documented in 26/146 (17.8%) of the patients and manifested as nodular/mass (34.8%), maculopapule (30.4%), ulcer/pustule/abscess (30.4%), and cellulitis (30.4%) with 65.2% of the skin lesions occurred in the lower extremities. Localized disease developed in 30.8% (8/26), and disseminated disease in 69.2% (18/26) with involvement of the central nervous system (88.9%, 16/18), lung (33.3%, 6/18), or fungemia (55.6%, 10/18). Fluconazole (37.5%) was employed most often for localized and lipid formulations of amphotericin B (61.1%) for disseminated disease. Overall mortality at 90 days was 15.4% (4/26) with 16.7% in disseminated and 12.5% in localized disease (P = 0.78). SOT recipients who died were more likely to have renal failure (75.0% vs. 13.6%, P = 0.028), longer time to onset of disease after transplantation (87.5 vs. 22.6 months, P = 0.023), and abnormal mental status (75% vs. 13.6%, P = 0.028) than those who survived. Cutaneous cryptococcosis represents disseminated disease in most SOT recipients and preferentially involves the extremities. Outcomes with appropriate management were comparable between SOT recipients with localized and disseminated cryptococcosis.

Introduction

Cryptococcosis is a serious posttransplant infectious complication in solid organ transplant (SOT) recipients with an overall incidence of ∼2.8% (range 0.3–5%) and mortality ranging from 33–12% [1]. Following the central nervous system (CNS) and the lung, the skin, soft-tissue, or osteoarticular tissue is the most common site of cryptococcal disease [1,2]. Unlike CNS and pulmonary cryptococcosis however [2–4], cutaneous cryptococcosis in SOT recipients has been reported largely as case studies or case series comprising small numbers of patients [1,5–7]. Prospective studies systematically describing this entity in the SOT population are lacking, and little is known about the differences in clinical presentations, treatment, and outcome between SOT recipients with disease limited to the skin and those with cutaneous involvement as part of disseminated cryptococcosis. It has been shown that the receipt of calcineurin-inhibitors is associated with a lower risk for mortality in the SOT population with cryptococcosis [2]. It is not clear whether calcineurin-inhibitors also have such effects on outcome of SOT recipients with cutaneous cryptococcal disease.

Thus, the present study aimed to describe the clinical manifestations, approach to antifungal therapy, and outcomes of cutaneous cryptococcal disease in a prospectively followed cohort of SOT recipients with cryptococcosis.

Materials and methods

One hundred forty-six SOT recipients with cryptococcosis at participating centers were prospectively studied from 2001 through 2007. A detailed description of this cohort has been reported elsewhere [2–4]. None of the patients were HIV-positive. Cryptococcosis was defined per criteria proposed by the European Organization for Research and Treatment in Cancer and the Mycoses Study Group [8]. Localized cutaneous cryptococcosis was considered as disease limited to the skin with or without involvement of contiguous muscle or bone. Disseminated disease was defined as involvement of at least one noncontiguous site in addition to the skin and/or fungemia. Data collected included demographic characteristics, type of organ transplant, immunosuppressive regimen at the time of diagnosis, baseline renal failure (defined as serum creatinine >2 mg/dl at diagnosis and prior to the initiation of antifungal therapy), prior rejection, retransplantation, cytomegalovirus infection or disease, clinical presentation, sites of infection, initial antifungal therapy, and mortality at 90 days after the diagnosis of cutaneous cryptococcosis. Immune reconstitution syndrome was defined as previously proposed [9], and one case with immune reconstitution syndrome included in this study has been reported before [10].

Statistical analyses

Statistical analyses were performed using Intercooled Stata version 9.2 (College Station, TX). Categorical data were compared using the Chi-square test or Fisher exact test. Continuous variables were compared using the rank-sum test.

