Ganciclovir Therapy Research Articles

Gene Therapy: The First Approved Gene-Based Medicines, Molecular Mechanisms and Clinical Indications

As gene therapy has matured from clinical trials to the first commercial products, understanding of the mechanisms of gene delivery has increased tremendously. This has also been reflected in viral vector development, creating a number of new approaches to tackle issues in transduction efficiency, biodistribution and viral safety. This review will highlight the most important issues and advancements in vector development, administration, surface modification, integration to host genome and safety. The gene therapy products currently available or near market approval, based on p53 expression (Gendicine and Advexin), conditionally replicative adenoviruses (Oncorine) and thymidine kinase + ganciclovir therapy (Cerepro), are introduced with emphasis on the molecular mechanisms of action.

A Case of Valganciclovir Treatment for Cytomegalovirus Retinitis

Purpose: To report a case of a patient with cytomegalovirus (CMV) retinitis who was treated with oral valganciclovir. Case summary: A 34-year-old man who had undergone anti-cancer chemotherapy for Non-Hodgkin lymphoma was referred to the ophthalmologic oncology clinic because of decreased vision in both eyes. Fundus examination showed white, opaque, and granular retinal lesions in both eyes, and a serologic test showed a positive response to CMV antibody IgG and a negative response to CMV antibody IgM. The patient received induction therapy with intravenous ganciclovir and maintenance therapy with oral valganciclovir 900 mg once daily. CMV retinitis reactivated 4 weeks after maintenance therapy was discontinued. At that point, the patient received induction therapy with oral valganciclovir 900 mg twice daily for 3 weeks and maintenance therapy with 900 mg once daily for 5 weeks. The retinal lesion disappeared and did not recur after oral administration of valganciclovir. The patient discontinued valganciclovir after 5 weeks of maintenance therapy, and CMV retinitis did not reactivate during 6 months of follow-up. Conclusion: Oral valganciclovir was clinically effective in the treatment of CMV retinitis in a patient who was treated with anti-cancer chemotherapy for non-Hodgkin lymphoma.

Plasma HHV-6 viral load-guided preemptive therapy against HHV-6 encephalopathy after allogeneic stem cell transplantation: a prospective evaluation

Human herpesvirus 6 (HHV-6) causes life-threatening encephalopathy in recipients of allogeneic SCT, but no consensus has been reached regarding appropriate preventive methods. This study evaluated a plasma HHV-6 viral load-guided preemptive approach against HHV-6-associated encephalopathy. Plasma real-time PCR assay was performed once a week. Among 29 patients, 19 developed positive plasma HHV-6 DNA. Median maximum plasma HHV-6 DNA was 4593.5 copies/ml plasma (range, 150.0-127 891.0 copies/ml plasma). In one of eight events with low-level HHV-6 DNA (defined as <1000 copies/ml plasma) and four of seven events with mid-level HHV-6 DNA (1000-9999.5 copies/ml plasma), HHV-6 loads in plasma subsequently continued increasing. Ganciclovir was administered against six of nine patients with high-level HHV-6 DNA (> or =10,000 copies/ml plasma). High-level HHV-6 DNA resolved similarly in both groups with or without ganciclovir therapy. Among the nine patients with high-level HHV-6 DNA two developed encephalopathy. As encephalopathy developed before the detection of high-level HHV-6 DNA in plasma, these two patients had not received preemptive ganciclovir therapy. In conclusion, our preemptive approach against HHV-6-associated encephalopathy cannot prevent all cases of HHV-6 encephalopathy in SCT recipients due to the dynamic kinetics of plasma HHV-6 viral load.

