Strategies for the prevention of cytomegalovirus disease after marrow transplantation

The purposes of this review are to examine the epidemiology of disease due to cytomegalovirus (CMV) in recipients of autologous and allogeneic marrow transplants and to compare different antiviral regimens used for the prevention of such disease in recipients of allogeneic marrow transplants, with an emphasis on ganciclovir. In seven studies, ganciclovir reduced the incidence of CMV infection and disease after allogeneic marrow transplantation. In one study mortality after transplantation was reduced because of a decreased rate of CMV-related death among ganciclovir-treated patients. Ganciclovir was effective when given to all CMV-seropositive patients (prophylaxis) or to patients who were considered at high risk for CMV disease on the basis of a positive surveillance culture (early treatment). The effectiveness of ganciclovir for the prevention of CMV infection and disease is limited by drug-induced neutropenia. Experience with other antiviral agents, such as foscarnet, has been limited. Initial studies of the adoptive transfer of CMV-specific CD8+ cytotoxic T cells have been conducted. In short, ganciclovir is currently effective for the prevention of CMV disease in allogeneic marrow transplant recipients, but its usefulness is limited by neutropenia. Future studies must be aimed at confining the toxicity of ganciclovir to patients at the highest risk for CMV disease.     

Self-inflicted intramyocardial injury with a sewing needle: a rare cause of pneumothorax

Ganciclovir susceptibilities and UL97 sequences were analyzed in 20 cytomegalovirus (CMV) isolates recovered from 15 bone marrow transplant recipients with active CMV infection after prophylaxis with acyclovir (group I; 12 isolates) or after acyclovir prophylaxis followed by ganciclovir therapy (group II; 8 isolates). All group I isolates were susceptible to ganciclovir. Five group II isolates were susceptible to ganciclovir, and 3 isolates (all from the same person) were resistant to ganciclovir (IC50 > 12 microM). Ganciclovir resistance UL97 mutations were found in 4 group II isolates, including a ganciclovir-susceptible isolate obtained from 1 patient after 41 days of therapy with ganciclovir and 3 ganciclovir-resistant isolates obtained from another patient after 73, 116, and 132 days of treatment with ganciclovir. Ganciclovir-resistant CMV isolates may emerge rapidly in bone marrow transplant recipients who are treated with ganciclovir after receiving prophylaxis with acyclovir.     

Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients

BACKGROUND: Treatment with prophylactic oral acyclovir, intravenous ganciclovir, or immunoglobulins to prevent cytomegalovirus (CMV) infection and disease in renal transplantation is associated with variable efficacy and significant expense. We studied control of CMV in renal transplant recipients using either prophylactic oral ganciclovir or deferred therapy with intensive monitoring with polymerase chain reaction (PCR) analysis. METHODS: Forty-two recipients were followed for 6 months after transplantation. Ganciclovir (1000 mg p.o. t.i.d.; n=19) or acyclovir (200 mg p.o. b.i.d.; n=23) was begun at transplantation and continued for 12 weeks. PCR for CMV was performed on buffy-coat specimens every week for 15 weeks and at months 5 and 6. RESULTS: No patients in the ganciclovir group, compared with 14 of 23 patients (61%) in the deferred-therapy group (P<0.0001), developed CMV disease during the first 12 weeks. In the ganciclovir group, 4 of 19 patients (21%) subsequently experienced 5 episodes, whereas 14 patients in the deferred-therapy group experienced 18 episodes (P=0.013 for subjects and P=0.026 for episodes). The time to disease was also delayed in the ganciclovir group compared with the deferred-therapy group (133+/-17 days vs. 51+/-7 days; P<0.0001). Oral ganciclovir also prevented CMV viremia during prophylaxis (2/19 patients [11%] vs. 23/23 patients [100%]). Time to CMV viremia was delayed in the ganciclovir group; however, 13/19 patients (68%) ultimately showed PCR evidence for CMV viremia (P=0.005). CONCLUSIONS: An initial 12-week course of oral ganciclovir prevents CMV disease and infection in renal transplant recipients during prophylaxis, and the benefits persist after discontinuation.     