Results

Of the 146 SOT recipients with cryptococcosis, cutaneous cryptococcosis (17.8%, 26/146) was the third most common manifestation of cryptococcosis following CNS (54.8%, 80/146) and pulmonary (56.8%, 83/146) cryptococcosis. The 26 patients with cutaneous cryptococcosis comprised the present study population, and their diagnosis was established by positive serum cryptococcal antigen only in 46.2% (12/26), positive blood culture only in 19.2% (5/26), positive blood cultures and skin histopathology in 11.5% (3/26), positive skin cultures only in 11.5% (3/26), positive blood and skin cultures in 7.7% (2/26), and positive skin histopathology only in 3.8% (1/26). Except for two skin isolates of which species identification was not performed, all the remaining were C. neoformans, and the most common description of skin pathology was yeast forms consistent with Cryptococcus. Demographic and clinical characteristics of these 26 patients are presented in Table 1. The primary immunosuppressive agent employed was calcineurin inhibitors, including tacrolimus in 65.4% (17/26) and cyclosporine A in 23.1% (6/26) (Table 1).

Table 1

Demographic and clinical characteristics of 26 solid organ transplant recipients with cutaneous cryptococcosis.

Age, mean (interquartile range), year 52 (46–60) 
Female, % (n23.1 (6) 
Type of transplant, % (n 
Kidney 50.0 (13) 
Liver 23.1 (6) 
Lung 11.5(3) 
Heart 11.5(3) 
Pancreas 3.8 (1) 
Primary immunosuppressive agents, % (n) Tacrolimus 65.4 (17) 
Cyclosporine A 23.1 (6) 
Others1 11.5(3) 
Other immunosuppression, % (n) Prednisone 96.2 (25) 
Dose, median (interquartile range), mg/day 10 (6.5–15) 
Mycophenolate mofetil 46.2 (12) 
Anti-T cell antibody 7.7 (2) 
Retransplantation, % (n7.7 (2) 
Rejection, % (n30.8 (8) 
Cytomegalovirus infection2, % (n16.0 (4/25) 
Cytomegalovirus disease3, % (n7.7 (2) 
Renal failure at baseline, % (n23.1 (6) 
Age, mean (interquartile range), year 52 (46–60) 
Female, % (n23.1 (6) 
Type of transplant, % (n 
Kidney 50.0 (13) 
Liver 23.1 (6) 
Lung 11.5(3) 
Heart 11.5(3) 
Pancreas 3.8 (1) 
Primary immunosuppressive agents, % (n) Tacrolimus 65.4 (17) 
Cyclosporine A 23.1 (6) 
Others1 11.5(3) 
Other immunosuppression, % (n) Prednisone 96.2 (25) 
Dose, median (interquartile range), mg/day 10 (6.5–15) 
Mycophenolate mofetil 46.2 (12) 
Anti-T cell antibody 7.7 (2) 
Retransplantation, % (n7.7 (2) 
Rejection, % (n30.8 (8) 
Cytomegalovirus infection2, % (n16.0 (4/25) 
Cytomegalovirus disease3, % (n7.7 (2) 
Renal failure at baseline, % (n23.1 (6) 
1

Others included azothiprine (1), mycophenolate mofetil and prednisone (1), sirolimus and prednisone (1).

2

Cytomegalovirus infection was defined as evidence of detectable virus, viral proteins or nucleic acid [26].

3

Cytomegalovirus disease was defined as viral syndrome characterized by fever, leucopenia and thrombocytopenia or as tissue-invasive disease including pneumonitis, hepatitis and focal gastrointestinal disease [26].

Cutaneous cryptococcosis developed at a median of 27.3 months (interquartile range 9.5–68.4 months) after transplantation, and 65.4% (17/26) of the cases occurred after 1 year post-transplant (Table 2). Description of the characteristics of the cutaneous lesions was available in 23/26 patients. The lower extremities (65.2%, 15/23) were the most common site of involvement followed by the trunk (26.1%, 6/23), upper extremities (21.7%, 5/23), and head and/or neck (4.3%, 1/23) (Table 2). Overlapping/ multiple cutaneous morphologies were present at the time of diagnosis, and detailed descriptions of skin manifestations are presented in Table 2. Immune reconstitution syndromelike illness associated with cryptococcosis manifesting as cutaneous disease was observed in one patient who has been reported [10]. Worsening myonecrosis with a declining cryptococcal serum antigen (from 1:1024 to 1:256) under oral fluconazole and tapered immunosuppression occurred as immune reconstitution syndrome in this renal transplant recipient leading to amputation of the right forearm for persistent symptoms despite receipt of liposomal amphotericin B.

