Enhanced cyclosporine-itraconazole interaction with cola in lung transplant recipients

BACKGROUND: Invasive aspergillosis is a major cause of morbidity and mortality in lung transplant recipients (LTR), occurring in up to 15% of patients post-transplant. The 14% aspergillus incidence at the Cleveland Clinic Foundation prompted institution of universal prophylaxis with oral itraconazole (ICZ) in 1997. We report our experience with two protocols of ICZ administration in non-cystic fibrosis LTR and the interaction with cyclosporine (CSA). METHODS: Group 1 patients (n=12) were administered ICZ capsules in a fasting or fed state, with or without a histamine-2 (H-2) receptor antagonist or proton pump inhibitor. Group 2 patients (n=12) received the same protocol as group I, but in a fed state with a carbonated beverage (cola) to increase acidity in the stomach to enhance absorption of ICZ. The ICZ dose was 200 mg/d, given as one daily dose. A historical control group (n=10) did not receive chemoprophylaxis with ICZ. CSA daily doses, dose intervals, concentration, cost, and random ICZ levels were documented over a 4-month period of time and compared using generalized estimating equations. RESULTS: The daily CSA mg/kg/d dose decreased over time in all three groups, but no differences were found between the three groups. The CSA dosing interval over time was significantly prolonged in group 2 compared to group 1 or the control group (p< or =0.003). Over time, there was no difference in CSA concentration between all groups. There was no difference in cost over time between the three groups; however, the mean cost of CSA therapy was significantly lower in group 2 compared to the control group (p=0.025). Group 2 administered ICZ with cola had greater random blood concentrations of ICZ (p=0.019). CONCLUSIONS: ICZ capsules administered in a fed state with a cola resulted in greater random levels of ICZ, a decrease in cost/d of CSA, and a prolongation of CSA dosing interval. Although daily CSA dosage trended lower in group 2, it did not reach statistical significance. We believe these changes in CSA dosing over time reflect increased absorption of ICZ and recommend verifying ICZ absorption with an itraconazole level, especially when CSA intervals are not prolonged.     

Leishmaniasis in solid organ and hematopoietic stem cell transplant recipients

Leishmaniasis occurs in <1% of solid organ and hematopoietic stem cell transplant recipients in endemic countries in which transplants are performed. Visceral leishmaniasis (VL) makes up the bulk of reported cases. The onset generally occurs months after transplantation and the mode of acquisition is often impossible to determine, but de novo vector‐borne infection and reactivation of inapparent infection are thought to be the principal means. The potential role of clinically inapparent donor infection is uncertain and screening is not currently recommended, nor is it recommended for recipients from endemic areas, some of whom may have detectable circulating protozoan nucleic acid. While transplant recipients with VL often present with the non‐specific findings of fever and cytopenia, the additional presence of hepatosplenomegaly in patients from endemic areas should lead to a directed diagnostic evaluation with bone marrow examination and PCR testing of marrow and peripheral blood having a high yield. Management may often be complicated by the presence of concomitant infections. A lipid formulation of amphotericin B is the preferred treatment, especially for VL, but the relapse rate in transplant recipients is approximately 25%. PCR monitoring of blood for either secondary prophylaxis or preemptive therapy requires further study.     

Hyperhomocysteinemia and transplant coronary artery disease in cardiac transplant recipients