Acute retinal necrosis by cytomegalovirus in an immunocompetent adult: case report and review of the literature

A rare case of acute retinal necrosis caused by cytomegalovirus in an immunocompetent adult, diagnosed by polymerase chain reaction of vitreous aspirate, with good visual outcome after intravitreal and intravenous ganciclovir and oral prednisolone therapy, is reported. A 50-year-old healthy lady presented with redness and diminution of vision in her right eye of 10 days duration. She had anterior chamber inflammation, marked vitritis, and anterior retinal necrosis in the right eye. Blood and other investigations did not reveal any infectious diseases and HIV testing was negative. The retinal lesions and panuveitis resolved with treatment. Two months later she developed retinal detachment which was treated successfully. The best-corrected vision was 6/12 in the right eye. Seven cases of cytomegalovirus ocular infection in immunocompetent healthy adults, reported in the literature, were reviewed. The different presentations of this disease and the importance of suspecting this causative agent are highlighted.

Incidence and Characteristics of Infections Following Cord Blood Stem Cell Transplantation in Children.

Infection is one of the most important causes of morbidity and mortality after hematopoietic stem cell transplantation. We assessed the incidence and characteristics of infections in 163 cord blood stem cell transplantation (CBT) recipients from 13 transplant centers of Korea between October, 1996 and April, 2005. The patients underwent CBT with standardized conditioning, GVHD prophylaxis and supportive care including pre-emptive ganciclovir therapy for cytomegalovirus (CMV) antigenemia. The median time to neutrophil engraftment was 19 days (10–62 days) and to platelet engraftment was 45 days (14–394 days). Within the post-transplant day 0 to day 30, 81.6% of patients (133/163) experienced febrile episodes with 11.7% (19/163) of clinically documented infection (CDI) and 19.6% (32/163) of microbiologically documented infection (MDI). The neutrophil engraftment was delayed in the patients with CDI and MDI rather than without CDI and MDI (day 26.3 vs day 21.5, P=0.03) before day 30. In the time period of day 30 to 100, febrile episodes, CDI and MDI occurred in 54.3% (82/151), 14.6% (42/151) and 13.2% (20/151), respectively. After day 100, 38.5% of patients (45/117) experienced febrile episodes with 17.9% (21/117) of CDI and 7.7% (9/117) of MDI. Although the incidence of febrile episodes before day 30 was significantly higher than after day 30, the incidence of CDI and MDI was comparable. There were no significant differences of infection rate according to the infused cell dose, the degree of HLA disparity, acute GVHD and chronic GVHD. The overall mortality rate after CBT was 40% (65/163). Infection was considered the primary cause of transplant-related mortality and represented 18.4% (106/163) of the causes of death with the median day of 96.5 (1∼1,081 days). The incidence of pre-transplant CMV-seropositivity was 85.5% of the patients (106/123) and CMV antigenemia developed in 52.7% of CMV-seropositive patients compared to 11.8% of CMV-seronegative patients (P=0.002). CMV disease developed in 25.7% of CMV-seropositive patients and 6.7% of CMV-seronegative patients, which showed statistiacally not significant. Pre-transplant conditioning regimens such as antithymocyte globulin did not affect on the incidence of CMV antigenemia or CMV disease. Based on our study, the infection was still the primary cause of mortality after CBT, particularly in patients with delayed neutrophil engraftment. The high prevalence of CMV seropositive patients in Korea was associated with increased incidence of CMV antigenemia, not with CMV disease.

Preemptive therapy with ganciclovir 5 mg/kg once daily for cytomegalovirus infection after unrelated cord blood transplantation