A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients

BACKGROUND: Posttransplantation cytomegalovirus (CMV) infection remains a significant cause of morbidity in kidney transplant recipients. We performed a randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for CMV prophylaxis in a group of renal allograft recipients considered at high risk for CMV disease due to the use of OKT3 induction therapy. METHODS: A total of 101 recipients of cadaveric (83) and zero haplotype-matched live donor (18) kidney transplants were entered into the trial. A total of 22 D-R- patients received no prophylaxis. Twenty-seven D+R-, 29 D+R+, and 23 D-R+ patients were randomized to receive 3 months of either oral acyclovir (800 mg q.i.d.) or oral ganciclovir (1000 mg t.i.d.). Doses were adjusted according to the level of renal function. The D+R- patients were also given CMV immune globulin biweekly for 16 weeks. Surveillance blood cultures were obtained at transplantation, at months 1, 2, 3, and 6, and when clinically indicated. The primary study end points were time to CMV infection and disease the first 6 months after transplantation. RESULTS: The mean follow up was 14.4 months. Both agents were well tolerated, and no drug interruptions for toxicity occurred. CMV was isolated in 14 of 39 (35.9%) acyclovir-treated and 1 of 40 (2.5%) ganciclovir-treated recipients by 6 months (P=0.0001). Symptomatic CMV disease occurred in 9 of 14 (64%) of the acyclovir patients, two with tissue-invasive disease. Infection rates for acyclovir vs. ganciclovir, respectively, stratified by CMV serology were: D+R-, 54 vs. 0%, P=0.0008; D+R+, 43 vs. 6.6%, P=0.01; D-R+, 8.3 vs. 0%, P=NS. No patient developed CMV infection while taking oral ganciclovir, however three delayed infections occurred 2-7 months after finishing therapy. Each patient had been previously treated for acute rejection. CONCLUSIONS: Oral acyclovir provides effective CMV prophylaxis only for recipients of seronegative donor kidneys. Oral ganciclovir is a superior agent providing effective CMV prophylaxis for recipients of seropositive donor kidneys. Recipients who are treated for acute rejection are at risk for delayed CMV infection during the first posttransplantation year.     

Effect of oral acyclovir or ganciclovir therapy after preemptive intravenous ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus seropositive renal and liver transplant recipients receiving antilymphocyte antibody therapy

BACKGROUND: Organ transplant recipients who are seropositive for cytomegalovirus (CMV) and who are treated with antilymphocyte antibody (ALA) therapy have a high rate of symptomatic CMV disease. The intravenous administration of ganciclovir therapy once daily during ALA therapy decreased the incidence from 24% to 10% in patients receiving ALA as an induction therapy and from 64% to 22% in those treated for rejection. The present study was undertaken to determine whether a more intensive and sustained antiviral regimen could be more effective. METHODS: From April 1995 to December 1997, all CMV seropositive renal and liver transplant recipients who received ALA therapy were treated with intravenously administered ganciclovir (5 mg/kg/day with dose adjusted for renal dysfunction) for the length of ALA therapy and then with orally administered acyclovir (400 mg three times/day) or ganciclovir (1 gm twice/day) for 3 to 4 months. The incidence of CMV viremia and of CMV disease was determined during the 6 months after completion of ALA therapy. RESULTS: Forty-one patients (35 renal and 6 liver transplant recipients) were studied. CMV disease occurred in 2 patients (4.9%), both of whom were treated for rejection; it occurred in 1 of 21 patients (4.8%) treated with orally administered acyclovir, and in 1 of 20 patients (5%) treated with orally administered ganciclovir. The only patient who developed CMV disease in the ganciclovir group had received only 26 days of oral antiviral therapy. No CMV disease was documented in the group of patients receiving ALA therapy as induction therapy. CMV viremia occurred in three patients in the acyclovir group (14.3%) and in one patient in the ganciclovir group (5%). Among renal transplant recipients only, 1 of 35 patients developed CMV disease (2.9%) and no case of CMV disease was documented in patients treated with orally administered ganciclovir. All six patients receiving two courses of ALA therapy each were free of CMV disease. Toxicity of the regimen was minimal, and antiviral resistance did not develop. CONCLUSIONS: Preemptive antiviral therapy with intravenously administered ganciclovir during ALA therapy and then orally administered ganciclovir for 3 to 4 months provides virtually complete protection against the excessive rate of CMV disease that occurs in CMV seropositive allograft recipients receiving ALA therapy.     