BACKGROUND: In cardiac transplant recipients, long-term survival may be limited by transplant coronary artery disease (TxCAD). Hyperhomocysteinemia (Hhcy) has been associated with vascular disease and is common in transplant recipients. The objective of this study was to determine the relationship between fasting homocysteine (Hcy) concentrations and TxCAD in a cohort of cardiac transplant recipients. METHODS: Forty-eight patients more than 5 yr after transplant were recruited from a cohort of 72 consecutive patients with in-depth analysis of homocysteine levels from the Cardiac Transplant Clinic. Early morning fasting blood was obtained, and the plasma separated and frozen within 30 min. Hcy concentrations were determined by high-performance liquid chromatography (HPLC) with pulsed integrated amperometry. Coronary angiograms were reviewed in a blinded fashion. TxCAD was diagnosed, using the most recent angiogram, when a >25% lesion was present anywhere in the coronary tree. RESULTS: Forty-eight patients transplanted between 1985 and 1994 were studied. The mean Hcy concentration for the cohort was 23.5+/-5.0 micromol/L, all patients had homocysteine levels above the upper range of normal (5-15 micromol/L). Hcy concentrations were significantly higher in patients with angiographic evidence of TxCAD: 25.0+/-5.9 vs. 21.9+/-3.4 micromol/L, p=0.03. This effect persisted when covariates were taken into account using logistic regression analysis. CONCLUSIONS: Hhcy is associated with TxCAD. Prospective studies are required to confirm this association and to assess the efficacy of Hcy-lowering therapy in this patient population.     

Fatigue in kidney transplant recipients

Fatigue is still present in approximately 40%‐50% of kidney transplant recipients (KTR), rates comparable to that of the hemodialysis population. Correlates of fatigue include inflammation, symptoms of depression, sleep disorders, and obesity. Fatigue in KTR determines a significant severe functional impairment, either when globally considered or when analyzed at the level of the single domains such as sleep and rest, homemaking, mobility, social interaction, ambulation, leisure activities, alertness behavior, and work limitations. In addition, fatigue in KTR is significantly associated with a severe deterioration of quality of life. Fatigue is very common among KTR poorly adherent to immunosuppressive therapy. Unfortunately, there is no evidence of studies about the treatments of this symptom in KTR. Efforts to detect and treat fatigue should be a priority in order to improve quality of life of KTR.     

Management of leukopenia in kidney and pancreas transplant recipients

Abstract: Leukopenia is frequently observed in the setting of solid organ transplantation. The risk factors, natural history, and outcomes associated with leukopenia post‐transplantation have not been well defined. We retrospectively studied 102 adult kidney and/or pancreas transplant recipients over a one‐yr period of time. By defining leukopenia as a white blood cell count ≤3000 cells/mm³ and neutropenia as an absolute neutrophil count ≤2000/mm³, the combined incidence of either leukopenia or neutropenia was 58% (59/102); the first episode occurred at a mean of 91 d post‐transplant. A significant increase in the incidence of leukopenia was found in patients who either received alemtuzumab induction (42% with alemtuzumab vs. 9% with rabbit anti‐thymocyte globulin induction, p < 0.05) and/or had rapid steroid withdrawal in the early post‐transplant period (44% with vs. 16% without steroid withdrawal, p < 0.05). The most common intervention performed for leukopenia was reducing the dose of mycophenolate mofetil and/or valganciclovir. When granulocyte stimulating factors were used, a mean of 3.1 doses were needed to successfully manage the leukopenia. Although leukopenia was a common finding in our study of kidney and/or pancreas transplant recipients, there was no difference in the rates of infection or acute rejection in patients with and without leukopenia.     

Pneumocystis carinii pneumonia in renal transplant recipients

In 1991 and 1992 Pneumocystis carinii pneu monia (PCP) was diagnosedin 28 renal transplant recipients. The incidence of PCP in ourrenal transplant centre was remarkably increased from 1.1% before1991 to 11.5% in 1991–1992. We compared 28 PCP patientswith a control group of 27 renal transplant recipients, matchedfor transplantation day and with out an episode of PCP. Themean age was significantly higher in the PCP group (50±13 versus 38±13 years). We observed no differences inbasic immunosuppres sive and rejection treatment nor in antibioticconsump tion, number of hospitalization days, and incidenceof CMV infection. In March 1993 we introduced PCP prophylaxis.More than 140 renal transplant recipients received co-trimoxazole,starting 1 day after trans plantation and continued for a periodof 4 months. To the time of writing no one in this group haddeveloped PCP.     