The efficacy and safety of preemptive therapy using ganciclovir (GCV) 5 mg/kg once daily for CMV infection after unrelated cord blood transplantation (CBT) were studied. The initial preemptive therapy with GCV 5 mg/kg once daily led to resolution of CMV antigenemia in 25 of 34 patients (74%). In the remaining 9 patients (26%), antigenemia resolved after dose-escalation of GCV or change to foscarnet therapy. Recurrence of antigenemia was seen in 18 patients (53%). A total of 12 patients received the second preemptive therapy with GCV 5 mg/kg once daily, which led to resolution of antigenemia in 11 of 12 patients (92%). The remaining 1 patient (8%) required change to foscarnet therapy. None of 34 patients developed CMV disease. Neutropenia with an absolute neutrophil number of less than 1 and 0.5 x 10(9) per liter after GCV therapy occurred in 12 (35%) and 1 (3%) patients, respectively, after the initial therapy, and in 2 (17%) and 0 (0%) patients, respectively, after the second therapy. No patients developed neutropenic fever or secondary graft failure after GCV therapy. There were no deaths directly attributable to GCV therapy. The present study suggests that antigenemia-based preemptive strategy using GCV 5 mg/kg once daily is feasible and effective for CBT recipients.

Rituximab therapy increased post-transplant cytomegalovirus complications in Non-Hodgkin’s lymphoma patients receiving autologous hematopoietic stem cell transplantation

The use of monoclonal antibody, rituximab, had been reported to be associated with some severe viral infections. The inference of rituximab therapy and post-transplant cytomegalovirus (CMV) infectious complications in non-Hodgkin's lymphoma (NHL) patients is still unclear now. From 2002 to 2005, 46 patients with relapsed indolent or high-risk aggressive B cell NHL who received rituximab (17 patients) or not (29 patients) before autologous hematological stem cell transplantation (HSCT) in one institute were retrospectively analyzed for the risk factors of CMV complications after transplantation. Pre-transplant and post-transplant CMV infectious conditions, conditioning regimens, transplant types, and post-transplant complications were recorded. Post-transplant infectious complications were followed up until 6 months after transplantation. Seventeen of 46 patients received rituximab before HSCT. Three of them suffered from CMV infection and two of them developed CMV disease. All of the patients with CMV disease recovered after ganciclovir and CMV-specific immunoglobulin therapy. Twenty-nine of 46 patients without rituximab treatment before HSCT did not have CMV complications after HSCT. The risks to develop CMV infections after autologous HSCT were higher in rituximab-treated patients (17.6% vs 0%, p = 0.045, Fisher exact test, two-sided). The risks to develop CMV diseases had higher trend with rituximab therapy than without rituximab therapy (11.7% vs 0%, p = 0.131, Fisher exact test, two-sided). The NHL patients receiving rituximab therapy had higher risk to develop CMV infectious complications after autologous HSCT.

Prevention of CMV disease in pediatric kidney transplant recipients: Evaluation of pp67 NASBA‐based pre‐emptive ganciclovir therapy combined with CMV hyperimmune globulin prophylaxis in high‐risk patients

A new prevention strategy for CMV infection was evaluated in our pediatric kidney transplant unit. This approach comprises a pre-emptive therapy, based upon the monitoring of CMV pp67 mRNA in whole blood by the qualitative NASBA, combined with prophylactic CMV-IG in high risk (R-/D+) children. Thirty-one kidney transplant children were followed for six months with serial measurements of CMV pp67 mRNA in the blood. The R-/D+ patients were given prophylactic CMV-IG for the first 16 wk after transplantation. I.v. ganciclovir was administered upon CMV detection by NASBA and was discontinued after two consecutive negative results. CMV infection, detected by NASBA, developed in 11 (35%) recipients: one (33%) of the R+/D- patients and 10 (72%) of the R-/D+ patients. CMV disease developed in 9.6% of the patients (3/31), exclusively in the R-/D+ group. These three patients presented concurrently with CMV viremia and disease. It is noteworthy that two of the three patients could not receive a complete course of CMV-IG, and one of the latter two subjects had been treated for acute rejection 15 days before CMV infection. Ganciclovir was given for the 11 cases of primary infection, and for three cases of relapsed CMV infection. pp67 NASBA-based pre-emptive ganciclovir therapy, combined with prophylactic CMV-IG in high-risk patients leads to a lower rate of CMV disease, as long as a complete course of CMV-IG has been administered and ganciclovir is given during the period of treatment for acute rejection in high-risk populations.