Table 2

Characteristics of cutaneous cryptococcosis in 26 solid organ transplant recipients.

Time to onset of cutaneous cryptococcosis Median (interquartile range), month 27.3 (9.5–68.4) 
0–30 days, % (n3.8 (1) 
31–90 days 0(0) 
91 days-1 year 30.8 (8) 
>1 year 65.4 (17) 
Cutaneous lesions1, % (n) Sites  
Lower extremities 65.2 (15) 
Trunk2 26.1 (6) 
Upper extremities 21.7 (5) 
Head and neck3 4.3 (1) 
Distribution  
Multiple 47.8 (11) 
Diffuse 13.0 (3) 
Type of lesion  
Nodule/mass 34.8 (8) 
Maculopapule 30.4 (7) 
Ulcer/pustule/abscess 30.4 (7) 
Cellulitis 30.4 (7) 
Vesicle/bullae 8.7 (2) 
Miscellaneous4 13.0 (3) 
Site of infection5, % (n 
Localized disease 30.8 (8) 
Disseminated disease 69.2 (18) 
Central nervous system 61.5 (16) 
Lung 23.1 (6) 
Fungemia 38.5 (10) 
Time to onset of cutaneous cryptococcosis Median (interquartile range), month 27.3 (9.5–68.4) 
0–30 days, % (n3.8 (1) 
31–90 days 0(0) 
91 days-1 year 30.8 (8) 
>1 year 65.4 (17) 
Cutaneous lesions1, % (n) Sites  
Lower extremities 65.2 (15) 
Trunk2 26.1 (6) 
Upper extremities 21.7 (5) 
Head and neck3 4.3 (1) 
Distribution  
Multiple 47.8 (11) 
Diffuse 13.0 (3) 
Type of lesion  
Nodule/mass 34.8 (8) 
Maculopapule 30.4 (7) 
Ulcer/pustule/abscess 30.4 (7) 
Cellulitis 30.4 (7) 
Vesicle/bullae 8.7 (2) 
Miscellaneous4 13.0 (3) 
Site of infection5, % (n 
Localized disease 30.8 (8) 
Disseminated disease 69.2 (18) 
Central nervous system 61.5 (16) 
Lung 23.1 (6) 
Fungemia 38.5 (10) 
1

Twenty-three patients had information about cutaneous lesions available.

2

The specific locations included the abdomen (1 patient), back and chest (1), shoulder (1), upper trunk (1), pubis (1), and left breast (1).

3

The distribution was forehead and neck.

4

Miscellaneous lesions were crusted lesions (1 patient), hemorrhagic lesions (1), and myositis (1).

5

Site of infection was localized if disease was limited to the skin with or without involvement of contiguous muscle or bone, and was disseminated if disease involved at least one noncontiguous site in addition to the skin and/or fungemia.

Cryptococcosis was limited to the skin in 30.8% (8/26) of the cases, and disseminated to other organs in 69.2% (18/26), including the central nervous system in 16/26 patients (61.5%), lung in 6/26 (23.1%), and fungemia 10/26 (38.5%) (Table 2). Infection sites, distributions, and type of cutaneous lesions did not differ for SOT recipients with localized and those with disseminated disease (all P > 0.05). Similar proportions of patients in the localized and disseminated groups had serum cryptococcal antigen and blood cultures performed. Patients with disseminated cutaneous disease were more likely to have fever (55.6% vs. 0%, P = 0.024), serum cryptococcal antigen >1:64 [93.3% (14/15) vs. 40.0% (2/5), P = 0.032], and to receive prednisone > 10 mg/day [82.4% (14/17) vs. 25.0% (1/4), P = 0.053] than patients with localized disease (Table 3). No significant differences existed between the two groups with regards to age, gender, type of organ transplant, receipt of calcineurin inhibitors or anti-T-cell antibody, renal failure, rejection, retransplantation, CMV infection, or time to onset of cutaneous cryptococcosis (Table 3).

Table 3

Comparison of demographic and clinical presentations between solid organ transplant recipients with localized and disseminated cutaneous cryptococcosis.

