Influenza Virus Infection in Adult Solid Organ Transplant Recipients

BACKGROUND: Solid organ transplant (SOT) recipients have been reported to be more susceptible to influenza virus. However, little is known about the clinical epidemiology and the implications of influenza viral infection among SOT recipients. METHODS: Cohort study of influenza viral infection in SOT recipients at the University of Pittsburgh Medical Center. RESULTS: Between November 1990 and April 2000, 30 cases of influenza were diagnosed in SOT recipients at our center, including influenza A (n = 22) and influenza B (n = 8). These included recipients of lung (n = 19), liver (n = 5) and kidney (n = 6) transplants. The incidence of influenza viral infection was 41.8 cases/1,000 person years (PYs), 2.8 cases/1000 PYs and 4.3 cases/ 1,000 PYs among lung, liver and renal transplant patients, respectively (p <0.0001). Symptoms were reported in all patients and included malaise, myalgia/ arthralgia, fever, cough, and shortness of breath. Secondary bacterial pneumonia occurred in five patients (17%). Other complications were seen in three SOT recipients (2 liver and 1 kidney) and included: myocarditis, myositis, and bronchiolitis obliterans. Biopsy of the transplanted organ was performed in 21 SOT recipients (18 lung, 1 liver and 2 kidney) at the time of influenza viral infection. Overall, 62% (13/21) showed variable degrees of acute allograft rejection, and included 61% (11/18) of lung, and 100% (2/2) of kidney transplant recipients. CONCLUSIONS: Influenza infection is associated with significant morbidity in different groups of SOT recipients. Studies are needed to determine if yearly chemoprophylaxis with antiviral drugs might benefit this patient population.     

Voriconazole Prophylaxis in Lung Transplant Recipients

Lung transplant recipients have one of the highest rates of invasive aspergillosis (IA) in solid organ transplantation. We used a single center, nonrandomized, retrospective, sequential study design to evaluate fungal infection rates in lung transplant recipients who were managed with either universal prophylaxis with voriconazole (n = 65) or targeted prophylaxis (n = 30) with itraconazole ± inhaled amphotericin in patients at high risk (pre- or posttransplant Aspergillus colonization [except Aspergillus niger ]). The rate of IA at 1 year was better in lung transplant recipients receiving voriconazole prophylaxis as compared to the cohort managed with targeted prophylaxis (1.5% vs. 23%; p = 0.001). Twenty-nine percent of cases in the targeted prophylaxis group were in patients colonized with A. niger who did not receive itraconazole. A threefold or higher increase in liver enzymes was noted in 37–60% of patients receiving voriconazole prophylaxis as compared to 15–41% of patients in the targeted prophylaxis cohort. Fourteen percent in the voriconazole group as compared to 8% in the targeted prophylaxis group had to discontinue antifungal medications due to side effects. Voriconazole prophylaxis can be used in preventing IA in lung transplant recipients. Regular monitoring of liver enzymes and serum concentrations of calcineurin inhibitors are required to avoid hepatotoxicity and nephrotoxicity.     

Donor Monoclonal Gammopathy May Cause Lymphoproliferative Disorders in Solid Organ Transplant Recipients

Prior research on donor monoclonal gammopathy of undetermined significance (MGUS) has been inadequate regarding the risk for lymphoproliferative disease in solid organ transplantation recipients. Seven organ recipients from two different donors developed lymphoproliferative disease. The origin of the malignancy was determined by use of microsatellite analysis, and the plasma of the two donors was analyzed with the use of electrophoresis. The clinical courses of the seven recipients were followed for 36–60 months. One donor transmitted lymphoplasmacytic lymphoma to two kidney recipients and MGUS to a liver recipient, all IgMκ. A second donor caused IgGλ myeloma in two kidney and one liver recipient, and IgGλ gammopathy in a heart recipient. Transplant nephrectomy was performed in three kidney recipients and remission was achieved. The fourth kidney recipient has kept the graft and the disease has progressed. The liver recipient died from myeloma. There were no clinical signs of lymphoproliferative disease in the donors, but retrospective serum analyses showed M‐components, IgMκ (37 g/L) and IgGλ (8 g/L). Donors with MGUS may cause donor‐transmitted malignancies via passenger lymphocytes/plasma cells in solid organ recipients. The results call for a large register study of the incidence of donor MGUS and lymphoproliferative disease in their recipients.     

