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We determined the characteristics of posttransplant tuberculosis and the impact of rifampin-based antituberculosis regimens on outcomes in the current era. Patients comprised 64 transplant recipients with tuberculosis, divided into 2 consecutive cohorts: an earlier cohort (cases occurring from 2003 to 2007) and a later cohort (cases from 2008 to 2011). Patients from the later versus earlier era had tuberculosis develop later after transplant (odds ratio, 1.01; 95% CI, 1.00-1.02; P= .05), were more likely to be liver transplant recipients (odds ratio, 4.52; 95% CI, 1.32-15.53; P= .02), and were more likely to receive tacrolimus-based immunosuppression (odds ratio, 3.24; 95% CI, 1.14-9.19; P= .03). Mortality rate was 10% in the later cohort and 21% in the earlier cohort (P= .20). Rifampin-based treatment was less likely to be used in patients with prior rejection (P= .04). However, neither rejection rate (P= .71) nor mortality (P= .93) after tuberculosis differed between recipients who received rifampin and recipients who did not. Thus, notable changes have occurred in the epidemiological characteristics of tuberculosis in transplant recipients. Overall mortality rate has improved, with about 90% of the patients now surviving after tuberculosis.

Background: Incidence, characteristics, and risk factors for tuberculosis (TB)-associated immune reconstitution inflammatory syndrome (IRS) in solid-organ transplant (SOT) recipients are not known., Methods: Patients are composed of 64 consecutive SOT recipients with TB followed for 12 months. IRS was defined based on previously proposed criteria., Results: IRS developed in 14% (9/64) of the patients, a median of 47 days after the use of anti-TB therapy. Liver versus other types of organ transplant recipients (adjusted odds ratio [OR], 6.11; 95% confidence interval [CI], 1.08-34.86), prior cytomegalovirus infection (adjusted OR, 5.65; 95% CI, 0.93-34.47), and rifampin use (adjusted OR, 4.56; 95% CI, 0.74-27) were associated with a higher risk of IRS. The presence of more than one factor (liver transplantation, cytomegalovirus infection, and rifampin use) when compared with none of these factors conferred a 19-fold increase in the risk of IRS (P=0.01). Mortality at 1 year after diagnosis was 33.3% in patients with IRS and 17.2% in those without IRS (P=0.31)., Conclusions: IRS was documented in 14% of the SOT recipients with TB. We determined clinically identifiable factors that may be useful in assessing the risk of tuberculosis-associated posttransplantation IRS.

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.

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.

Fifty-eight solid organ transplant recipients with zygomycosis were studied to assess the presentation, radiographic characteristics, risks for extra-pulmonary dissemination and mortality of pulmonary zygomycosis. Pulmonary zygomycosis was documented in 31 patients (53%) and developed a median of 5.5 months (interquartile range, 2-11 months) posttransplantation. In all, 74.2% (23/31) of the patients had zygomycosis limited to the lungs and 25.8% (8/31) had lung disease as part of disseminated zygomycosis; cutaneous/soft tissue (50%, 4/8) was the most common site of dissemination. Pulmonary disease presented most frequently as consolidation/mass lesions (29.0%), nodules (25.8%) and cavities (22.6%). Patients with disseminated disease were more likely to have Mycocladus corymbifer as the causative pathogen. The mortality rate at 90 days after the treatment was 45.2%. In summary, pulmonary zygomycosis is the most common manifestation in solid organ transplant recipients with zygomycosis, and disseminated disease often involves the cutaneous/soft tissue sites but not the brain.

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.

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.

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.

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.

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.

Tuberculosis has a major adverse impact on solid organ transplant recipients; this article attempts to define this fact. The prevalence of posttransplant tuberculosis is increasing globally and currently is 13.7% at our center. The transplant surgery divides the continuum of pretransplant tuberculosis and posttransplant tuberculosis; immunosuppression accounts for a greater severity of the latter. Cyclosporin and tacrolimus are associated with an earlier onset of tuberculosis when compared with prednisolone and azathioprine immunosuppression. Disseminated disease is more common in nonrenal transplants. The risk for developing posttransplant tuberculosis in renal transplant recipients increased 2.25 times independently with cytomegalovirus (CMV) and twice with chronic liver disease; OKT3 treatment enhances the risk 1.8-fold. Tuberculosis occurring after 2 years of transplantation, diabetes mellitus, posttransplant diabetes mellitus, chronic liver disease, CMV, and deep mycoses each independently confer a risk, 1.5-times or higher, for death. Disseminated disease entails a 2-fold risk. Treatment with or without rifampicin is possible; the former is associated with a higher risk for allograft rejection. Isoniazid prophylaxis is recommended for high-risk patients with apparent clinical efficacy. However, in endemic areas, attendant liver disease makes it a difficult goal., (Copyright 2002, Elsevier Science (USA). All rights reserved.)