Transduction patterns and efficiencies in rabbit uterine tissues after intraluminal uterine adenovirus administration vary with the reproductive cycle

The options for destroying the full thickness of endometrium are very limited, relying mainly on surgical endometrial ablation. A nonsurgical, safe method would benefit many women in clinical settings. This study was undertaken to investigate the potential of gene therapy to transfect and destroy endometriun at different stages of the reproductive cycle in rabbits. We used adenoviruses carrying the LacZ (AdvLacZ) marker gene, indicating the transfection efficiency, and adenoviruses carrying thymidine kinase (AdvTK) followed by intravenous ganciclovir therapy as a potential treatment for excess endometrial growth. Ganciclovir was given intravenously after AdvTK treatment. Adenoviruses were injected intraluminally into the uterus of nonpregnant, pseudopregnant, and pregnant New Zealand White rabbits (n=25). After AdvLacZ gene transfer into the uterus of intact rabbits, transduced cells were observed in uterine muscle and endometrial stroma. In pseudopregnant and pregnant rabbits the endometrium was proliferative and transduction was restricted to endometrial epithelium. However, no treatment effect was observed after AdvTK gene therapy although the transduction with AdvLacZ was clearly detectable. It is concluded that the transduction pattern of uterine tissues varies significantly with the reproductive cycle. Secondly, although the transduction efficiency was relatively high in the endometrial epithelium, the effect of the AdvTK and ganciclovir treatment was poor and not sufficient for clinical applications.

Cytomegalovirus as an Etiologic Factor in Corneal Endotheliitis

To investigate clinical manifestations and response to antiviral therapy of 8 patients with cytomegalovirus (CMV)-induced corneal endotheliitis who were diagnosed and treated at 2 university hospitals in Japan. Retrospective, consecutive, multicenter case series. Eight eyes of 8 patients diagnosed with active CMV corneal endotheliitis at Kyoto Prefectural University of Medicine and Ehime University School of Medicine. The diagnosis was made based on the detection by polymerase chain reaction assay of CMV, but not herpes simplex virus (HSV) and varicella zoster virus (VZV) DNA, in the aqueous humor from the affected eye. Retrospective review of the clinical manifestations and responses to antiviral treatment. Patient profiles, including duration of corneal endotheliitis, systemic disease, intraocular pressure, and clinical manifestation of anterior and posterior segments. The clinical response to systemic and topical antiviral treatment was evaluated by slit-lamp examination. Corneal endothelial density was examined by specular microscopy. The average observation period after CMV detection was 10.4 months (range, 2-24 months). None of the patients had systemic immunodeficiency. Corneal manifestations included linear keratic precipitates associated with multiple coin-shaped lesions and local corneal stromal edema. Of the 8 patients, 4 had undergone penetrating corneal transplantation. Systemic ganciclovir therapy was used in 7 patients, and in 1 patient, valacyclovir was administered, with the corneal endotheliitis responding quickly to the early administration of galovir. At the final examination, 6 eyes had a clear cornea, but 2 eyes had bullous keratopathy. Besides HSV and VZV, CMV must be considered as an etiologic agent in patients with corneal endotheliitis. Cytomegalovirus corneal endotheliitis may be a newly identified clinical entity of reactivated CMV in the anterior chamber of individuals free of accompanying systemic symptoms.

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

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. 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. 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. 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.

