Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study

Tessari G, Naldi L, Piaserico S, Boschiero L, Nacchia F, Forni A, Rugiu C, Faggian G, Dall’Olio E, Fortina AB, Alaibac M, Sassi F, Gotti E, Fiocchi R, Fagioli S, Girolomoni G. Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study.
Clin Transplant 2010: 24: 328–333. © 2009 John Wiley & Sons A/S. Abstract: Background: Primary opportunistic deep cutaneous fungal
infections may cause significant morbidity and mortality in solid organ transplant recipients (OTR), but no data exist about their incidence, timing, and clinical predictors in a long‐term follow‐up. Patients and methods: A series of 3293 consecutive OTR including 1991 kidney, 929 heart, and 373 liver transplant recipients were enrolled. Patients were regularly followed up since time at transplantation (mean 5.5 yr ±5.9 SD) and primary opportunistic fungal infections registered. Persons‐year at risk (PYs), incidence rates (IR), incidence rate ratios (IRR), and 95% confidence intervals were computed. Results: Twenty‐two cases of deep cutaneous mycoses were detected, (IR 1.2 cases per 1000 PYs) after a mean follow‐up time since transplantation of 2.5 yr ± 2.0 SD (median 1.8 yr). Six patients had subsequent systemic involvement and three patients died of systemic dissemination. A higher risk for mycoses was observed in the first two yr after transplantation, (IRR 35.9, p < 0.0001), in renal transplant recipients (IRR 5.1 p = 0.030), and in patients transplanted after the age of 50 (IRR 11.5 p = 0.020). Conclusions: Primary deep cutaneous opportunistic mycoses in OTR occur mainly in the first two yr after transplantation, in renal transplant recipients, and in older patients.     

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.     

Cost of prophylaxis in the management of cytomegalovirus infection in solid organ transplant recipients

BACKGROUND: Limited economic data exist on the use of valganciclovir for the prevention of cytomegalovirus (CMV) infection and disease in solid organ transplant (SOT) recipients. We compared the economics of sequential i.v. and oral ganciclovir prophylaxis vs. oral valganciclovir prophylaxis alone in high-risk (D+/R-) SOT patients. METHODS: A cost-minimization analysis was performed from the perspective of the Spanish National Health System comparing the cost of sequential ganciclovir prophylaxis (induction with i.v. ganciclovir 10 mg/kg daily for 14 d followed by oral ganciclovir 1 g t.i.d. for 3 months) vs. oral valganciclovir prophylaxis (900 mg once daily for 100 d). Resource utilization data for both regimens were obtained from the literature and from clinical records of 83 patients in nine Spanish hospitals. Results were expressed as average cost per patient treated. RESULTS: The average cost per patient treated with sequential ganciclovir or valganciclovir prophylaxis was euro3715.51 and euro3295.90, respectively. The higher cost of ganciclovir therapy was due to concomitant administration of anti-CMV immunoglobulin (euro313.73), drug administration costs (euro401.45), catheter culture tests (euro13.64) and adverse events associated with catheter use (euro3.30). Following a sensitivity analysis, taking into account dose and duration of drug, concomitant medications and adverse events, costs for valganciclovir and sequential therapy were similar. CONCLUSIONS: Valganciclovir prophylaxis is as economical as sequential ganciclovir prophylaxis in high-risk D+/R- SOT patients. In addition, the once-daily dosing regimen of valganciclovir is more convenient, and avoids the complications associated with catheter use.     

Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients

Over 1 000 000 cases of coronavirus disease 2019 (COVID‐19) have been confirmed since the worldwide outbreak began. Not enough data on infected solid organ transplant (SOT) recipients are available, especially data about the management of immunosuppressants. We report two cases of COVID‐19 in two transplant recipients, with different treatments and prognoses. The first patient received liver transplantation due to hepatitis B virus–related hepatocellular carcinoma and was confirmed to have COVID‐19 9 days later. Following a treatment regimen consisting of discontinued immunosuppressant use and low‐dose methylprednisolone‐based therapy, the patient developed acute rejection but eventually recovered. The other patient had undergone a renal transplant from a living‐related donor 17 years ago, and was admitted to the hospital because of persistent fever. This patient was also diagnosed with COVID‐19. His treatment regimen consisted of reduced immunosuppressant use. No signs of rejection were observed during the regimen. In the end, the patient successfully recovered from COVID‐19. These effectively treated cases can provide a basis for immunosuppressant management of COVID‐19‐positive SOT recipients.     