Evolution of the Sry genes

Cytomegalovirus (CMV) infection is a major cause of morbidity and occasionally of mortality in immunosuppressed allograft recipients. At the University of Cincinnati Medical Center, ganciclovir has been administered for the prevention of CMV infection since July 1992. Forty-six recipients of cadaveric renal allografts (Group I) received ganciclovir at a dose of 2.5 or 5 mg/kg/day (adjusted for renal function) for 14-21 days, during induction treatment and during antirejection treatment with monoclonal or polyclonal antilymphocyte preparations. In this retrospective study, these 46 patients were compared with 77 recipients of cadaveric renal allografts transplanted prior to July 1992 (Group II) for the prevalence, severity and time of CMV occurrence after transplantation. CMV diagnosis was based on clinical evaluation and was confirmed by blood cultures, CMV antigen immunofluorescence assay and/or histology. Patients were stratified according to CMV serology (+) or (-) in donor and recipient. CMV infection developed in 16 of 46 (35%) patients in Group I vs. 27 of 77 (35%) patients in Group II (p = 0.97). A total of 25 episodes of CMV infection occurred in Group I compared to 44 in Group II (p = 0.76). CMV infection was diagnosed an average of 97.4 days after transplant in Group I compared to 48.3 days in Group II (p = 0.0003). Tissue-invasive CMV infection occurred in 3 patients in Group I (19%) vs. 12 in Group II (44%) (p = 0.5). In conclusion, ganciclovir prophylaxis resulted in a delayed onset of clinical CMV infection with a trend towards less severe infection in patients treated with antilymphocyte antibody preparations.     

Psychiatric diseases presenting as infectious diseases

BACKGROUND: Cytomegalovirus (CMV) disease is an important cause of organ transplant-related morbidity and mortality. During the last 5 years at our institution, prophylactic ganciclovir and hyperimmune globulin have been routinely administered to lung transplant recipients whenever the donor or the recipient was CMV antibody-positive. We sought to assess the efficacy of prophylaxis on viremia, CMV disease, and bronchiolitis obliterans syndrome (BOS). METHODS: A retrospective chart review of 61 consecutive lung transplants performed between recipients between January 1993 and August 1995 was performed. Fifty-six patients who survived at least 1 month were analyzed. Patients were considered at risk for CMV disease whenever pretransplant donor or recipient serology was positive. RESULTS: Fourteen of the 39 patients at risk (36%) had viremia while on prophylaxis. The rate of CMV disease was 13% during the first 6 months following transplantation. A donor whose CMV serology was positive appeared to increase the risk of BOS in a Cox regression model (relative risk=2.4; 95% confidence interval=0.86-6.74; p=0.0957). Neither age, CMV infection (viremia or a positive specimen from BAL), recipient's serology at the time of transplantation, or CMV disease was associated with BOS. None of these variables was associated with mortality on Cox regression analysis or univariate analysis. CONCLUSIONS: Administration of combination ganciclovir and hyperimmune globulin prophylactic therapy to lung transplant recipients at risk for CMV infection and disease is associated with a relatively low incidence of disease, which appears only after prophylaxis treatment with ganciclovir is completed. Ganciclovir prophylaxis does not prevent CMV viremia; however, viremia while on prophylaxis is not predictive of disease.     

Calcium transport by Frankia sp. strain EAN1pec

Some important aspects of human cytomegalovirus (CMV) infection were discussed from a clinical point of view. Congenital infection: The mass-screening of pregnant women is not justified at present, mainly because of limited value of diagnostic methods for detecting fetal infection and unavailability of effective measure for prevention. Extensive diagnostic approach and intrauterine therapy may be applicable in the case of intrauterine growth retardation or abnormal ultrasonographic findings. Diagnosis and treatment: The demonstration of viral antigens in peripheral blood leukocytes has been proven to be a useful tool for monitoring organ transplant recipients for the early diagnosis of CMV disease, timely application of antiviral therapy and evaluating the efficacy of the treatment. However, this method is not a valid support for detecting CMV disease due to perinatal infection. Future prospects: Future prospects of research may include investigations for the possible pathogenic role of chronic CMV infection in diseases of unknown etiology such as diabetes mellitus, neurological disorders, ischemic heart disease, autoimmune diseases, or cancers especially in cervix, prostate and rectum.     

