The Problem of Cytomegalovirus Infection in Renal Allograft Recipients

A prospective study of the effects of cytomegalovirus (CMV)infection on 145 recipients of 155 renal allografts is reported.Immunosuppression was either with azathioprine and low-dosepred nisolone (103 transplants) or with Cyclosporin A (52 transplants).Sixty-one cases of CMV infection were diagnosed; of those 21were primary (i.e. in CMV sero-negative recipients) and 40 weresecondary (i.e. in previously sero-positive recipients). Theinfection rate in patients treated with azathioprine and low-doseprednisolone did not differ from the rate in those treated withCyclosporin A. Eighteen of the 21 primary CMV infections wereclinically overt; several of these patients became seriouslyill, and one of them died. Only four of the 40 secondary infectionswere overt, and these were all mild. Graft and patient survivalwere not adversely affected by CMV infection. Indeed the groupwith secondary CMV had significantly better survival rates thanthe uninfected sero-positive or sero-negative patient groups.Recommendations to minimise the effects of primary CMV infectionsare given.     

The Effects of Viral Infections on Renal Transplants and Their Recipients

A prospective study of viral infections occurring after 188renal transplants in 167 patients showed active cytomegalovirus(CMV) infection after 52 per cent of transplantations. All 37CMV seronegative cases who received grafts from seronegativedonors remained free of infection, while 24 (70·6 percent) of 34 seronegative recipients whose donors were seropositivedeveloped primary CMV infection (p<0·001). The diagnosisof 92 per cent of these primary infections was made betweenone and two months after grafting. Secondary CMV infection wasfound in 71(62 per cent) of 114 seropositive cases, and thefrequency of infection was not affected by the CMV status ofthe renal donor. Neither acute rejection episodes nor totalgraft rejections were associated with primary or secondary infections.CMV was isolated from a colonic abscess and the relationshipof the virus to the intestinal disease is discussed. Herpes simplex virus was isolated from 47 per cent of casesand 32 per cent had an increase in antibody titre. Zoster wasseen in nine patients, representing an incidence of 3·4per cent per year. Other viral or mycoplasmal infections diagnosedincluded 71 due to respiratory tract pathogens, and a singlecase of hepatitis B. None of these infections was particularlysevere or frequent and no association with graft rejection wasdetected.     

Orthotopic heart transplantation at the 2d Surgical Department of the University of Vienna: 4-year experience

Between March 1984 and August 1988, 89 orthotopic cardiac transplants were performed in 87 patients at the Second Department of Surgery, University of Vienna. 2 patients underwent retransplantation and 3 patients received previously a total artificial heart bridge. Recipients were immunosuppressed with low dose cyclosporine, azathioprine and since May 1986 with additional low dose prednisolone; all patients were supplemented perioperatively with either ATG or OKT3. 1-year survival rates continuously increased from 33% in 1984 to 88% in 1987 (p = 0.07). The one-year survival rate in recipients given double drug therapy (cyclosporine and azathioprine) was 43% as compared with 77% on triple therapy (cyclosporine, azathioprine and prednisolone, p = 0.003). Acute rejection was the leading cause of death. These data indicate that the substantial improvement in survival rates is attributable to augmented immunosuppression and to improved patient management and recipient selection.     

Long-term use of cyclosporin in liver grafting

The clinical course of 29 liver graft recipients in the Cambridge/King's College Hospital series who have received cyclosporin A (CyA) for up to five years (median 40 months) was analysed with particular reference to the immunosuppressive effectiveness and adverse effects of the drug. Eight patients had been maintained on prednisolone and azathioprine for two to six years before treatment was changed to cyclosporin A and the remainder were started on cyclosporin A after operation. Results in both groups over a one to five year study period are similar, and showed that cyclosporin A was effective in maintaining adequate immunosuppression, allowing complete withdrawal of prednisolone in 16 patients. Episodes of rejection were observed in only three patients and in two of these it was of the chronic 'vanishing bile duct' variety. Some evidence of nephrotoxicity (serum creatinine greater than 150 mumol/l) occurred in 72 per cent (21 of 29 patients) but it was necessary to discontinue treatment in only two. Hypertension, occasionally of sudden onset, was found in nine patients and led to the withdrawal of the drug in two. Additional hypotensive drug treatment was required in five. In one other patient cyclosporin A was discontinued on account of severe headaches. Cyclosporin A was withdrawn in two further patients. Withdrawal led to considerable risk of acute rejection and increased doses of corticosteroids as well as substitution of azathioprine were required at that time.     

