Unrecognized pretransplant and donor­derived cryptococcal disease in organ transplant recipients.

BACKGROUND: Cryptococcosis occurring ≤30 days after transplantation is an unusual event, and its characteristics are not known. METHODS: Patients included 175 solid-organ transplant (SOT) recipients with cryptococcosis in a multicenter cohort. Very early-onset and late-onset cryptococcosis were defined as disease occurring ≤30 days or >30 days after transplantation, respectively. RESULTS: Very early-onset disease developed in 9 (5%) of the 175 patients at a mean of 5.7 days after transplantation. Overall, 55.6% (5 of 9) of the patients with very early-onset disease versus 25.9% (43 of 166) of the patients with late-onset disease were liver transplant recipients (P = .05). Very early cases were more likely to present with disease at unusual locations, including transplanted allograft and surgical fossa/site infections (55.6% vs 7.2%; P < .001). Two very early cases with onset on day 1 after transplantation (in a liver transplant recipient with Cryptococcus isolated from the lung and a heart transplant recipient with fungemia) likely were the result of undetected pretransplant disease. An additional 5 cases involving the allograft or surgical sites were likely the result of donor‐acquired infection. CONCLUSIONS: A subset of SOT recipients with cryptococcosis present very early after transplantation with disease that appears to occur preferentially in liver transplant recipients and involves unusual sites, such as the transplanted organ or the surgical site. These patients may have unrecognized pretransplant or donor-derived cryptococcosis.

Cutaneous cryptococcosis in solid organ transplant recipients.

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.

Lipid formulations of amphotericin B significantly improve outcome in solid organ transplant recipients with central nervous system cryptococcosis.

BACKGROUND: Whether outcome of central nervous system (CNS) cryptococcosis in solid organ transplant recipients treated with lipid formulations of amphotericin B is different from the outcome of the condition treated with amphotericin B deoxycholate (AmBd) is not known. METHODS: We performed a multicenter study involving a cohort comprising consecutive solid organ transplant recipients with CNS cryptococcosis. RESULTS: Of 75 patients treated with polyenes as induction regimens, 55 (73.3%) received lipid formulations of amphotericin B and 20 (26.7%) received AmBd. Similar proportions of patients in both groups had renal failure at baseline (P = .94 ). Overall, mortality at 90 days was 10.9% in the group that received lipid formulations of amphotericin B and 40.0% in the group that received AmBd. In univariate analysis, nonreceipt of calcineurin inhibitors (P = .034), renal failure at baseline (P = .016), and fungemia (P = .003) were significantly associated with mortality. Compared with AmBd, lipid formulations of amphotericin B were associated with a lower mortality (P = .007). Mortality did not differ between patients receiving lipid formulations of amphotericin B with or without flucytosine (P = .349). In stepwise logistic regression analysis, renal failure at baseline (odds ratio [OR], 4.61; 95% confidence interval [CI], 1.02-20.80; P = .047) and fungemia (OR, 10.66; 95% CI, 2.08-54.55; P = .004 ) were associated with an increased mortality, whereas lipid formulations of amphotericin B were associated with a lower mortality (OR, 0.11; 95% CI, 0.02-0.57; P = .008). CONCLUSIONS: Lipid formulations of amphotericin B were independently associated with better outcome and may be considered as the first-line treatment for CNS cryptococcosis in these patients.

Pulmonary cryptococcosis in solid organ transplant recipients: clinical relevance of serum cryptococcal antigen.

BACKGROUND: The role of serum cryptococcal antigen in the diagnosis and determinants of antigen positivity in solid organ transplant (SOT) recipients with pulmonary cryptococcosis has not been fully defined. METHODS: We conducted a prospective, multicenter study of SOT recipients with pulmonary cryptococcosis during 1999-2006. RESULTS: Forty (83%) of 48 patients with pulmonary cryptococcosis tested positive for cryptococcal antigen. Patients with concomitant extrapulmonary disease were more likely to have a positive antigen test result (P=.018), and antigen titers were higher in patients with extrapulmonary disease (P=.003) or fungemia (P=.045). Patients with single nodules were less likely to have a positive antigen test result than were those with all other radiographic presentations (P=.053). Among patients with isolated pulmonary cryptococcosis, lung transplant recipients were less likely to have positive cryptococcal antigen test results than were recipients of other types of SOT (P=.003). In all, 38% of the patients were asymptomatic or had pulmonary cryptococcosis detected as an incidental finding. Nodular densities or mass lesions were more likely to present as asymptomatic or incidentally detected pulmonary cryptococcosis than as pleural effusions and infiltrates (P=.008). CONCLUSIONS: A positive serum cryptococcal antigen test result in SOT recipients with pulmonary cryptococcosis appears to reflect extrapulmonary or more advanced radiographic disease.

Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.

BACKGROUND: : The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. METHODS: : Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. RESULTS: : Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30-1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12-0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16-0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. CONCLUSIONS: : Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.

An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients.

BACKGROUND: We describe an immune reconstitution syndrome (IRS)-like entity in the course of evolution of Cryptococcus neoformans infection in organ transplant recipients. METHODS: The study population comprised a cohort of 83 consecutive organ transplant recipients with cryptococcosis who were observed for a median of 2 years in an international, multicenter study. RESULTS: In 4 (4.8%) of the 83 patients, an IRS-like entity was observed a median of 5.5 weeks after the initiation of appropriate antifungal therapy. Worsening of clinical manifestations was documented, despite cultures being negative for C. neoformans. These patients were significantly more likely to have received tacrolimus, mycophenolate mofetil, and prednisone as the regimen of immunosuppressive therapy than were all other patients (P = .007). The proposed basis of this phenomenon is reversal of a predominantly Th2 response at the onset of infection to a Th1 proinflammatory response as a result of receipt of effective antifungal therapy and a reduction in or cessation of immunosuppressive therapy. CONCLUSIONS: This study demonstrated that an IRS-like entity occurs in organ transplant recipients with C. neoformans infection. Furthermore, this entity may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy in such cases.

Antifungal management practices and evolution of infection in organ transplant recipients with cryptococcus neoformans infection.

BACKGROUND: Therapeutic practices for Cryptococcus neoformans infection in transplant recipients vary, particularly with regards to antifungal agent employed, and duration of therapy. The risk of relapse and time to recurrence is not known. We assessed antifungal treatment practices for cryptococcosis in a cohort of prospectively followed organ transplant recipients. METHODS: The patients comprised 83 transplant recipients with cryptococcosis followed for a median of 2.1 and up to 5.2 years. RESULTS: Patients with central nervous system infection (69% vs. 16%, P = 0.00001), disseminated infection (82.7% vs. 20%, P = 0.00001), and fungemia (29% vs. 8%, P = 0.046) were more likely to receive regimens containing amphotericin B than fluconazole as primary therapy. The use of fluconazole, on the other hand, was more likely for infection limited to the lungs (64% vs. 14%, P = 0.00002). Survival at 6 months tended to be lower in patients whose CSF cultures at 2 weeks were positive compared to those whose CSF cultures were negative (50% vs. 91%, P = 0.06). Maintenance therapy was employed in 68% (54/79) of the patients who survived >3 weeks. The median duration of maintenance therapy was 183 days; 55% received maintenance for > or = 6 months and 25% for >1 year. Relapse was documented in 1.3% (1/79) of the patients. CONCLUSIONS: A majority of the organ transplant recipients with cryptococcosis receive maintenance antifungal therapy for 6 months with low risk of relapse. These data can assist in trials to assess the optimal therapeutic approach and duration of therapy for cryptococcosis in transplant recipients.

Allograft loss in renal transplant recipients with cryptococcus neoformans associated immune reconstitution syndrome.

This study describes the association of allograft loss and immune reconstitution syndrome (IRS) in the course of Cryptococcosis neoformans infection in renal transplant recipients. Patients comprised 54 renal allograft recipients with cryptococcosis in a prospective, multicenter study. IRS developed in 5.5% (3/54) of the renal transplant recipient with C. neoformans infection. The renal allograft was lost to chronic rejection in 66% (2/3) of the patients with cryptococcosis who developed IRS compared to 5.9% (3/51) of those who did not (P=0.012). Kaplan-Meier survival analysis showed that subsequent to cryptococcal infection the probability of allograft survival was significantly lower in patients who developed IRS compared to those who did not develop IRS (P=0.0004). Temporal association of graft loss with IRS suggests a common pathophysiologic basis for these entities with implications relevant for the optimal management of renal transplant recipients with cryptococcosis.

Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi.

To determine the spectrum and impact of mycelial fungal infections, particularly those due to non-Aspergillus molds, 53 liver and heart transplant recipients with invasive mycelial infections were prospectively identified in a multicenter study. Invasive mycelial infections were due to Aspergillus species in 69.8% of patients, to non-Aspergillus hyalohyphomycetes in 9.4%, to phaeohyphomycetes in 9.4%, to zygomycetes in 5.7%, and to other causes in 5.7%. Infections due to mycelial fungi other than Aspergillus species were significantly more likely to be associated with disseminated (P=.005) and central nervous system (P=.07) infection than were those due to Aspergillus species. Overall mortality at 90 days was 54.7%. The associated mortality rate was 100% for zygomycosis, 80% for non-Aspergillus hyalohyphomycosis, 54% for aspergillosis, and 20% for phaeohyphomycosis. Thus, non-Aspergillus molds have emerged as significant pathogens in organ transplant recipients. These molds are more likely to be associated with disseminated infections and to be associated with poorer outcomes than is aspergillosis.

Decreasing methicillin-resistant Staphylococcus aureus surgical site infections with chlorhexidine and mupirocin.

BACKGROUND: Surgical site infections (SSIs) associated with methicillin-resistant Staphylococcus aureus (MRSA) are a major complication of surgery. This study is part of a large infection control quality improvement effort to eliminate MRSA SSIs. METHODS: This is an Institutional Review Board-approved, case-control study examining MRSA SSI rates before and after implementation of a facility-wide MRSA SSI prevention protocol in 2007. The protocol involved a 5-day course of intranasal mupirocin and nonrinse 2% chlorhexidine gluconate cloths. RESULTS: In 2006, a total of 39 MRSA SSIs occurred after 9,976 procedures in patients who underwent orthopedic, vascular, cardiac, or neurosurgical procedures (rate = 0.39 per 100 procedures). The highest incidence occurred after cardiac surgery (rate = 1.24/100 procedures), and the lowest occurred after orthopedic surgery (rate = 0.28/100 procedures). In 2007, the MRSA SSI rate decreased to 20 of 9,818 procedures (rate = 0.20/100 procedures) in the 4 categories (P = .016; odds ratio, 1.92). In 2008, the MRSA SSI rate dropped again to 13 of 10,068 procedures (rate = 0.13/100 procedures) in the 4 categories (P = .0003; odds ratio, 3.04). CONCLUSION: A 5-day course of intranasal mupirocin and nonrinse 2% chlorhexidine gluconate cloths may be beneficial in preventing MRSA SSIs in the non-general surgery population.

Geographic differences in disease expression of cryptococcosis in solid organ transplant recipients in the United States.

BACKGROUND: Whether there are geographic differences in clinical presentation of cryptococcosis in solid organ transplant (SOT) recipients in the United States (US) is not known. MATERIAL/METHODS: Patients comprised a cohort of 120 SOT recipients from US transplant centers who fulfilled the EORTC/MSG criteria for cryptococcal disease. RESULTS: Central nervous system, pulmonary, and cutaneous cryptococcal disease were observed in 51% (61/120), 64% (77/120), and 15% (18/120) of the patients, respectively. Cutaneous disease was documented in 9% (3/32) of the patients from South Atlantic region, 19% (6/32) from Mid Atlantic, 26% (6/23) from Southern, 7% (2/29) from Midwestern, and in 1 of 4 patients from the Northwestern region of the US. When controlled for age, immunosuppressive regimen, type of transplant, and renal failure at baseline, patients from the Southern compared with other regions of the US were significantly more likely to have cutaneous cryptococcal disease (OR 3.8, 95% CI 1.1-14, P=0.045). CONCLUSIONS: Post-transplant cryptococcosis is more likely to present with cutaneous disease in the Southern region compared with other regions in the US. This predilection for cutaneous cryptococcosis could not be explained on the basis of differences in immunosuppression or the type of transplant. Whether our findings are related to strain-related variations in characteristics of the yeast or other transplant variables remains to be determined.