Factor Localized Disseminated P value 
Patient number 18  
Age, years, median (interquartile range) 49.5 (44–58) 57 (49–63) 0.26 
Female, % (n12.5 (1) 27.8 (5) 0.63 
Type of organ transplant, % (n   
Kidney 50.0 (4) 50.0 (9) 0.99 
Liver 25.0 (2) 22.2 (4)  
Lung 12.5 (1) 11.1 (2)  
Heart 12.5 (1) 11.1 (2)  
Pancreas 0(0) 5.6 (1)  
Immunosuppression    
Tacrolimus, % (n50.0 (4) 72.2 (13) 0.38 
Cyclosporine A, % (n25.0 (2) 22.2 (4) 0.88 
Anti-T-cell antibody, % (n0(0) 11.1 (2) 0.99 
Prednisone ≥10 mg/day, % (n25.0 (1/4) 82.4 (14/17) 0.053 
Renal failure, % (n12.5 (1) 27.8 (5) 0.63 
Rejection, % (n37.5 (3) 27.8 (5) 0.67 
Retransplantation, % (n12.5 (1) 5.6 (1) 0.53 
Cytomegalovirus infection, % (n25.0 (2) 11.8(2/17) 0.57 
Time to onset of disease, month, median (interquartile range) 22.9 (10–40.6) 39.7 (9.4–76.1) 0.69 
> 1 year post-transplantation, % (n62.5 (5) 66.7 (12) 0.99 
Fever, % (n0(0) 55.6 (10) 0.024 
Abnormal mental status, % (n0(0) 33.3 (6) 0.13 
Central nervous system involvement NA1 88.9 (16) – 
Pulmonary involvement NA 33.3 (6) – 
Fungemia NA 55.6 (10) – 
Serum antigen2    
>1:64, % (n40.0 (2/5) 93.3 (14/15) 0.032 
Factor Localized Disseminated P value 
Patient number 18  
Age, years, median (interquartile range) 49.5 (44–58) 57 (49–63) 0.26 
Female, % (n12.5 (1) 27.8 (5) 0.63 
Type of organ transplant, % (n   
Kidney 50.0 (4) 50.0 (9) 0.99 
Liver 25.0 (2) 22.2 (4)  
Lung 12.5 (1) 11.1 (2)  
Heart 12.5 (1) 11.1 (2)  
Pancreas 0(0) 5.6 (1)  
Immunosuppression    
Tacrolimus, % (n50.0 (4) 72.2 (13) 0.38 
Cyclosporine A, % (n25.0 (2) 22.2 (4) 0.88 
Anti-T-cell antibody, % (n0(0) 11.1 (2) 0.99 
Prednisone ≥10 mg/day, % (n25.0 (1/4) 82.4 (14/17) 0.053 
Renal failure, % (n12.5 (1) 27.8 (5) 0.63 
Rejection, % (n37.5 (3) 27.8 (5) 0.67 
Retransplantation, % (n12.5 (1) 5.6 (1) 0.53 
Cytomegalovirus infection, % (n25.0 (2) 11.8(2/17) 0.57 
Time to onset of disease, month, median (interquartile range) 22.9 (10–40.6) 39.7 (9.4–76.1) 0.69 
> 1 year post-transplantation, % (n62.5 (5) 66.7 (12) 0.99 
Fever, % (n0(0) 55.6 (10) 0.024 
Abnormal mental status, % (n0(0) 33.3 (6) 0.13 
Central nervous system involvement NA1 88.9 (16) – 
Pulmonary involvement NA 33.3 (6) – 
Fungemia NA 55.6 (10) – 
Serum antigen2    
>1:64, % (n40.0 (2/5) 93.3 (14/15) 0.032 
1

NA= not applicable because of the definition of disseminated cutaneous cryptococcosis.

2

Information regarding serum antigen was not available in 4 patients, and results of the remaining 22 patients were reported as positive without titer available in 2 patients. Thus, a total of 20 patients were evaluable to access whether their titer was >1:64 or not.