Detection of cytomegalovirus-specific IGM in renal transplant recipients

We have compared two IgM-specific cytomegalovirus (CMV) antibody assays, an immunofluorescence assay (IFA-M) and an enzyme-linked antigen immunoassay (ELA-M), with an assay for CMV total antibody (ELISA) and viral culture for the detection of active CMV infection in renal transplant recipients. Of 75 patients (49 ELISA negative pretransplant, 26 ELISA positive), CMV-specific IgM was detected in 35 (27 ELISA negative pretransplant, 8 ELISA positive) using the IFA-M assay and in 25 (16 ELISA negative pretransplant, 9 ELISA positive) using the ELA-M test. Of the 25 patients identified as positive by ELA-M, 21 had positive viral cultures post-transplant, two seronegative patients had evidence of infection indicated by post-transplant seroconversion, and two patients were seropositive pretransplant but remained viral culture negative throughout the follow-up period. ELA-M and CMV total antibody ELISA detected primary infection in renal transplant recipients equally well, but ELA-M was found to be superior to ELISA and IFA-M for detecting reinfection and reactivation infections.     

异基因造血干细胞移植后实时定量聚合酶链反应在巨细胞病毒感染诊断和治疗中的应用

目的 探讨异基因造血干细胞移植(allo-HSCT)后应用实时定量聚合酶链反应(RQ-PCR)技术检测血浆巨细胞病毒(CMV)DNA载量,诊断CMV感染及指导临床抗CMV治疗的意义.方法 统以318例接受allo-HSCT患者为研究对象,其中同胞HLA相合HSCT患者160例,血缘关系配型不合127例,非血缘关系移植31例.移植前供受者采用ELISA方法 进行CMV血清学抗体检测.移植后采用RQ-PCR方法 检测血浆CMV DNA,6×102拷贝数/ml为CMV PCR阳性.全部患者在预处理阶段-9 d到-2 d应用更昔洛韦预防CMV感染.抢先治疗主要应用更昔洛韦或膦甲酸钠,或两药联合治疗.结果 移植后100天(+100 d)内CMV感染累计发生率40.6%,同胞相合、血缘关系配型不合及非血缘关系移植三种移植方式,+100 d内CMV感染累计发生率分别为17.5%、66.1%、45.2%.无论是单因素还是多因素分析均表明,血缘关系配型不合移植和非血缘关系移植,预处理方案中使用抗胸腺细胞球蛋白(ATG)以及中重度急性移植物抗宿主病是导致CMV感染发生的危险因素.在早期应用抢先治疗后,总体+100 d内CMV病累计发生率为8.8%.三种移植方式+100 d内CMV病累计发生率分别为5.6%、9.4%、22.6%.且三种移植方式CMV感染患者2年生存率差异无统计学意义.结论 allo-HSCT后RQ-PCR检测血浆CMV DNA可有效用于CMV感染诊断和监测,并有利于指导临床抗CMV治疗,减少移植后CMV感染高危患者CMV疾病的发生.     

High levels of circulating cytomegalovirus DNA reflect visceral organ disease in viremic immunosuppressed patients other than marrow recipients.

Although viremia is a hallmark of disseminated cytomegalovirus (CMV) infection, not all viremic patients have visceral organ CMV disease. We used blot hybridization with a cloned subgenomic probe to quantitate viral DNA in blood leukocytes of 60 viremic patients (25 with solid organ transplants, 20 with AIDS, and 15 marrow recipients) who had different clinical manifestations of CMV infection. The results are expressed as pg of viral DNA/10 micrograms of leukocyte DNA. Patients with AIDS or with solid organ transplants who had CMV visceral organ disease had the largest amounts of viral DNA in their granulocytes (median 632 and 237 pg, respectively). These amounts were significantly greater than those in similar viremic patients without CMV visceral disease (17 and 21 pg; P < 0.005 and 0.002, respectively). All patients in the study with > 150 pg of CMV DNA in their granulocytes had visceral CMV disease. The amounts of viral DNA in granulocytes of AIDS and organ transplant patients with CMV retinitis were low (median 22 pg). Marrow transplant patients were unique in that the amounts of CMV DNA in granulocytes were low whether CMV visceral organ disease was present (17 pg) or absent (14 pg). We conclude that high levels of circulating CMV DNA in viremic AIDS and solid organ transplant patients reflect viral involvement of visceral organs but not the retina. In marrow recipients, the severity of CMV disease, even when fatal, is not reflected quantitatively in peripheral blood leukocytes.     