Identifying predictors of central nervous system disease in solid organ transplant recipients with cryptococcosis.

BACKGROUND: Cerebrospinal fluid (CSF) analysis is often deferred in patients with cryptococcal disease, particularly in the absence of neurologic manifestations. We sought to determine whether a subset of solid organ transplant (SOT) recipients with high likelihood of central nervous system (CNS) disease could be identified in whom CSF analysis must be performed. METHODS: Patients comprised a multicenter cohort of SOT recipients with cryptococcosis. RESULTS: Of 129 (88%) of 146 SOT recipients with cryptococcosis who underwent CSF analysis, 80 (62%) had CNS disease. In the overall study population, abnormal mental status, time to onset of cryptococcosis more than 24 months posttransplantation (late-onset disease), serum cryptococcal antigen titer more than 1:64, and fungemia were independently associated with an increased risk of CNS disease. Of patients with abnormal mental status, 95% had CNS cryptococcosis. When only patients with normal mental status were considered, three predictors (serum antigen titer >1:64, fungemia, and late-onset disease) independently identified patients with CNS cryptococcosis; the risk of CNS disease was 14% if none, 39% if one, and 94% if two of the aforementioned predictors existed (chi for trend P<0.001). CONCLUSIONS: CSF analysis should be strongly considered in SOT recipients with cryptococcosis who have late-onset disease, fungemia, or serum cryptococcal antigen titer more than 1:64 even in the presence of normal mental status.

Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome.

BACKGROUND: Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined. METHODS: In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days. RESULTS: Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables. CONCLUSIONS: The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

Central nervous system cryptococcosis in solid organ transplant recipients: clinical relevance of abnormal neuroimaging findings.

BACKGROUND: Prognostic implications of cryptococcal antigen and outcomes associated with central nervous system (CNS) cryptococcal lesions in solid organ transplant recipients have not been fully defined. METHODS: Patients were derived form a cohort of 122 solid organ transplant recipients with cryptococcosis in a multicenter study from 1999 to 2006. RESULTS: Central nervous system cryptococcosis was documented in 61 patients. Serum or cerebral spinal fluid antigen titers did not correlate with mortality at 90 days or cerebral spinal fluid sterilization at 2 weeks. Central nervous system lesions were identified in 16 patients and included leptomeningeal lesions in eight, parenchymal lesions in six, and hydrocephalus in two. Overall, 13/16 CNS lesions were present at the time of diagnosis. One parenchymal and two hydrocephalus lesions, however, developed after diagnosis and fulfilled the criteria for immune reconstitution syndrome. Cerebral spinal fluid antigen titers were higher with meningeal versus parenchymal lesions, and hydrocephalus (P=0.015). Mortality was 50% (3/6) for patients with parenchymal, 12.5% (1/8) for those with leptomeningeal, and 0/3 for patients with hydrocephalus. Mortality was 31% (4/13) for patients with CNS lesions at baseline and 0/3 in those with new onset lesions. CONCLUSIONS: Despite a higher antigen titer with meningeal lesions, outcomes tended to be worse with parenchymal compared with meningeal lesions or hydrocephalus. New onset CNS lesions may represent immune reconstitution syndrome and seemed to be associated with better outcome.

Calcineurin inhibitor agents interact synergistically with antifungal agents in vitro against Cryptococcus neoformans isolates: correlation with outcome in solid organ transplant recipients with cryptococcosis.

Synergistic interactions were observed between CIs and antifungal agents against 53 (90%) of 59 Cryptococcus neoformans isolates from solid organ transplant recipients with cryptococcosis and may account for better outcomes in patients with cryptococcosis receiving these immunosuppressive agents.

Cryptococcus neoformans in organ transplant recipients: impact of calcineurin-inhibitor agents on mortality.