Outcome

Except for one patient (12.5%, 1/8) in whom information regarding treatment was unavailable, fluconazole (37.5%, 3/8) was the most frequently employed initial antifungal agent for the treatment of localized disease followed by amphotericin B deoxycholate (25.0%, 2/8) and lipid formulations of amphotericin B (25.0%, 2/8). For disseminated cutaneous disease, the most common therapeutic agent used was lipid formulations of amphotericin B (61.1%, 11/18) followed by amphotericin B deoxycholate (27.8%, 5/18), and fluconazole (11.1%, 2/18). Flucytosine was employed concurrently in 2/8 patients (25%) with localized disease and in 12/18 (66.7%) of the patients with disseminated disease (P = 0.090).

Overall, mortality at 90 days after the diagnosis of cutaneous cryptococcosis was 15.4% (4/26); 12.5% (1/8) in localized disease and 16.7% (3/18) in disseminated disease (P = 0.78). Compared with SOT recipients who survived at 90 days, recipients who died at 90 days were more likely to have renal failure at baseline (75% vs. 13.6%, P = 0.028), longer time to onset of disease after transplantation (87.5 months vs. 22.6 months, P = 0.023), and abnormal mental status (75% vs. 13.6%, P = 0.028) (Table 4). There were no statistical differences between SOT recipients who died versus those who survived at 90 days posttransplant with regards to age, gender, type of organ transplant, use of specific immunosuppressive agents, rejection, retransplantation, CMV infection, disseminated cutaneous disease, fungemia, serum antigen >1:64, and initial antifungal agents (Table 4).

Table 4

Comparisons of demographic and clinical presentations between solid organ transplant recipients with cutaneous cryptococcosis who died and who survived at 90 days posttransplantation.

Factor Death Survival P value 
Patient number 22  
Age, years, median (interquartile range) 57 (46–62) 56 (42–60) 0.62 
Female, % (n25.0 (1) 22.7 (5) 0.99 
Type of organ transplant, % (n   
Kidney 50.0 (2) 50.0 (11) 0.46 
Liver 0(0) 27.3 (6)  
Lung 25.0 (1) 9.1 (2)  
Heart 25.0 (1) 9.1 (2)  
Pancreas 0(0) 4.6 (1)  
Immunosuppression, % (n   
Tacrolimus 50.0 (2) 68.2 (15) 0.59 
Cyclosporine A 25.0 (1) 22.7 (5) 0.92 
Anti-T-cell antibody 0(0) 9.1 (2) 0.71 
Prednisone ≥10 mg/day 100.0 (4) 64.7 (11/17) 0.28 
Renal failure at baseline, % (n75.0 (3) 13.6 (3) 0.028 
Rejection, % (n25.0 (1) 31.8 (7) 0.79 
Retransplantation, % (n0(0) 9.1 (2) 0.53 
Cytomegalovirus infection, % (n0(0) 18.2 (4) 0.35 
Time to onset of disease, months, median (interquartile range) 87.5 22.6 0.023 
> 1 year post-transplantation, % (n100.0 (4) 59.1 (13) 0.26 
Abnormal mental status, % (n75.0 (3) 13.6 (3) 0.028 
Disseminated cutaneous disease 75.0 (3) 68.2 (15) 0.78 
Central nervous system involvement 75.0 (3) 59.1 (13) 0.55 
Pulmonary involvement 50.0 (2) 18.2 (4) 0.22 
Fungemia 75.0 (3) 33.3 (7/21) 0.26 
Serum antigen1 >1:64, % (n100.0 (2/2) 77.8 (14/18) 0.99 
Initial treatment, % (n   
Amphotericin B deoxycholate 25.0 (1) 27.3 (6) 0.99 
Concurrent use of flucytosine 100 (1/1) 33.3 (2/6)  
Lipid formulations of amphotericin B 50.0 (2) 50.0 (11)  
Concurrent use of flucytosine 100 (2/2) 72.7 (8/11)  
Fluconazole 25.0 (1) 18.2 (4)  
Concurrent use of flucytosine 0 (0/1) 25.0 (1/4)  
Factor Death Survival P value 
Patient number 22  
Age, years, median (interquartile range) 57 (46–62) 56 (42–60) 0.62 
Female, % (n25.0 (1) 22.7 (5) 0.99 
Type of organ transplant, % (n   
Kidney 50.0 (2) 50.0 (11) 0.46 
Liver 0(0) 27.3 (6)  
Lung 25.0 (1) 9.1 (2)  
Heart 25.0 (1) 9.1 (2)  
Pancreas 0(0) 4.6 (1)  
Immunosuppression, % (n   
Tacrolimus 50.0 (2) 68.2 (15) 0.59 
Cyclosporine A 25.0 (1) 22.7 (5) 0.92 
Anti-T-cell antibody 0(0) 9.1 (2) 0.71 
Prednisone ≥10 mg/day 100.0 (4) 64.7 (11/17) 0.28 
Renal failure at baseline, % (n75.0 (3) 13.6 (3) 0.028 
Rejection, % (n25.0 (1) 31.8 (7) 0.79 
Retransplantation, % (n0(0) 9.1 (2) 0.53 
Cytomegalovirus infection, % (n0(0) 18.2 (4) 0.35 
Time to onset of disease, months, median (interquartile range) 87.5 22.6 0.023 
> 1 year post-transplantation, % (n100.0 (4) 59.1 (13) 0.26 
Abnormal mental status, % (n75.0 (3) 13.6 (3) 0.028 
Disseminated cutaneous disease 75.0 (3) 68.2 (15) 0.78 
Central nervous system involvement 75.0 (3) 59.1 (13) 0.55 
Pulmonary involvement 50.0 (2) 18.2 (4) 0.22 
Fungemia 75.0 (3) 33.3 (7/21) 0.26 
Serum antigen1 >1:64, % (n100.0 (2/2) 77.8 (14/18) 0.99 
Initial treatment, % (n   
Amphotericin B deoxycholate 25.0 (1) 27.3 (6) 0.99 
Concurrent use of flucytosine 100 (1/1) 33.3 (2/6)  
Lipid formulations of amphotericin B 50.0 (2) 50.0 (11)  
Concurrent use of flucytosine 100 (2/2) 72.7 (8/11)  
Fluconazole 25.0 (1) 18.2 (4)  
Concurrent use of flucytosine 0 (0/1) 25.0 (1/4)  
1