Retrospective study on the utilization and cost of immunosuppressive agents among kidney transplant recipients in Taiwan: a 5-year review

This study examined the utilization and cost of immunosuppressive agents among kidney transplant recipients in view of the growth under the Taiwan National Health Insurance payment system. Using inpatient expenditures by admissions and the files of the Registry for contracted medical facilities released from the Taiwan National Health Insurance Research Database, we totalled all renal implantations from 1999-2003, sorting them by drug expenditures reimbursed by contracted hospitals. The systematic sampling files of ambulatory care files were used to compute the Defined Daily Dose (DDD) and track drug utilization. The batch analysis was completed using the SPSS English version 13.0 for Windows. During the 5-year period, a total of 663 kidney transplantation surgeries were identified at 26 hospitals. Up to 90% of transplantation surgeries were performed at medical centers with about 55% in Northern Taiwan. Ninety-nine percent of drug expenditures were claimed by the top 12 hospitals. According to the Anatomical Therapeutic Chemical Classification, the most frequently prescribed immunosuppressive agents were Sandimmum Neoral cyclosporine (43%), mycophenolate (30.8%), and tacrolimus (21.3%) with DDDs of 137.5, 1187, and 5.54 mg, respectively. The ambulatory drug expenditure for patients increased 2-fold within the first 5 years, and 11.8 million in 2003 was estimated to be approximately 20 million Taiwanese dollars in 2010.     

Biomarkers of the immunomodulatory effect of immunosuppressive drugs in transplant recipients

Nowadays, monitoring of the immunosuppressive therapy received by solid organ transplant recipients is based on measuring drug blood levels to achieve concentrations within the established therapeutic range. This strategy largely prevents the toxicity associated with this kind of treatment but is insufficient to determine the individual response in each patient or to tailor the dose to each patient's real requirements. In the field of solid organ transplantation, new approaches able to reflect the individual responses produced in each patient are required to monitor immunosuppressive therapy and to improve the efficacy and safety of treatment. Thus, in the last few years, preliminary studies evaluating new specific biomarkers of the biologic effect of immunosuppressive drugs (pharmacodynamic monitoring) have been carried out. The results of these pilot studies show the potential of monitoring of these specific biomarkers to improve the safety and efficacy of immunosuppression, although the complexity of these analyses and the lack of standardized methodologies currently limit the routine application of this technique. Based on the previous studies performed to date on biomarkers, which included a small number of patients, no conclusions can be drawn as to which are the most appropriate biomarkers to prevent organ rejection or adverse events. Consequently, these biomarkers need to be validated in multicenter clinical trials.The present article reviews some biomarkers that have been proposed to evaluate currently approved immunosuppressants, such as target enzymes, cytokines, lymphocyte activation biomarkers, and cellular immune response, as well as the most promising results in this field.     

Efficacy and safety of caspofungin in solid organ transplant recipients

Efficacy and safety data for the echinocandins in solid organ transplant (SOT) recipients are limited. We reviewed data from three clinical trials that enrolled SOT patients receiving caspofungin therapy for an invasive fungal infection (IFI). Caspofungin was administered at doses ranging from 50 to 100 mg/day. Efficacy was assessed in all patients at the end of caspofungin therapy (EOT). Adverse events (AE) and laboratory data were collected from all patients. We identified data from 22 SOT patients (aged 34-67 years) with proven invasive candidiasis (IC; 6 patients) or proven or probable invasive aspergillosis (IA; 16 patients) who received at least one dose of caspofungin therapy. All patients with IC received caspofungin as primary therapy. Caspofungin success against IC at EOT was 83% (5 of 6), with responses seen across Candida spp. Success by SOT type was: kidney 4 of 5 and liver 1 of 1. All 16 patients with IA (all pulmonary) received caspofungin as salvage therapy. Caspofungin success against IA at EOT was 50% (8 of 16), with responses seen for both definite (3 of 4) and probable IA (5 of 12). Success by SOT type was: heart 2 of 2, heart/lung 0 of 2, kidney 3 of 3, liver 1 of 3, and lung 2 of 6. The outcome was not influenced by caspofungin dose. Caspofungin, dosed for 2 to 162 (mean 36.8) days, was well tolerated. No patient had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Based on these limited data, caspofungin appears to be an effective and well-tolerated option for the treatment of IC and IA in SOT recipients.     