Experimental syringomyelia: late ultrastructural changes of spinal cord tissue and magnetic resonance imaging evaluation

Seroprevalence for CMV varies from 70% in the general population to more than 90% in HIV infected patients. Immunodepression whatever its origin, either post therapeutic as in transplant recipients, or induced by HIV, leads to the reactivation of this virus, present in a latent form in the host. In CMV-seronegative patients, the main prevention is based on donor matching before a graft (graft of seronegative donor) and on the use of seronegative blood products or deleukocyted blood. Since the availability of efficient strategies of prophylaxis (before infection) or of early treatment (pre-emptive therapy), CMV disease is now infrequent in most transplantation centers. A real prophylaxis with ganciclovir is usually selected in high risk patients (lung, bone marrow transplants in case of a CMV seropositive recipient or seronegative but with a seropositive donor). It has replaced in most centers aciclovir that has only a modest efficacy. A pre-emptive therapy by ganciclovir is proposed in case of lower risk of CMV disease (kidney, liver or heart transplants) or if the local virology laboratory provides sensitive virological markers to detect the first signs of CMV reactivation. Besides viremia or pp65 antigenemia, currently used to initiate a pre-emptive therapy, the standardisation of other virological markers such as leukocytic or plasmatic PCR is in progress. The prophylaxis of CMV disease in less developed for HIV infected patients. Immunosuppression, continuously progressing in absence of antiretroviral agents, requires a continuous prophylaxis for months or years, treatment that is difficult to propose at the present time considering the modest activity of oral ganciclovir, the only oral agent available. Future progresses in this field will be obtained when a sensitive and reproductible CMV marker will allow to identify the patients at highest risk of CMV disease, and with new anti-CMV agents having a good oral bioavailability.     

Prophylactic ganciclovir treatment reduces fungal as well as cytomegalovirus infections after heart transplantation

Cytomegalovirus (CMV) infection is associated with an increased incidence of other opportunistic infections in organ transplant recipients. Whether this is related to immunomodulating effects of CMV or independent of CMV but associated with a host risk factor common to both infections is unclear. The purpose of this study was to determine whether the reduction in CMV infections seen with prophylactic ganciclovir treatment after heart transplantation is associated with a reduced incidence of other opportunistic infections. Of 149 patients prospectively enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of ganciclovir to prevent CMV disease, 74 patients enrolled at this center (33 control and 41 ganciclovir-treated) were retrospectively identified. All received prophylactic OKT-3 and standard 3 drug maintenance immunosuppressive therapy. Actuarial survival and rejection rates and incidence of opportunistic infections (bacterial, fungal, and protozoal) for the 2 treatment groups were determined and compared using Cox-Mantel analysis. CMV disease occurred 2.5 times more frequently in the control group. There were no significant differences in survival or rejection rates nor in bacterial or protozoal infection incidence between the 2 groups. Bacterial infections occurred in 54% of control and 39% of ganciclovir-treated patients (P = 0.18). There were significantly fewer fungal infections in the ganciclovir-treated group (7% vs. 27%, P = 0.0071). CMV and fungal infections were both significantly reduced in patients who received ganciclovir prophylaxis. This suggests that active CMV disease may be causally associated with the development of opportunistic fungal infections.     

Increasing breast and cervical cancer screening in low-income women

Active cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) was treated with an intraocular sustained-release ganciclovir implant. A total number of 19 implants were performed in 15 eyes of 9 AIDS patients. The intraocular sustained-release ganciclovir was effective in preventing reactivation of CMV retinitis in 15 of the 19 implants, ineffective in 3, and undetermined in 1. All ineffective cases had been resistant to ganciclovir therapy before the implants. Vision after the therapy was maintained at better than 0.5 except for one eye. There were no serious ocular complications caused by the therapy. Among 5 patients with unilateral CMV retinitis, 2 unaffected eyes developed CMV retinitis during this therapy. In addition, another patient developed presumed CMV infection in other systemic organs. Based on these data, the intraocular sustained-release ganciclovir implant was considered to be useful for the treatment of CMV retinitis in AIDS.     

