Jaime Villanueva

Emergence of ganciclovir-resistant cytomegalovirus in lung transplant recipients.

BACKGROUND Since ganciclovir-resistant cytomegalovirus (CMV) disease was initially described in a patient with acquired immunodeficiency syndrome (AIDS) in 1986, the incidence of ganciclovir-resistant CMV disease appears to be increasing in immunocompromised patients. More recently, there have been sporadic reports of ganciclovir-resistant CMV disease in solid organ transplantation. METHODS We retrospectively assessed the incidence of ganciclovir-resistant CMV disease in all lung transplant recipients transplanted between 6/93 and 6/01 at Loyola University Medical Center. All patients underwent routine CMV blood culture, shell vial assay as well as phenotypic and genotypic anti-viral susceptibility testing according to a pre-determined schedule. The number of CMV episodes, intravenous ganciclovir use, acute and chronic rejection and survival data were documented for all patients. RESULTS Twelve of 212 (6%) transplant recipients developed ganciclovir-resistant CMV disease. Ganciclovir resistance was associated with a higher number of CMV episodes (3.4 +/- 2.3 episodes/patient vs 1.7 +/- 0.7 episodes/patient [p < 0.05]) and an increased exposure to cumulative intravenous ganciclovir in the primary CMV-mismatched (D(+)R(-)) population (22 +/- 10 vs 13 +/- 7 days [p < 0.05]) compared with patients who did not develop ganciclovir resistance. In addition, the use of daclizumab therapy was associated with a 7-fold greater likelihood of developing ganciclovir resistance (p < 0.0001). The presence of ganciclovir-resistant CMV disease in our population was associated with a decreased survival that could be attributed to CMV disease itself (p < 0.05). CONCLUSIONS By screening all lung transplant recipients with CMV disease for ganciclovir resistance, we were able to detect a higher incidence of ganciclovir-resistant CMV disease (6%) than previously seen in solid organ transplantation. High-risk patients (D(+)R(-) CMV serostatus) who receive anti-lymphocytic therapy should be monitored aggressively and treated to prevent the development of ganciclovir resistance and avert a negative outcome.

Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody.

Background. The incidence and the severity of acute lung allograft rejection has been linked to the development of bronchiolitis obliterans syndrome. Therefore, we investigated the effects of daclizumab, a humanized monoclonal antibody directed against the alpha subunit of the interleukin 2 receptor, in reducing acute rejection after transplantation. Methods. We retrospectively evaluated 27 patients who received daclizumab as induction immunosuppression and compared them with a historical control group of 34 patients. Both groups received similar immunosuppressive regimens involving tacrolimus, prednisone, and either azathioprine or mycophenolate mofetil. All patients received cytomegalovirus and aspergillus prophylaxis. Results. Twenty-one patients in the control group and 22 patients in the daclizumab group were available for analysis at 6 months after lung transplantation. Ten (48%) patients in the control group had at least grade 2 acute rejection compared with four (18%) in the daclizumab group (P <0.04). The incidence of infection was similar in both groups. One patient in each group developed posttransplant lymphoproliferative disease. Conclusion. Therapy with daclizumab resulted in a significant decrease in the incidence of grade 2 or greater acute rejection after lung transplantation compared with historical controls. There seems to be no increase in the incidence of adverse effects in the patients treated with daclizumab.

Comparison of Three Tacrolimus‐Based Immunosuppressive Regimens in Lung Transplantation

Immunosuppressive therapy for solid organ transplantation has significantly evolved over the past decade. While these therapies have been found to be beneficial in abdominal organ transplantation, the efficacy of these therapies remains unclear in lung transplantation. We retrospectively compared three potent immunosuppressive regimens in our lung transplant population: Group 1 (tacrolimus/azathioprine/prednisone), Group 2 (tacrolimus/azathioprine/prednisone/daclizumab) and Group 3 (tacrolimus/mycophenolate mofetil/prednisone/daclizumab). We compared these three groups with respect to 3‐year rates of acute rejection, chronic rejection, infection and survival. A total of 109 patients was followed during the course of this study. There were 32 patients in Group 1, 49 patients in Group 2 and 28 patients in Group 3. Freedom from acute rejection at 1 and 3 years were higher in Group 3 compared with Group 1 (p < 0.05). The overall incidence of infection up to 3 years after transplantation was comparable among all three groups. Freedom from chronic rejection and survival at 1 and 3 years did not differ among the three groups. In conclusion, we determined the safety and efficacy of three potent immunosuppressive regimens in lung transplantation. Addition of daclizumab and MMF to a tacrolimus‐based immunosuppressive regimen decreased the incidence of acute rejection episodes without increasing any adverse events in our lung transplantation population.

CASE REPORT: Acute Intracranial Hemorrhage in a Cirrhotic Controlled with Recombinant Factor VIIa

Human factor VIIa is a vitamin K-dependent glycoprotein consisting of 406 amino acids having a molecular weight of 50 kDa (1). Factor VIIa is the initiating factor in the conversion of prothrombin to thrombin via the extrinsic pathway (1). Specifically, factor VIIa forms a complex with tissue factor that activates factor X and factor IX, which in turn forms a multimolecular complex with factor V, which then converts prothrombin to thrombin on the surface of platelets with the resultant production of fibrin monomers. The resultant fibrin undergoes self-polymerization until a critical size is achieved and the protein becomes insoluble as the hemostatic plug or clot. Recently, recombinant human factor VIIa (rhFVIIa) has become commercially available for the treatment of hemophiliacs with antibodies to factor VIII or factor IX and individuals who are congenitally factor VIIdeficient (1). Even more recently, rhFVIIa has been used to control bleeding in cases of trauma in both hemophiliacs as well as nonhemophiliac patients (2–9). This use of rhFVIIa in surgical and trauma units has raised the possibility that rhFVIIa might also be clinically useful in other medical situations. Herein, we report a case of a 68-year-old man with a severe coagulopathy due to alcohol-associated cirrhosis, who experienced a spontaneous acute intracranial hemorrhage and was treated with rhFVIIa with cessation of the intracranial bleeding with clinical and radiological stabilization of his intracranial injury.

Coping with the lung donor shortage: donor pool expansion and organ redistribution

The disparity between the number of donor lungs and the number of people awaiting transplantation continues to grow. The increasing number of patients dying while on the waiting list has led the transplant community to evaluate new strategies to improve organ procurement and distribution. Increasing public and health care staff awareness about transplantation, improving the consent process, using marginal and non–heart-beating donors, and improving the efficiency of the procurement process may help expand the lung donor pool. Although controversial, changes to the current lung allocation process that will take into account a patients medical urgency may help decrease the number of patients that die while awaiting transplantation.

Case 5: recurrent cytomegalovirus infection in a lung transplant recipient.

Interactive Grand Rounds is designed to provide health care providers with the opportunity to earn CME credit by accessing the Internet at www.immunologyed.com. The program features a clinical case accompanied by a discussion of the case.