The pharmacokinetics and immunosuppressive response of tacrolimus in paediatric renal transplant recipients

The aims of our trial were to study the pharmacokinetics of tacrolimus in paediatric kidney transplant recipients. The study comprised 25 patients (median age 13 years, range 2–20 years) followed for 12 months; five pharmacokinetics profiles (within the first and second week and after 1 month, 6 months and 12 months) were obtained. Patients were divided into two groups: six children <6 years old and 19 older children. Tacrolimus was given at an initial dose of 0.15 mg/kg twice a day. Blood samples were drawn before and 1 h, 2 h, 3 h, 4 h, 6 h, 9 h and 12 h after drug administration. Patient and kidney survival rates were 100% at 1 year. At 6 months and 12 months creatinine clearance was 68.5±16.3 ml/min per 1.73 m² and 64.0±15.2 ml/min per 1.73 m² body surface area, respectively. Tacrolimus trough levels were 7.8±1.9 ng/ml and 7.3±2.5 ng/ml. The area under the concentration–time curve for 0 h to 12 h (AUC_0–12) normalised to a dose of 0.15 mg/kg, increased with time from the kidney transplantation and stabilised after the 6th month post-transplantation. During the first month after transplantation the normalised tacrolimus concentration–time profiles were significantly greater in the older children (P<0.05); the actual doses were significantly greater in the younger children (P<0.05). In conclusion, initial doses of 0.15 mg/kg twice a day orally are safe and guarantee a satisfactory degree of immunosuppression, with our therapeutic regimen. Children <6 years old need to start with a 50% higher tacrolimus dose to achieve the same pharmacokinetic and immunosuppressive results.     

Physical and psychological attributes of fatigue in female heart transplant recipients.

BACKGROUND: The attributes of fatigue after orthotopic heart transplantation (OHT) are poorly understood. We conducted this study to assess the prevalence, severity and correlates of fatigue among female OHT survivors. METHODS: Fifty women (age 54.7 +/- 13.0 years) from a single heart transplant center, who underwent OHT 5.1 +/- 4.4 (mean +/- SD) years earlier, completed a battery of questionnaires including the Profile of Mood States-fatigue sub-scale to assess levels of fatigue, the Beck Depression Inventory to measure depression, and the Short Form-36 to measure functional status and mental health. Demographic and clinical data were obtained from self-reports and medical chart reviews. RESULTS: Women reported mean scores of 15.7 +/- 6.8 (range 3 to 27), 13.2 +/- 8.2 (range 0 to 38), 37.2 +/- 10.8 (range 22 to 62) and 41.5 +/- 11.2 (range 17 to 60) for fatigue, depression, functional status and mental health, respectively. Univariate analyses revealed that sociodemographic and clinical variables (e.g., age, employment status, anemia, renal insufficiency) were significantly related to fatigue (p < 0.001). Likewise, depression, functional status and mental health were also significantly related to fatigue (p < 0.001). In a multivariate model, age (adjusted R(2) = 0.23, p < 0.001), anemia (adjusted R(2) = 0.39, p < 0.001), functional status (adjusted R(2) = 0.60, p < 0.001) and depression (adjusted R(2) = 0.69, p < 0.001) were significant predictors of fatigue. The model explained 69% of the variance in fatigue (p < 0.001). CONCLUSIONS: Fatigue is common in women after OHT and is associated with both physiologic and psychologic factors. Clinicians should evaluate all female recipients for symptoms of fatigue, especially those with anemia, renal insufficiency, poor functional status and depression. Other potential mediators of fatigue, such as the denervated donor heart and type of immunosuppressive regimen, may also play a role and require further study.     

Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation

Development of cancer is a feared, and increasingly apparent, complication of long-term immunosuppressive therapy in transplant recipients. In addition to the need to reduce cancer occurrence in these patients, therapeutic protocols are lacking to simultaneously attack the malignancy and protect the allograft when neoplasms do occur. In this overview, we present the current literature regarding the pro- and anti-neoplastic effects of immunosuppressive agents on cancer growth and development. Recent experimental findings are paving the way for new therapeutic strategies aimed at both protecting an allograft from immunologic rejection and addressing the problem of cancer in this high-risk population.