Randomized comparison of ganciclovir plus intravenous immune globulin (IVIG) with IVIG alone for prevention of primary cytomegalovirus disease in children receiving liver transplants

A randomized placebo-controlled trial was conducted to determine the benefit of ganciclovir (5 mg/[kg x d]) for 30 days in addition to intravenous immune globulin (IVIG) for 16 weeks for prevention of primary cytomegalovirus (CMV) disease in children receiving liver transplants. Patients were monitored for 6 months after transplantation. The two groups of patients (recipients of 29 ganciclovir plus IVIG and 27 recipients of IVIG alone) were similar in terms of age, sex, and underlying disease. The incidence of CMV disease among the ganciclovir plus IVIG recipients and the IVIG alone recipients was 17% and 26%, respectively, and the time to disease in these recipients was 46 days and 32 days, respectively. There was no difference between groups in terms of survival; episodes of rejection, bacteremia, or fungemia; use of immunosuppressive agents; and incidence of leukopenia or thrombocytopenia. These results suggest that a 4-week course of ganciclovir with IVIG is not more effective than IVIG alone for prevention of primary CMV disease. Since short-term prophylaxis with ganciclovir may delay the onset of CMV disease, further studies with a longer course of ganciclovir prophylaxis are warranted.     

Image manipulation and error estimation for MRI analysis

This trial was designed to compare foscarnet with ganciclovir as pre-emptive therapy for CMV infection in patients undergoing allogeneic hemopoietic stem cell transplant (HSCT). Thirty-nine patients were randomized to receive foscarnet 90 mg/kg every 12 h (n = 20) or ganciclovir 5 mg/kg every 12 h (n = 19) for 15 days at the time of development of CMVAg-emia. Primary-end points of the study were (1) outcome of CMVAg-emia; (2) progression to CMV disease; and (3) side-effects of treatment. The secondary end-point was transplant-related mortality (TRM). The two groups were comparable for diagnosis, status of disease, donor type, acute graft-versus-host (aGVHD) prophylaxis, interval between HSCT and CMVAg-emia and number of CMVAg positive cells; the donor and recipient age were borderline older in the foscarnet group. Increments of serum creatinine in the foscarnet group, and cytopenia in the ganciclovir group were controlled by reducing the administered dose: in the first 15 days of therapy 9/20 foscarnet and 10/19 ganciclovir patients had a dose reduction greater than 20% (P = 0.43). Clearance of CMVAg-emia was faster in the foscarnet group although with borderline statistical significance. Failures of treatment occurred in 3/20 patients in foscarnet group vs 8/19 patients in ganciclovir group (P= 0.06): causes of failure were the need for combination therapy to control antigenemia (1/20 vs 5/19), and reactivation during treatment for 2 vs 3 patients, respectively. CMV disease was diagnosed in 1 vs 2 patients (P = 0.5) who subsequently died. The actuarial 1-year TRM was 25 vs 12%, respectively (P = 0.3). This study suggests that foscarnet and ganciclovir are both effective for pre-emptive therapy of CMVAg-emia, although the number of failures would seem to be slightly higher in the ganciclovir patients. Side-effects are seen in both groups and can be managed with appropriate dose reduction.     

A case of severe cytomegalovirus infection after the repair of coarctation of aorta

We report a 2-month-old boy without any immuno-compromised diseases, who suffered from the severe cytomegalovirus (CMV) infection after the subclavian flap aortoplasty and pulmonary artery banding for coarctation complex. He underwent the operation at 2 months old and received 2 units of irradiated packed red blood cells before and after the surgery. His postoperative course was uneventful but the interstitial pneumonitis, until he developed watery diarrhea 10 days after the surgery following hepatitis with the marked hepatomegaly 3 weeks after. Since CMV infection was confirmed as the cause of the pneumonitis, enterocolitis and hepatitis, he was initially treated by gamma-globulin with the high CMV titer at a dose of 200 mg/kg/day for 2 days and ganciclovir at a dose of 10 mg/kg/day for 14 days. Because of the persistent CMV infection, he needed two more treatments of ganciclovir at the same dosage and gamma-globulin once a week for 2 months. He finally recovered from severe CMV infection 5 months after the above treatments. In conclusion, the severe CMV infection can occur by blood transfusion even in the surgical case with normal immune system. If one finds pneumonitis, hepatitis or enterocolitis after any type of surgery with history of blood transfusion, CMV infection should be suspected as the cause of these diseases.     