Risk of Thyroid Cancer Among Solid Organ Transplant Recipients

Solid organ transplant recipients have an elevated incidence of thyroid cancer. We evaluated a wide range of potential risk factors in a cohort of 229 300 U.S. solid organ transplant recipients linked with 15 stage/regional cancer registries (1987–2012). Incidence rate ratios (IRRs) were adjusted for age, sex, race/ethnicity, transplanted organ, year of transplantation, and time since transplantation. Hazard ratios (HRs) for death and/or graft failure were adjusted for age, sex, race/ethnicity, transplanted organ, and year of transplantation. After transplantation, 356 thyroid cancers were diagnosed. Thyroid cancer incidence was 2.50‐fold higher in transplant recipients than the general population (95% confidence interval [CI] 2.25–2.77). Among recipients of different organs, kidney recipients had the highest incidence of thyroid cancer (IRR = 1.26, 95% CI 1.03–1.53). Elevated thyroid cancer incidence was associated with cholestatic liver disease/cirrhosis as an indication for liver transplantation (IRR = 1.69, 95% CI 1.09–2.63), hypertensive nephrosclerosis as an indication for kidney transplantation (IRR = 1.41, 95% CI 1.03–1.94), and longer prior dialysis among kidney recipients (5+ vs. <1 year, IRR = 1.92, 95% CI 1.32–2.80; p‐trend <0.01). Posttransplantation diagnosis of thyroid cancer was associated with modestly increased risk of death (HR = 1.33, 95% CI 1.02–1.73). Overall, our results suggest that end‐stage organ disease and longer duration of dialysis may contribute to higher thyroid cancer incidence in transplant recipients.     

Clinical Aspects of Intravenous Immunoglobulin Use in Solid Organ Transplant Recipients

Intravenous immunoglobulin products (IVIG) are derived from pooled human plasma from thousands of donors and have been used for the treatment of primary immunodeficiency disorders for nearly 30 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders, however the precise mechanism(s) of immune modulation are unknown. Recent data suggests that IVIG has a much broader ability to regulate cellular immunity, including innate and adaptive components. IVIG is also a recently recognized modifier of complement activation and injury. These attributes suggests IVIG would have clinical applications in solid organ transplantation. Analysis of clinical studies examining the use of IVIG in desensitization protocols and for treatment of antibody‐mediated rejection (AMR) are supportive for kidney transplant recipients, although no clinical trials using IVIG in sensitized patients were performed seeking an Federal Drug Administration indication. Data regarding the use of IVIG for desensitization and treatment of AMR in cardiac and lung allograft recipients is not conclusive. IVIG is useful in the treatment and prevention of posttransplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus. In addition, we address the risk of adverse events associated with IVIG use in sensitized end‐stage renal disease and transplant patients.     

Primary CMV Infections Are Common in Kidney Transplant Recipients After 6 Months Valganciclovir Prophylaxis

Prolonging cytomegalovirus (CMV) prophylaxis in CMV seronegative recipients of a kidney from CMV seropositive donor (D+/R–) may reduce the incidence of late infections. We analyzed late‐onset primary CMV infections after 6 months valganciclovir prophylaxis. Data from all CMV D+/R– kidney transplant recipients between January 2004 and December 2008 at our center were analyzed. Patients with a functioning graft at 6 months after transplantation who received 6 months of valganciclovir prophylaxis 900 mg once daily were included (N = 127). CMV was diagnosed with quantitative PCR. Prophylaxis was completed in 119 patients. Prophylaxis was stopped at 3–5 months due to leukopenia or gastrointestinal side effects in eight patients. Late‐onset primary CMV infection developed in 47/127 (37%) patients median 244 days after transplantation (range 150–655) and median 67 days after the cessation of prophylaxis (range 1–475). Four infections were asymptomatic. In others, symptoms included fever (N = 28), gastrointestinal symptoms (nausea, vomiting, diarrhea) (N = 24), respiratory tract symptoms (N = 12), and hepatopathy (N = 6). Median peak viral load was 13500 copies/mL (range 400–2 831 000). Recurrent CMV infection developed in 9/47 (19%) patients. No significant risk factors for CMV infection were identified. Symptomatic primary CMV infections were commonly detected also after prolonged valganciclovir prophylaxis.     

De novo Cancer‐Related Death in Australian Liver and Cardiothoracic Transplant Recipients

Evidence is sparse on the relative mortality risk posed by de novo cancers in liver and cardiothoracic transplant recipients. A retrospective cohort study was conducted in Australia using population‐based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984–2006). Standardized mortality ratios (SMRs) were computed by cancer type, transplanted organ, recipient age and sex. During a median 5‐year follow‐up, de novo cancer‐related mortality risk in liver and cardiothoracic recipients was significantly elevated compared to the matched general population (n = 171; SMR = 2.83; 95% confidence interval [95%CI], 2.43–3.27). Excess risk was observed regardless of transplanted organ, recipient age group or sex. Non‐Hodgkin lymphoma was the most common cancer‐related death (n = 38; SMR = 16.6; 95%CI, 11.87–22.8). The highest relative risk was for nonmelanocytic skin cancer (n = 23; SMR = 49.6, 95%CI, 31.5–74.5), predominantly in males and in recipients of heart and lung transplants. Risk of death from de novo cancer was high in pediatric recipients (n = 5; SMR = 41.3; 95%CI, 13.4–96.5), four of the five deaths were non‐Hodgkin lymphoma. De novo cancer was a leading cause of late death, particularly in heart and liver transplantation. These findings support tailored cancer prevention strategies, surveillance to promote early detection, and guidelines for managing immunosuppression once cancer occurs.     