Information regarding serum antigen was not available in 4 patients, and results of the remaining 22 patients were reported as positive without titer available in 2 patients. Thus, a total of 20 patients were evaluable to access whether their titer was >1:64 or not.

Discussion

In our study, cutaneous cryptococcosis was documented in 17.8% of our SOT recipients with cryptococcal disease, a majority of whom had disseminated disease that most often involved the central nervous system and the lung (Tables 2 and 3). Additionally, no cutaneous manifestations or distribution were specific to disseminated disease. Thus, these observations indicate that most cutaneous cryptococcosis is a manifestation of disseminated disease and accordingly, a diagnosis of cutaneous cryptococcosis should prompt a thorough investigation of cerebrospinal fluid, blood, the lungs, and serum cryptococcal antigen.

Primary cutaneous cryptococcosis, defined as lesions confined to a circumscribed body region with skin cultures positive for C. neoformans and without signs of simultaneous dissemination, was described in a French nationwide survey of cryptococcosis [11]. These patients were generally older, typically did not have an underlying disease, resided in rural areas, and had a history of cutaneous injury, outdoor activities, and exposure to bird droppings [11]. Skin lesions developed on the hand in 71.5% of the cases with primary cutaneous cryptococcosis, and manifested most frequently as whitlow with/without phlegmon (60.7%) followed by cellulitis (14.3%) and nodules or ulceration (10.7%) [11].

Unlike aforementioned manifestations of primary cutaneous cryptococcosis, a majority of cutaneous lesions in our SOT recipients occurred in the lower extremities, and their manifestations were protean (Table 2). Nodular/ mass, maculopapule, ulcer/pustule/abscess, and cellulitis were most commonly seen in the present study (Table 2). Necrotizing fasciitis [12], eschar [13], involvement of bone or joint [5,14,15], and cellulitis with necrotizing vasculitis have also been reported in the SOT population [16]. Most cryptococcal disease in SOT recipients in the US is due to C. neoformans var. grubii (serotype A) which has no particular geographical predilection [17]. Of 30 cryptococcal isolates from our study previously sero-typed, all but one were serotype A [17]. In contrast, 71% and 44% of the isolates associated with primary or cutaneous cryptococcosis in the French survey were C. neoformans var. neoformans (serotype D), respectively [11]. Thus, host or pathogen related factors may account for differences in the clinical characteristics of cutaneous cryptococcal disease.