Variables influencing the risk of dissemination and outcome of Cryptococcus neoformans infection were assessed in 111 organ transplant recipients with cryptococcosis in a prospective, multicenter, international study. Sixty-one percent (68/111) of the patients had disseminated infection. The risk of disseminated cryptococcosis was significantly higher for liver transplant recipients (adjusted hazard ratio [HR], 6.65; P=.048). The overall mortality rate at 90 days was 14% (16/111). The mortality rate was higher in patients with abnormal mental status (P=.023), renal failure at baseline (P=.028), fungemia (P=.006), and disseminated infection (P=.035) and was lower in those receiving a calcineurin-inhibitor agent (P=.003). In a multivariable analysis, the receipt of a calcineurin-inhibitor agent was independently associated with a lower mortality (adjusted HR, 0.21; P=.008), and renal failure at baseline with a higher mortality rate (adjusted HR, 3.14; P=.037). Thus, outcome in transplant recipients with cryptococcosis appears to be influenced by the type of immunosuppressive agent employed. Additionally, discerning the basis for transplant type-specific differences in disease severity has implications relevant for yielding further insights into the pathogenesis of C. neoformans infection in transplant recipients.

Invasive aspergillosis in the recipients of liver retransplantation.

Retransplantation is a major risk factor for invasive aspergillosis in liver transplant recipients. However, the risk for invasive aspergillosis with time elapsed since retransplantation, clinical characteristics, and outcome of patients who develop this infection after retransplantation of the liver has not been defined. Patients comprised 17 liver retransplant recipients with invasive aspergillosis between 1990 and 2004. Retransplantation was considered early if it was performed within 30 days and late if performed after 30 days of the first or primary transplant. Retransplant recipients comprised 25% of all cases of invasive aspergillosis after liver transplantation. Fifty-three percent of the Aspergillus infections occurred within 30 days, and 76% within 90 days of retransplantation. In all, 53% (9/17) of the patients were late retransplant recipients. Late compared to early retransplant recipients with invasive aspergillosis were more likely to have central nervous system involvement with invasive aspergillosis (56% vs. 0%, P = 0.03). Mortality rate was 100% for late and 63% for early retransplant recipients with Aspergillus infections. In conclusion, time-varying risk for invasive aspergillosis after retransplantation has implications relevant for guiding antifungal prophylaxis. Given a greater risk for disseminated infection and poor outcome in late retransplant recipients with aspergillosis, potent and aggressive antifungal therapy should be considered upfront in these patients.

Late-onset invasive aspergillosis in organ transplant recipients in the current era.

We assessed predictive factors and characteristics of patients with late-onset invasive aspergillosis in the current era of novel immunosuppressive agents. Forty transplant recipients with invasive aspergillosis were included in this prospective, observational study initiated in 2003 at our institutions. In 50% (20/40) of these patients, the infections were late-occurring. Receipt of sirolimus in conjunction with tacrolimus for refractory rejection or cardiac allograft vasculopathy (P=0.047) was significantly associated with late-onset infection. The use of depleting or non-depleting T or B-cell antibodies, either as induction or as antirejection therapy did not correlate with time to onset of invasive aspergillosis. Mortality at 90 days was 20% (4/20) for the patients with early-onset infection and 45% (9/20) for those with late-onset infection (P=0.17). Thus, nearly one-half of the Aspergillus infections in transplant recipients in the current era are late-occurring. These data have implications relevant for prophylactic strategies and guiding clinical management of transplant recipients presenting with pulmonary infiltrates.

Anxiety and depression in hospitalized patients in resistant organism isolation.

BACKGROUND: Previous studies have reported an increase in psychiatric symptoms in seriously ill patients who were placed in resistant organism isolation. We conducted this study to assess whether there is an increase in symptoms of anxiety and depression in patients who are not critically ill and are placed in isolation. METHODS: Patients hospitalized with methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus species infections were evaluated with the Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale at baseline and again during hospitalization. The results were then compared with the results of patients who were hospitalized for infectious diseases that did not require isolation. RESULTS: Patients in isolation had significantly higher scores on both the anxiety and depression scales at the time of follow-up than did patients who were not isolated. There was no significant difference between the scores of the two groups before isolation. CONCLUSION: The results of this preliminary study suggest that placement in resistant organism isolation may increase hospitalized patients' levels of anxiety and depression.