Clostridium difficile‐associated disease in allogeneic hematopoietic stem‐cell transplant recipients: risk associations,protective associations,and outcomes

Dubberke ER, Reske KA, Srivastava A, Sadhu J, Gatti R, Young RM, Rakes LC, Dieckgraefe B, DiPersio J, Fraser VJ. Clostridium difficile‐associated disease in allogeneic hematopoietic stem‐cell transplant recipients: risk associations, protective associations, and outcomes.
Clin Transplant 2009. DOI: 10.1111/j.1399‐0012.2009.01035.x
© 2009 John Wiley & Sons A/S. Abstract:  The purpose of this study was to evaluate risk factors, protective factors, and outcomes associated with Clostridium difficile‐associated disease (CDAD) in allogeneic hematopoietic stem‐cell transplant (HSCT) recipients. A case–control study was performed with 37 CDAD cases and 67 controls. In the multivariable logistic regression analysis, receipt of a third or fourth generation cephalosporin was associated with increased risk of CDAD (OR = 4.6, 95% CI 1.6–13.1). Receipt of growth factors was associated with decreased risk of CDAD (OR=0.1, 95% CI 0.02–0.3). Cases were more likely to develop a blood stream infection after CDAD than were controls at any point before discharge (p < 0.001). CDAD cases were more likely than controls to develop new onset graft‐vs.‐host disease (GVHD) (p < 0.001), new onset severe GVHD (p < 0.001), or new onset gut GVHD (p = 0.007) after CDAD/discharge. Severe CDAD was a risk factor for death at 180 d in multivariable Cox proportional hazards regression (HR=2.6, 95% CI 1.1–6.2). CDAD is a significant cause of morbidity and mortality in allogeneic HSCT patients, but modifiable risk factors exist. Further study is needed to determine the best methods of decreasing patients’ risk of CDAD.     

Nocardiosis in renal transplant recipients in Kuwait

BACKGROUND.: Nocardiosis has emerged as an important bacterial disease amongrenal transplant recipients, leading to considerable morbidityand mortality. Apart from the increasing problem of resistancein pathogenic nocardiae, the spectrum of species causing diseasehas enlarged in recent years. There are no published reportson nocardiosis from Middle-East countries. METHODS.: A retrospective review of case records of 513 renal transplantrecipients between January 1989 and January 1995 was done inthe transplant unit of our hospital. Information was collectedon clinical details, type of donor, immunosuppressive therapy,prophylaxis, and outcome. Isolation of Nocardia species fromappropriate clinical specimens was the sole criterion for diagnosis. RESULTS.: Nocardiosis was diagnosed in six recipients with a disease incidenceof 1.2%. Four patients had received unrelated kidneys. Co-morbidconditions were diabetes mellitus (3), viral hepatitis (2) andneutropenia (1). Clinical manifestations included deep-seatedskin abscesses and pulmonary disease in three each. Cerebralabscess and meningitis were found in two patients with pulmonarydisease. Pathogens were Nocardia asteroides in four and N. otitidiscaviarum and N. farcinica in one each. In contrast to invitro susceptibility results, clinical response was differentin that five patients who received trimethoprim-sulphamethoxazole(TMP-SMX) alone (2) or in combination with cefuroxime (3) respondedwell. CONCLUSION.: The study stresses a high index of suspicion for nocardiosisin susceptible hosts who present with cutaneous abscess, pulmonaryinfiltrative lesions, and cerebral manifestations. TMP-SMX incombination with cefuroxime seems to be a highly effective therapy.It does not appear mandatory to reduce or discontinue immunosuppressivetherapy during treatment of nocardiosis.     