Similar to one of our patients, cutaneous lesions have been reported as a manifestation of cryptococcosis-related immune reconstitution inflammatory syndrome in a renal transplant recipient [18]. This phenomenon has increasingly come to be recognized in SOT recipients with opportunistic infections, such as CNS cryptococcosis, tuberculosis, and cytomegalovirus disease [10,1824]. It has been proposed that this syndrome occurs as a result of shift in the dominant T helper responses that restrain inflammation towards generation of proinflammatory T cells after initiation of antimicrobial agents, and a reduction or cessation of immunosuppressive therapy [25]. Awareness of this unique entity and its manifestations in the SOT population is crucial to avoid misconstruing it as failure of therapy or as a relapse.

Mortality of cutaneous cryptococcosis was 15.4%, and patients who died were more likely to have renal failure, abnormal mental status, and longer time to onset of disease after transplantation than those who survived (Table 4). It is understandable that abnormal mental status denotes disseminated disease or higher disease severity which may predispose patients to a higher risk of death. Since the longer the time after transplantation is the less frequent follow-up the patients have, it is very likely that as cryptococcosis was diagnosed, patients had already been at an advanced stage. Additionally, comparable outcomes were observed between recipients with localized and disseminated disease which might be the results of appropriate management or the limitation of small study population.

Unlike our previous finding that receipt of calcineurin-inhibitor agent is associated with a lower mortality [2], the present study showed mortality was not affected by the receipt of calcineurin-inhibitors in SOT recipients with cutaneous cryptococcosis (Table 4). It is possible that the majority of our patients received calcineurin-inhibitors, and the numbers of study population and death events are small which prevents us from detecting the influence of calcineurin-inhibitors. On the other hand, it is also possible that the severity of cryptococcosis overrode the protective effects of calcineurin-inhibitors.

Some limitations of our study deserve to be acknowledged. This investigation included patients from geographically diverse transplant centers and clinical practices in each institution may vary. Additionally, given the observational study design, not all patients underwent all the diagnostic investigation once the diagnosis was established. Further, our cohort was relatively small and this may have affected our analyses. With that said, this is the largest cohort of patients with cutaneous cryptococcosis reported to date, and to our knowledge, is the first to systematically characterize cutaneous cryptococcosis and associated outcomes in SOT recipients in the current era.

In conclusion, cutaneous cryptococcosis is the third most common manifestation of cryptococcosis in SOT recipients and heralds disseminated disease in most cases, particularly in patients presenting with fever or serum antigen titer >1:64. Cutaneous lesions most often involve the extremities, vary widely in their manifestations, and are indistinguishable clinically from those caused by other pathogens.

Acknowledgements

Funding sources: National Institutes of Health, National Institute of Allergy and Infectious Diseases (R01 AI 054719-01 to Nina Singh).

Declarations of interest: Barbara D. Alexander has served on advisory boards for Enzon, Basilea, Abbott, and Schering-Plough, served on speaker's bureaus of Astellas and Pfizer, and received grants from Astellas, Enzon, and Pfizer; Graeme Forrest has received a grant from Astellas. G. Marshall Lyon has served on advisory boards for and received grants from Merck and Astellas, and on speaker's bureaus of Astellas, Schering-Plough, and Wyeth; Kenneth Pursell has served on a speaker's bureau of Merck; Michele I. Morris has served on advisory boards for Astellas, Pfizer, and Merck, has received grants from Astellas, Basilea, and Pfizer, and has served on speaker's bureaus of Astellas and Pfizer; Patricia Munoz has served on speaker's bureaus of Merck and Novartis and on an advisory board for Pfizer; Sally H. Houston has served on speaker's bureaus of Astellas and Pfizer; Leonard B. Johnson has served on a speaker's bureau of Pfizer; Shahid Husain has served on consultant boards for and received grants from Pfizer, Astellas, and Schering-Plough; Nina Singh has received a grant from Pfizer; other authors have no conflicts.

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This paper was first published online on Early Online on 25 January 2010.