Intercellular trafficking and cytotoxicity of recombinant HSV-1 thymidine kinase fused with HSV-2 US11 RXP repeat peptide

To improve the therapeutic efficacy of herpes simplex virus type 1 (HSV-1) thymidine kinase (tk)/ganciclovir (GCV) therapy, we have made recombinant tk chimeras fused with the arginine-rich (RXP) repeat of herpes simplex virus type 2 (HSV-2) US11 and examined their activity of intercellular trafficking and cytotoxicity. When examined the immunofluorescence staining patterns of RXP/tk fusion proteins in transfected COS7 cells, the RXP chimeras revealed a conservation of the trafficking activity of RXP. We also found that transfection of tkC Delta 6-RXP (lacking the C-terminal six amino residues of tk), tk-RXP, and tkN Delta 66-RXP (lacking the N-terminal 66 amino residues of tk) induced apoptosis even in the absence of GCV. The results suggest that these tk/RXP chimeras themselves have apoptosis-inducing activity, and that the HSV tk nucleoside-binding domain may be involved in the induction of apoptosis. Furthermore, treatment with 5 muM GCV induced efficient cell death in cells tranfected with tk-RXP in comparison to the cells transfected with tk (P < 0.0001).

Effective Ablation of Pancreatic Cancer Cells in SCID Mice Using Systemic Adenoviral RIP-TK/GCV Gene Therapy

Studies have demonstrated that adenovirus subtype 5 mediated rat insulin promoter directed thymidine kinase (A-5-RIP-TK)/ganciclovir (GCV) gene therapy resulted in significant enhanced cytotoxicity to both PANC-1 and MIA PaCa2 pancreatic cancer cells in vitro. However, little is known about the effect in vivo. In this study we examine the in vivo safety and efficacy of intravenous A-5-RIP-TK/GCV gene therapy. 1 x 10(6) Mia PaCa2 cells were injected intraperitoneally (i.p.) into SCID mice to create a mouse model of human pancreatic cancer. A-5-RIP-TK gene construct was administered intravenously (i.v.), followed by i.p. GCV administration. Intravenous injection of A-5-RIP-lacZ reporter gene constructs was used for evaluation of Ad-RIP-gene expression in tumors and other tissues. Optimal adenoviral and GCV doses and treatment duration were determined. Tumor volume, serum insulin, and glucose levels were measured. Immunohistochemical staining of pancreata and tumors were performed to assess morphology and hormone expression and apoptotic rates were determined. All A-5-RIP-TK/GCV-treated mice had reduced tumor volume compared with controls, but maximal tumor volume reduction was observed with 10(8) vp followed by GCV treatment for 4 wk. A-5-RIP-TK/GCV gene therapy contributed to significant survival advantage in MIA PaCa2 bearing mice, and the greatest survival benefit was observed with 10(8) vp and was not affected by length of treatment of GCV. A-5-RIP-TK/GCV therapy increased PDX-1 expression and tumor cells apoptosis, and altered islet morphology. However, A-5-RIP-TK/GCV gene therapy caused diabetes associated with islet cell apoptosis, increased delta-cells and reduced pancreatic polypeptide (PP)-cell numbers. Systemically administered A-5-RIP-TK/GCV is an effective treatment of pancreatic cancer. A-5-RIP-TK/GCV cytotoxicity to malignant cells varies with adenoviral dose and length of GCV treatment. However, A-5-RIP-TK/GCV is associated with islet cell toxicity and diabetogenesis. The type of diabetes observed is distinct from Types 1 and 2 and is associated with islet cell apoptosis and reduced delta- and PP-cells.

The use of sirolimus in ganciclovir‐resistant cytomegalovirus infections in renal transplant recipients

The widespread use of prophylactic ganciclovir and anti-lymphocyte/thymocyte therapies are associated with increased induction of ganciclovir-resistant cytomegalovirus (CMV) strains. The use of sirolimus has been associated with a lower incidence of CMV infection in transplant recipients. We questioned whether it could also be effective as a therapeutic treatment of resistant CMV infection. Patients with ganciclovir-resistant CMV infections determined clinically and by DNA sequencing analysis were enrolled. Antigenaemia and DNA sequencing were used to diagnosis and follow the mutations. Nine transplant patients were given sirolimus plus mycophenolate mofetil (n = 4) or a calcineurin inhibitor (n = 5). Seven out of nine recipients were CMV IgG negative before transplantation. We observed a rapid decrease in antigenaemia levels, reaching zero in eight out of nine (88.9%) patients within a median of 20.3 +/- 10.1 d. Graft function remained stable and no patient presented acute rejection or recurrence of the CMV infection. This suggests that the use of sirolimus plus ganciclovir therapy could be useful in ganciclovir-resistant CMV infections.