A Multicenter Study of Valganciclovir Prophylaxis up to Day 120 in CMV-Seropositive Lung Transplant Recipients

Seventy-six cytomegalovirus (CMV)-seropositive lung transplant recipients receiving valganciclovir (900 mg/day) for CMV prophylaxis were compared with a group of 87 patients receiving oral ganciclovir (3000 mg/day). Prophylaxis was administered to day 120 post-transplantation and follow-up was 1 year. In addition, a study was conducted on risk factors for CMV infection/disease. CMV disease incidence was 7.9% and 16.1% for valganciclovir and oral ganciclovir, respectively (p = 0.11). Patients receiving valganciclovir had fewer viral syndromes (2.6% vs. 11.5%, p < 0.05), a similar rate of tissue-invasive disease (5.2% vs. 4.6%, p = ns), longer time-to-onset of CMV infection/disease (197.5 vs. 155.2 days, p < 0.05), and a lower probability of infection/disease while on prophylaxis (1.3% vs. 12.6%, p < 0.01). Nonetheless, leukopenia incidence was higher with valganciclovir (15.8% vs. 2.3%, p < 0.01), as was the need for treatment withdrawal due to adverse effects (11.8% vs. 1.1%, p < 0.01). CMV infection was similar in both groups (32.9% vs. 34.5%). Induction therapy with basiliximab and glucocorticosteroid treatment were independent risk factors for developing CMV infection/disease. In conclusion, valganciclovir prophylaxis results in a low incidence of CMV disease in lung transplant recipients and appears more effective than oral ganciclovir. Despite the comparatively higher incidence of adverse events with valganciclovir, the drug can be considered safe for prophylaxis.     

Cell-Mediated Immunity to Predict Cytomegalovirus Disease in High-Risk Solid Organ Transplant Recipients

Late-onset cytomegalovirus (CMV) disease commonly occurs after discontinuation of antiviral prophylaxis. We determined the utility of testing CD8+ T-cell response against CMV as a predictor of late-onset CMV disease after a standard course of antiviral prophylaxis. Transplant patients at high-risk for CMV disease were enrolled. CD8+ T-cell-mediated immunity (CMI) was tested using the QuantiFERON-CMV assay at baseline, 1, 2 and 3 months posttransplant by measurement of interferon-γ response to whole blood stimulation with a 21-peptide pool. The primary outcome was the ability of CMI testing to predict CMV disease in the first 6 months posttransplant. There were 108 evaluable patients (D+/R+ n = 39; D-/R+ n = 34; D+/R- n = 35) of whom 18 (16.7%) developed symptomatic CMV disease. At the end of prophylaxis, CMI was detectable in 38/108 (35.2%) patients (cutoff 0.1 IU/mL interferon-γ). CMV disease occurred in 2/38 (5.3%) patients with a detectable interferon-γ response versus 16/70 (22.9%) patients with a negative response; p = 0.038. In the subgroup of D+/R- patients, CMV disease occurred in 1/10 (10.0%) patients with a detectable interferon-γ response (cutoff 0.1 IU/mL) versus 10/25 (40.0%) patients with a negative CMI, p = 0.12. Monitoring of CMI may be useful for predicting late-onset CMV disease.     

Antifungal Prophylaxis with Voriconazole or Itraconazole in Lung Transplant Recipients: Hepatotoxicity and Effectiveness

Invasive fungal infections (IFI) are common after lung transplantation and there are limited data for the use of antifungal prophylaxis in these patients. Our aim was to compare the safety and describe the effectiveness of universal prophylaxis with two azole regimens in lung transplant recipients.
This is a retrospective study in lung transplant recipients from July 2003 to July 2006 who received antifungal prophylaxis with itraconazole or voriconazole plus inhaled amphotericin B to compare the incidence of hepatotoxicity. Secondary outcomes include describing the incidence of IFI, clinical outcomes after IFI and mortality.
Sixty-seven consecutive lung transplants received antifungal prophylaxis, 32 itraconazole and 35 voriconazole and inhaled amphotericin B. There were no significant differences between groups in the acute physiology and chronic health evaluation (APACHE) score at the time of transplantation, demographic characteristics, comorbidities and concomitant use of hepatotoxic medications. Hepatotoxicity occurred in 12 patients receiving voriconazole and inhaled amphotericin B and in no patients receiving itraconazole (p < 0.001). There was no significant difference between groups with regard to the percentage of transplants with IFI, but one case of zygomycosis occurred in a transplant treated with voriconazole. Voriconazole prophylaxis after lung transplantation was associated with a higher incidence of hepatotoxicity and similar clinical effectiveness when compared to itraconazole.     