Quantitative polymerase chain reaction to predict occurrence of symptomatic cytomegalovirus infection and assess response to ganciclovir therapy in renal transplant recipients

Cytomegalovirus (CMV) DNA levels were measured by quantitative-competitive polymerase chain reaction (PCR) in weekly leukocyte samples from 50 renal transplant recipients, including 23 with symptomatic and 27 with asymptomatic CMV infection. Peak and week 4 CMV DNA levels were higher in symptomatic subjects (P = .07 and .02, respectively). In a logistic regression model, the logarithm of the week 4 level independently predicted symptomatic infection (odds ratio, 1.78 for a 1 log10 increase; 95% confidence interval, 1.14-2.78; P = .01). All subjects whose week 4 level exceeded 1000 copies/100,000 leukocytes developed symptoms. In subjects with adequate samples for analysis, CMV levels declined exponentially with ganciclovir treatment, with an average half-life of 3.3 days. Levels exceeding 10,000 copies were associated with prolonged time to clearing of CMV DNA. Potential clinical applications of quantitative CMV PCR include predicting occurrence of symptomatic first episodes after transplantation and individualizing duration of antiviral therapy.     

Should recurrent Cytomegalovirus infections in patients with liver transplantation be treated?

Cytomegalovirus (CMV) is the single most important viral pathogen in organ transplantation. Treatment strategy for CMV infection and disease is not well established in transplantation. We report a case of primary CMV infection and two relapses in a woman with a liver transplant in whom spontaneous clearing of the second CMV relapse was seen. A 23 year-old CMV-seronegative woman received a liver transplant with a CMV-negative organ. Six weeks after transplantation she had her primary CMV infection proved by seroconversion and virus isolation. She had no clinical symptoms. Treatment with ganciclovir for five weeks resulted in declining CMV-antigen positive cells from 300/200.000 PMNs to CMV-antigen negativity. Only a slight antibody response was seen. At week 13 the first relapse occurred evidenced by antigenaemia. Ganciclovir was reinstituted for six weeks resulting in reduced antigenaemia. At week 22 liver biopsy was performed due to slightly elevated ALAT. The biopsy showed evidence of focal CMV hepatitis and blood analysis showed 120 CMV-antigen positive cells/200.000 PMNs. In spite of this, ganciclovir was not reinstituted, but the immunosuppressive treatment was reduced to a minimum to stimulate the patient's immune response to CMV. During the following months the patient gradually developed IgG antibody, cleared the antigen and levels of liver enzymes returned to normal. We suggest that ganciclovir treatment, may be omitted in cases of relapse with minimal clinical symptoms, slight antigenaemia and a beginning antibody response and that, the immunosuppressive treatment should be reduced instead. Such an approach requires careful clinical monitoring of the patient.     

Comparative study of cytomegalovirus (CMV) antigenemia assay, polymerase chain reaction, serology, and shell vial assay in the early diagnosis and monitoring of CMV infection after renal transplantation

BACKGROUND: Early diagnosis of cytomegalovirus (CMV) infection, which is an important cause of morbidity and mortality in renal transplant recipients, remains of great importance. This prospective study was performed in kidney transplant recipients to determine the diagnostic value of the CMV antigenemia assay in comparison with polymerase chain reaction (PCR), serology, and shell vial assay. METHODS: Seventy-five consecutive renal transplant recipients were enrolled in this study and monitored by both antigenemia assay and serology. The initial 34 of the 75 patients were subjected to PCR and shell vial assay. RESULTS: Antigenemia, PCR, and shell vial assay became positive before the onset of CMV-related symptoms in 31/34 (89%), 13/16 (81%), and 2/16 (13%), respectively. None of the 34 patients who had symptomatic CMV disease showed a significant increase in IgG or IgM before the onset of symptoms. Antigenemia and PCR assays turned positive, 7 and 11 days (median), respectively, before the onset of clinical symptoms. Serology and shell vial assay became positive 21 and 25 days (median), respectively, after the onset of CMV-related clinical symptoms. To examine the clinical value of these assays, "good correlation" was defined based on the correlation between the clinical course and the results of the assays. Good correlation with the antigenemia assay was observed in 33 (96%) out of 34 renal transplant recipients who recovered from their CMV disease after ganciclovir therapy. Only one of 16 (7%) patients showed good correlation by shell vial assay, whereas PCR and serology did not show a good correlation. Consequently, antigenemia was considered the best way to monitor CMV infections after kidney transplantation. CONCLUSIONS: Only the CMV antigenemia assay can be successfully employed after renal transplantation for the early diagnosis and extensive monitoring of active CMV infection.     