Determination of mismatched donor HLA in kidney transplant recipients with unknown donor HLA phenotypes

Kwok J, Chan GSW, Lam MF, Yan T, Tang L, Kwong KM, Chan KW, Chan TM. Determination of mismatched donor HLA in kidney transplant recipients with unknown donor HLA phenotypes.
Clin Transplant 2010 DOI: 10.1111/j.1399‐0012.2010.01246.x
© 2010 John Wiley & Sons A/S. Abstract: Objective: To determine donor human leukocyte antigen (HLA) from renal allograft biopsies in transplant recipients whose donor HLA phenotype is not known. Methods: Renal allograft biopsies were obtained from seven renal transplant recipients when indicated for allograft dysfunction or proteinuria. DNA was extracted fresh from allograft specimens, and HLA typing was performed with polymerase chain reaction‐specific sequence primers (PCR‐SSP) and polymerase chain reaction‐sequence‐specific oligonucleotides (PCR‐SSO). Results: HLA typing of the seven renal allograft biopsies was composed of both recipient and donor HLA phenotypes, allowing the determination of the donor HLA and the degree of HLA mismatching. Conclusions: Deducing mismatched donor HLA antigens in renal allograft recipients enables detection of donor‐specific antibodies, and the management of humoral rejection, and enables more appropriate selection of a donor organ should future retransplantation be required.     

Cardiac allograft vasculopathy in pediatric heart transplant recipients

Metabolic parameters for coronary allograft vasculopathy (CAV) have not been well defined in children. CAV (by angiography or autopsy) was studied in 337 heart recipients on a cyclosporine-based steroid-sparing regimen. Freedom from CAV for all was 79% at 10 years. Fifty-nine patients (18%) developed CAV at a mean of 6.5 +/- 3 years post-transplant. First year rejections were significantly higher in CAV, mean 2.3 vs. 1.4, P = 0.003, odds ratio (OR) 1.8. Rejection with hemodynamic compromise beyond 1 year post-transplant was associated with CAV, P < 0.001, OR 8.4. There was no significant correlation among human leukocyte antigen DR (HLA DR) mismatch, pacemaker use or homocysteine levels and the development of CAV. Maximum cholesterol and low density lipoprotein (LDL) levels were not significantly different. Neither diabetes nor hypertension was significant predictors of CAV on multivariate logistic regression analysis. In conclusion, frequent and severe rejection episodes may predict pediatric CAV. Neither glucose intolerance nor lipid abnormalities appeared to alter risk for CAV in this population.     

Imaging evaluation of kidney transplant recipients

Renal transplantation is nowadays accepted as the treatment of choice for patients with end-stage renal disease. However, despite progress in immunosuppression and surgical techniques, various complications still can occur. Complications vary from vascular disorders and urologic diseases to parenchymal and immunologically related complications. The clinician evaluating the recipient with graft dysfunction has the option of choosing among a variety of imaging modalities including ultrasonography, nuclear medicine, computed tomography, and magnetic resonance imaging to start or continue the diagnostic work-up. In this article, we discuss the evaluation of the kidney transplant recipient using these imaging procedures, emphasizing the clinical diagnostic utility and role of each modality.     

Fluid balance of pediatric hematopoietic stem cell transplant recipients and intensive care unit admission

Fluid administration is essential in patients undergoing hematopoietic stem cell transplant (HSCT). Admission to pediatric intensive care unit (PICU) is required for 11–29% of pediatric HSCT recipients and is associated with high mortality. The objective of this study was to determine if a positive fluid balance acquired during the HSCT procedure is a risk factor for PICU admission. The medical records of 87 consecutive children who underwent a first HSCT were reviewed retrospectively for the following periods: from admission for HSCT to PICU admission for the first group (PICU group), and from admission for HSCT to hospital discharge for the second group (non-PICU group). Fluid balance was determined on the basis of weight gain (WG) and fluid overload (FO). PICU group consisted of 19 patients (21.8%). Among these, 13 (68.4%) developed ≥10% WG prior to PICU admission compared with 15 (22.1%) in the non-PICU group (p < 0.001). Thirteen patients (68.4%) developed ≥10% FO prior to PICU admission compared with 31 (45.6%) in the non-PICU group (p = 0.075). Following multivariate analysis, ≥10% WG (p = 0.018) and cardiac dysfunction on admission for HSCT (p = 0.036) remained independent risk factors for PICU admission. Smaller children (p = 0.033) and patients with a twofold increase in serum creatinine (p = 0.026) were at risk of developing ≥10% WG. This study shows that WG is a risk factor for PICU admission in pediatric HSCT recipients. Further research is needed to better understand the pathophysiology of WG in these patients and to determine the impact of WG prevention on PICU admission.     