Cytomegalovirus Prophylaxis and Graft Outcome in Solid Organ Transplantation: A Collaborative Transplant Study Report

We investigated relationships between cytomegalovirus (CMV) seropairing and CMV prophylaxis on graft outcome in recipients of solid organ transplants. Transplants carried out from 1985 to 2002 and reported to the Collaborative Transplant Study were analyzed. In cadaver kidney recipients, CMV prophylaxis was significantly associated with improved graft survival only in the seronegative-recipient/seropositive-donor combination (at 3 years: 79.4% with prophylaxis vs. 73.5% without prophylaxis; RR 0.80, p < 0.0001). Among patients who had a functioning graft at 1 year, significantly fewer patients who received CMV prophylaxis received rejection treatment in the preceding year (26.3%), compared with patients who did not receive prophylaxis (32.4%) (p = 0.0001), suggesting an inhibitory effect of CMV prophylaxis on acute rejection. Significant improvements in graft survival after CMV prophylaxis were found also in CMV-negative recipients of CMV-positive heart, and lung or heart-lung transplants, but not liver transplants. The age of the recipient had a differential effect on graft and patient survival after CMV prophylaxis. Use of antilymphocyte antibodies or mycophenolate mofetil was not associated with an enhanced CMV effect on graft outcome. These results may contribute to a better understanding of the influence of pretransplant CMV serology on the effect of CMV prophylaxis.     

Valganciclovir Dosing According to Body Surface Area and Renal Function in Pediatric Solid Organ Transplant Recipients

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients ≤2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 × body surface area × creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 ± 11.9 μg * h/mL; liver 61.7 ± 29.5 μg * h/mL; heart 58.0 ± 21.8 μg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults     

Wait List Death and Survival Benefit of Kidney Transplantation Among Nonrenal Transplant Recipients

The disparity between the number of patients waiting for kidney transplantation and the limited supply of kidney allografts has renewed interest in the benefit from kidney transplantation experienced by different groups. This study evaluated kidney transplant survival benefit in prior nonrenal transplant recipients (kidney after liver, KALi; lung, KALu; heart, KAH) compared to primary isolated (KA1) or repeat isolated kidney (KA2) transplant. Multivariable Cox regression models were fit using UNOS data for patients wait listed and transplanted from 1995 to 2008. Compared to KA1, the risk of death on the wait list was lower for KA2 (p < 0.001;HR = 0.84;CI = 0.81–0.88), but substantially higher for KALu (p < 0.001; HR = 3.80;CI = 3.08–4.69), KAH (p < 0.001; HR = 1.92; CI = 1.66–2.22), and KALi (p < 0.001; HR = 2.69; CI = 2.46–2.95). Following kidney transplant, patient survival was greatest for KA1, similar among KA2, KALi, KAH, and inferior for KALu. Compared to the entire wait list, renal transplantation was associated with a survival benefit among all groups except KALu (p = 0.017; HR = 1.61; CI = 1.09–2.38), where posttransplant survival was inferior to the wait list population. Recipients of KA1 kidney transplantation have the greatest posttransplant survival and compared to the overall kidney wait list, the greatest survival benefit.     

Pulmonary Zygomycosis in Solid Organ Transplant Recipients in the Current Era

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.     

Solid Organ Transplantation in AL Amyloidosis

Vital organ failure remains common in AL amyloidosis. Solid organ transplantation is contentious because of the multisystem nature of this disease and risk of recurrence in the graft. We report outcome among all AL patients evaluated at the UK National Amyloidosis Centre who received solid organ transplants between 1984 and 2009. Renal, cardiac and liver transplants were performed in 22, 14 and 9 patients respectively, representing <2% of all AL patients assessed during the period. One and 5‐year patient survival was 95% and 67% among kidney recipients, 86% and 45% among heart recipients and 33% and 22% among liver recipients. No renal graft failed due to recurrent amyloid during median (range) follow up of 4.8 (0.2–13.3) years. Median patient survival was 9.7 years among 8/14 cardiac transplant recipients who underwent subsequent stem cell transplantation (SCT) and 3.4 years in six patients who did not undergo SCT (p = 0.01). Amyloid was widespread in all liver transplant recipients. Solid organ transplantation has rarely been performed in AL amyloidosis, but these findings demonstrate feasibility and support a role in selected patients.