Intravitreal injection of cidofovir in cytomegalovirus retinitis

BACKGROUND: CMV retinitis is the most common opportunistic ocular infection and the main cause of blindness in AIDS patients with a T-helper cell count < or = 50/microliter. Cidofovir is a nucleotide analogue with a long half-life time after phosphorylation intracellularly. It is effective against CMV and can be given intravenously and intravitreally. The aim was to offer an alternative therapy for CMV retinitis to patients who could not receive standard treatment because of contraindications or refused it. The efficacy and tolerance of intravitreal injections of cidofovir should be evaluated. PATIENTS AND METHODS: We treated 16 eyes of 12 patients. The total number of injections with 15 micrograms of cidofovir each was 49, with an average of 3 injections per eye. The duration of follow-up was 75-295 days (median 170 days). Probenecid was given concomitantly. Injections were repeated after 6-10 weeks. Secondary prophylaxis of CMV organ infection was done with oral ganciclovir. RESULTS: Within a few days all areas with active retinitis turned into scars following the first injection. Under consequent treatment no reactivation was observed. Four eyes developed a mild iritis with hypotony within a mean time of 12 days after injection. All responded rapidly to topical steroids. None had a persisting loss of vision. Two eyes developed cystoid macular edema (CME). Two patients stopped anti-CMV treatment (ganciclovir orally and injections), followed by a recurrence after an average of 64-days. CONCLUSIONS: Intravitreal injection therapy with 15 micrograms cidofovir and concomitant oral probenecid is a valuable and safe alternative treatment for CMV retinitis in AIDS patients. Its main complication is iritis with hypotony, which is effectively treatable with topical steroids. No complications caused by the injection technique itself were noted. The occasional observation of CME in otherwise quiet eyes, however, is probably drug-related.     

Utility of major leukocyte subpopulations for monitoring secondary cytomegalovirus infections in renal-allograft recipients by PCR

The feasibility of the major peripheral blood leukocyte (PBL) subsets for use in qualitative and quantitative PCR to monitor secondary cytomegalovirus (CMV) infection and ganciclovir therapy was assessed with 188 blood samples derived from 40 CMV immunoglobulin G-positive renal-allograft recipients. In pp65 antigen-positive patients all leukocyte fractions, but only 79.5% of plasma preparations, were PCR positive. In pp65 antigen-negative samples from patients after antiviral treatment only 7.3% of polymorphonuclear cell (PMNL) samples, but 81.8% of peripheral blood mononuclear cells (PBMC), and 10.9% of plasma samples remained PCR positive. Similarly, in patients with latent infections only 5.0% of PMNL, but 51.7% of PBMC preparations, and 8.0% of plasma samples were PCR positive. Regarding patients with active CMV infection, CMV DNA copy numbers in PMNL correlated significantly with pp65 antigen-positive cell counts before and after onset of ganciclovir therapy. Significant differences in CMV DNA copy numbers in PMNL and plasma were observed (i) between patients with symptomatic infection and those with asymptomatic infection and (ii) between patients with active infection and those with latent infection. In contrast, PBMC harbored equally low CMV DNA levels both in patients with active infection and those with latent infections, and no decline of CMV DNA load in PBMC was observed during antiviral treatment. We conclude that detection of CMV DNA in PMNL, not in PBMC, is associated with active infections and is more sensitive than detection of CMV DNA in plasma. Negative PCR results for PMNL after antiviral therapy indicate recovery, and fewer unwanted positive results occur compared to PBMC and plasma. Therefore, purified PMNL should be preferred for analysis by qualitative CMV PCR to avoid unwanted positive results. The CMV DNA load in PBMC compared with that in PMNL is negligible during active infection, so mixed PBL are sufficient for use in quantitative PCR.     

Thrombotic microangiopathy in association with cytomegalovirus infection in a renal transplant patient: a new treatment strategy

BACKGROUND: Cytomegalovirus (CMV) associated with thrombotic microangiopathy (TMA) in transplant patients has not been extensively described. This case illustrates an association between CMV and TMA in a transplant patient with resolution of the latter after treatment of the CMV. METHODS AND RESULTS: At 6 weeks after renal transplantation, a 57-year-old woman presented with TMA. Cyclosporine was discontinued, and plasmapheresis was started. However, the patient continued to deteriorate and developed CMV pneumonitis. Plasmapheresis was discontinued, and intravenous ganciclovir was initiated. Both the TMA and the CMV resolved after initiation of the ganciclovir. CONCLUSION: This case identifies another potential etiological factor in the development of TMA after renal transplantation. It is the first reported case of TMA being cured with treatment of CMV.