Active CMV disease does not always correlate with viral load detection

The use of quantitative cytomegalovirus (CMV) real-time polymerase chain reaction (RT-PCR) and preemptive ganciclovir therapy is replacing prophylaxis as the management of choice in high-risk patients undergoing stem cell transplantation (SCT). However, there are limited data defining its role in this setting. In the current retrospective single-centre study, quantitative RT-PCR was used to determine CMV in 577 consecutive patients undergoing SCT (172 allogeneic and 405 autologous) over a 5-year period. CMV RT-PCR was performed weekly until cessation of immunosuppression (allogeneic) or for 30 days post-SCT (autologous). Treatment was commenced after two consecutive positive results or a high copy on the first occasion (> 1000 copies/ml, > 3 log). The overall CMV reactivation rate in patients undergoing allogeneic SCT was 30%, with reactivation observed in 72% of high-risk patients (recipient positive patients). CMV end-organ disease was observed in eight patients (1%); of these, four were CMV RT-PCR negative at the time of diagnosis of end-organ CMV disease, with three remaining negative throughout the course of the disease. CMV-related mortality was recorded in three patients. The current data support a preemptive treatment strategy-based CMV RT-PCR, but indicate that in symptomatic patients, a negative CMV PCR result does not exclude CMV end-organ disease.

Unexpectedly high inter‐ and intrapatient variability of Ganciclovir levels in children

Few studies report Ganciclovir or Valganciclovir levels in children. Single-center, retrospective study of all available Ganciclovir levels in transplanted children. Ganciclovir monitoring was performed as previously described [G. Filler (1998); Pediatric Nephrology, 12, 6]. For the normalization of dosing to GFR and target trough levels, we assumed first-order kinetics. We analyzed 57 Ganciclovir levels in 20 children (mean age 8.6 +/- 5.5 yr) treated with intravenous or oral Ganciclovir or oral Valganciclovir. Ganciclovir levels were drawn after IV therapy (n = 9), during oral Ganciclovir (n = 5), or during oral Valganciclovir (n = 15). Oral bioavailability of Valganciclovir was 42.0 +/- 21.8%. The dose-normalized intrapatient Valganciclovir variability was 83%. Mean GFR was 92 +/- 22 mL/min/1.73 m(2). Mean Ganciclovir concentration at last available measurement was 0.60 +/- 0.09 mg/L. While target trough Ganciclovir levels have not been established, possibly subtherapeutic Ganciclovir levels <0.5 mg/L on recommended IV doses were found in eight patients. This subset of patients was significantly younger (4.5 +/- 3.1 vs. 11.4 +/- 5.0 yr). Levels <0.5 mg/L were found in 24/57 instances and 10 patients subsequently had their dose increased. The last Valganciclovir dose adjusted to a GFR of 100 mL/min/1.73 m(2) was 842 +/- 323 mg/m(2)/day. A high proportion of patients had low Ganciclovir levels both on intravenous and oral therapy. The oral bioavailability of Valganciclovir was 42%. Our data suggest substantial inter- and intrapatient variability of Ganciclovir levels after pediatric renal transplantation and may support the need for pharmacokinetic monitoring of Ganciclovir and Valganciclovir therapy for the prevention and treatment of CMV disease after pediatric transplantation. It is currently unclear what target trough level would be most suitable.