Severe vitamin D deficiency among heart and liver transplant recipients

Abstract: Introduction: Although patients with end‐stage organ failure are at high risk for vitamin D deficiency because of limited sunlight exposure and hepatic dysfunction, few studies have measured 25‐hydroxy vitamin D (25OHD) at the time of transplantation. Methods: We measured serum 25OHD immediately after transplantation in 69 heart and liver transplant recipients. Results: Forty‐six heart and 23 liver transplant recipients were evaluated (mean age 53 yr). Mean 25OHD was well below the lower limit of the normal range (43.2 ± 21.2 nmol/L). Ninety‐one percent had levels below 75 nmol/L, the threshold commonly used to denote sufficiency, and 71% had levels below 50 nmol/L. Severe deficiency (25OHD <25 nmol/L) was found in 16%. Vitamin D levels did not differ by race, age, gender, or season. Mean 25OHD was lower among liver than heart transplant recipients (34.4 ± 17.5 vs. 47.7 ± 20.7 nmol/L; p < 0.03). Among liver transplant recipients, 22% had undetectable levels (<17 nmol/L). Conclusions: Vitamin D deficiency is highly prevalent among heart and liver transplant recipients; those with liver failure are at greatest risk. As vitamin D deficiency has many serious skeletal and extra‐skeletal sequelae, physicians who treat transplant patients should maintain a high degree of vigilance for this problem.     

BK virus nephropathy in renal transplant recipients

BK virus nephropathy (BKVN) occurs in up to 10% of renal transplant recipients and can result in graft loss. The reactivation of BK virus in renal transplant recipients is largely asymptomatic, and routine surveillance especially in the first 12–24 months after transplant is necessary for early recognition and intervention. Reduced immunosuppression and anti‐viral treatment in the early stages may be effective in stopping BK virus replication. Urinary decoy cells, although highly specific, lack sensitivity to diagnose BKVN. Transplant biopsy remains the gold standard to diagnose BKVN, good surrogate markers for surveillance using quantitative urinary decoy cells, urinary SV40 T immunochemical staining or polyoma virus‐Haufen bodies are offered by recent studies. Advanced BKVN results in severe tubulo‐interstitial damage and graft failure. Retransplantation after BKVN is associated with good outcomes. Newer treatment modalities are emerging.     

Improved outcome of pulmonary aspergillosis in heart transplant recipients with early diagnosis and itraconazole treatment

Pulmonary aspergillosis is a severe complication in heart transplant recipients. The drug of choice for this infection is amphotericin B, but its use is limited because of its side effects. We observed six cases of pulmonary aspergillosis in a group of 200 patients who had received heart transplants from January 1988 to January 1999. Predisposing factors such as previous rejection, neutropenia and/or cytomegalovirus reactivation were present in all patients. The clinical presentation was characterized by fever and a non-productive cough. X-rays showed monolateral or diffuse infiltrate with or without nodular lesions. The median interval between symptoms and diagnosis was 5 d (range 4–7). Diagnosis was made by culturing trans-tracheal aspirate samples. Aspergillus fumigatus was isolated in 3 patients and A. niger in the other 3. All patients were treated with itraconazole at 200–400 mg/day for 20–60 d and all recovered. One patient treated with the lowest dosage for the shortest term had a recurrence after 1 month and needed a second 30-day course of itraconazole at a higher dosage. No significant side effects were registered. Itraconazole is effective in the therapy of pulmonary aspergillosis, particularly when an early diagnosis is made.