Julia Garcia-Diaz

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.

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.

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.

Calcineurin Inhibitor Agents Interact Synergistically with Antifungal Agents In Vitro against Cryptococcus neoformans Isolates: Correlation with Outcome in Solid Organ Transplant Recipients with Cryptococcosis

ABSTRACT 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.

Histoplasmosis After Solid Organ Transplant

BACKGROUND To improve our understanding of risk factors, management, diagnosis, and outcomes associated with histoplasmosis after solid organ transplant (SOT), we report a large series of histoplasmosis occurring after SOT. METHODS All cases of histoplasmosis in SOT recipients diagnosed between 1 January 2003 and 31 December 2010 at 24 institutions were identified. Demographic, clinical, and laboratory data were collected. RESULTS One hundred fifty-two cases were identified: kidney (51%), liver (16%), kidney/pancreas (14%), heart (9%), lung (5%), pancreas (2%), and other (2%). The median time from transplant to diagnosis was 27 months, but 34% were diagnosed in the first year after transplant. Twenty-eight percent of patients had severe disease (requiring intensive care unit admission); 81% had disseminated disease. Urine Histoplasma antigen detection was the most sensitive diagnostic method, positive in 132 of 142 patients (93%). An amphotericin formulation was administered initially to 73% of patients for a median duration of 2 weeks; step-down therapy with an azole was continued for a median duration of 12 months. Ten percent of patients died due to histoplasmosis with 72% of deaths occurring in the first month after diagnosis; older age and severe disease were risk factors for death from histoplasmosis. Relapse occurred in 6% of patients. CONCLUSIONS Although late cases occur, the first year after SOT is the period of highest risk for histoplasmosis. In patients who survive the first month after diagnosis, treatment with an amphotericin formulation followed by an azole for 12 months is usually successful, with only rare relapse.

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 ≥ 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.

Vancomycin-resistant enterococcal bacteraemia: is daptomycin as effective as linezolid?

BACKGROUND The treatment of vancomycin-resistant enterococcal (VRE) bacteraemia remains challenging. Daptomycin is a new antibiotic with bactericidal activity against VRE, but available clinical data are limited. METHODS A retrospective study was performed on 98 adult patients with VRE bacteraemia admitted to two hospitals between September 2003 and December 2007 to compare the efficacy of daptomycin with that of linezolid. Multivariable analyses were performed to compare the microbiological and clinical outcomes of both groups. RESULTS Out of 98 patients with VRE bacteraemia, 68 were treated with linezolid and 30 with daptomycin. Univariate analyses showed no significant differences between the groups regarding baseline demographic and clinical characteristics, severity of illness and co-morbidity. Daptomycin was associated with a trend towards a higher mortality rate (26.7% versus 20.6%), longer median duration of bacteraemia (3 days versus 2 days) and higher relapse rate (6.7% versus 2.9%), but these differences did not reach statistical significance (P > 0.2). Microbiological cure rates were 90% for the daptomycin group and 88.2% for the linezolid group (P = 0.92). CONCLUSIONS Despite a trend towards worse outcomes, daptomycin was as effective as linezolid in treating VRE bacteraemia. A randomized clinical trial is needed to confirm these results.

Resolution of Rhinocerebral Zygomycosis Associated with Adjuvant Administration of Granulocyte-Macrophage Colony-Stimulating Factor

We successfully treated 3 consecutive patients who had nonneutropenic rhinocerebral zygomycosis, by use of subcutaneous granulocyte-macrophage colony-stimulating factor therapy combined with traditional surgical and medical treatment. All patients are currently free of disease. Granulocyte-macrophage colony-stimulating factor should be considered as adjuvant therapy for rhinocerebral zygomycosis; however, optimum dose and length of therapy are unknown.

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.

Unrecognized pretransplant and donor derived 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.