Cytomegalovirus infection with perineal pain after living donor liver transplantation: report of four cases

We report on 4 adult cases of presumptive cytomegalovirus (CMV) disease with perineal pain after living donor liver transplantation. Patients presented with severe perineal pain without any other symptoms related to CMV infection, except pyrexia. All patients had an episode of acute cellular rejection (ACR) before the onset of perineal pain, and 1 patient needed OKT3 therapy. The severe perineal pain was not well controlled with medication, and 1 patient needed epidural anesthesia. In the first 3 patients, pp65 CMV antigenemia (pp65CMV-Ag) test results were positive and intravenous administration of ganciclovir (GCV) therapy was initiated. In the last patient, GCV therapy was preemptively administered before a positive pp65CMV-Ag test result was confirmed. After administration of GCV, the pain gradually disappeared and all patients had negative pp65CMV-Ag test results. In conclusion, unusual perineal pain can be a symptom related to CMV infection. CMV infection needs to be kept in mind when a liver transplant recipient has severe perineal pain, especially after receiving treatment for ACR.

Acute esophageal necrosis (black esophagus) in the renal transplant recipient: manifestation of primary cytomegalovirus infection

We report a severe case of cytomegalovirus (CMV) esophagitis in a renal transplant recipient presenting as acute esophageal necrosis (AEN, 'black esophagus'). AEN is an uncommon entity that is a result of mucosal necrosis and has been described only a few times previously. To our knowledge, this is the first report of AEN due to a CMV infection. The disease was manifested by abdominal and epigastric pain, thrombocytopenia, leukopenia, and elevated liver enzymes. Upper endoscopy showed acute esophageal necrosis. Ganciclovir therapy was initiated immediately and resulted in a complete remission of symptoms. We conclude that the possibility of CMV infection should be suspected in any patient presenting with cytopenia, elevated liver enzymes, and epithelial gastrointestinal lesions in the first 6 months after transplantation, and that early viral detection and antiviral therapy can be lifesaving.

Leflunomide failure to control recurrent cytomegalovirus infection in the setting of renal failure after allogeneic stem cell transplantation

Cytomegalovirus (CMV) reactivation is common in the allogeneic stem cell transplant setting but the incidence of CMV organ disease and mortality has been dramatically reduced by prophylactic or preemptive antiviral therapy. We report the case of a CMV-seropositive 46-year-old man with non-Hodgkin's lymphoma who underwent an unrelated allogeneic stem cell transplant from a CMV-seronegative HLA-matched unrelated donor. CMV encephalitis and colitis developed that was refractory to single-agent therapy. The CMV isolate demonstrated genotypic resistance to both ganciclovir and foscarnet. CMV disease was controlled by prolonged combination ganciclovir and cidofovir therapy, but severe renal dysfunction developed. Leflunomide was selected as a last resort to avoid the nephrotoxicity of cidofovir. CMV antigenemia rapidly increased following leflunomide administration, necessitating discontinuing this agent and resuming prior antiviral therapy. The pharmacokinetics of leflunomide in the setting of renal insufficiency is presented. Options for salvage therapy in refractory CMV disease in allogeneic stem cell transplant recipients are briefly reviewed.

Resistance to combined ganciclovir and foscarnet therapy in a liver transplant recipient with possible dual-strain cytomegalovirus coinfection

We present a case report of a cytomegalovirus (CMV)-seronegative, 58-year-old male who received a CMV-seropositive donor liver transplant without CMV prophylaxis. On postoperative day 30, the patient developed primary CMV disease that responded to ganciclovir. On postoperative day 114, however, he was diagnosed with recurrent CMV infection. Despite aggressive, combined antiviral treatment with ganciclovir and foscarnet and reduction of immunosuppression, viral clearance was never achieved. Serum samples were collected throughout the infectious process for viral DNA analysis. Portions of the UL97 and UL54 genes were amplified and compared to the AD169 wild-type strain. Sequencing studies revealed the presence of mutations in viral isolates obtained after clinical resistance was observed. These mutations were not present in samples obtained during the primary CMV infection. Our findings suggest the presence of coinfection with at least 2 different strains of CMV rather than induction of mutations after ganciclovir therapy.