The risk of transfusion-acquired CMV infection in seronegative solid-organ transplant recipients receiving non-WBC-reduced blood components not screened for CMV antibody (1984 to 1996): experience at a single Canadian center

BACKGROUND: The use of CMV-safe cellular blood components has been recommended for CMV-sero- negative recipients of CMV seronegative (R-D-) solid- organ transplants. STUDY DESIGN AND METHODS: The incidence of CMV infection in 281 CMV-seronegative patients receiving renal, heart, heart-lung, lung, and liver transplants at our center between January 1984 and October 1996 was studied. The blood components that these patients received were neither WBC reduced nor screened for CMV antibody. RESULTS: One hundred thirty-one of 154 (85.1%) patients receiving organs from CMV-seropositive donors (R-D+) developed CMV infection compared with three cases of presumptive transfusion-acquired (TA) CMV infection in 127 R-D- recipients (2.4%) (relative risk, 36.0; 95% CI, 11.8-110.4). The organ-specific incidence of TA CMV infection in R-D- patients was as follows: renal, 0 of 57 (0%); heart, 0 of 29 (0%); heart-lung and/or lung, 1 of 6 (16.7%); and liver, 2 of 20 (10%). There was no significant difference in the transfusion requirements of CMV-infected and -uninfected R-D- patients. False-positive results were often (40%) observed when posttransfusion serum samples were used for determination of the organ donor CMV serostatus. CONCLUSION: The low risk of TA CMV infection observed in transplant patients who received standard blood components in our study should be considered when evaluating the efficacy of programs that provide CMV-safe blood components for this population.     

The impact of blood transfusion on the occurrence of pneumonitis in primary cytomegalovirus infection after liver transplantation

The influence of blood transfusion, and particularly the transfusion of blood from cytomegalovirus (CMV)-seropositive donors, on the incidence of primary CMV infection following liver transplantation was studied prospectively in 29 consecutive CMV-seronegative adult liver transplant recipients. Fourteen patients received a liver graft from a CMV- seropositive donor (Group A), whereas for 15 patients, the donor was CMV seronegative (Group B). Eleven patients (79%) in Group A but only two (13%) in Group B developed CMV infection (odds ratio, 23.8; 95% confidence interval, 3.5-169.4). In five Group A patients, primary CMV infection resulted in pneumonitis. There was no statistical difference in the total number of blood units and the number of units of CMV- seropositive blood given to patients who did or did not develop CMV infection in both Groups A and B (odds ratio for unit of CMV- seropositive blood transfused, 1.07; 95% confidence interval, 0.96- 1.19). However, Group A patients who developed CMV pneumonitis received a higher total number of blood units (median, 44) and of CMV- seropositive blood units (median, 18) than did patients who developed other CMV infections (asymptomatic CMV, CMV syndrome, or CMV hepatitis), who received a median of 9 total units of blood and 5 units of CMV-seropositive blood (p = 0.004). It is concluded that the total number of blood units and of CMV-seropositive blood units transfused does not have an effect on the incidence of primary CMV infection after liver transplantation, but it does have an impact on the severity of the infection in recipients of a CMV-seropositive allograft.     

Long-term graft survival with or without donor-specific transfusion in cyclosporine era in one haplo-identical living-related renal transplant recipients beyond the first year: a 19-year experience

With improvement in immunosuppressive drugs, the beneficial role of donor-specific blood transfusion (DST) in the preconditioning of renal allograft recipients has been diminished. This retrospective study was conducted to investigate the influence of DST on long-term graft survival in successful one haplotype-mismatched kidney transplantation in the cyclosporine (CsA) era at Iwate Medical University. Between August 1983 and October 1996, 52 one haplotype-mismatched living related first renal transplants were performed. Fifty grafts survived beyond the first year after transplantation. These 50 patients were divided into two groups according to maintenance immunosuppression, 12 kidney graft recipients received azathioprine (AZA), prednisolone (PSL), CsA, and DST, and 38 recipients received AZA, PSL and CsA. Our DST protocol consisted of three transfusions of 30 ml of donor-specific buffy-coat at 4-week intervals, without immunosuppressive coverage. In recipients receiving DST and CsA, the 5-, 10-, and 13-year graft survival rates were 100%, 83%, and 67%, respectively. In recipients without DST, the 5-, 10-, and 13-year graft survival rates were 95%, 74%, and 69%, respectively. There was no significant difference between the two groups in long-term graft survival. In conclusion, DST and CsA combination treatment in our protocol may not induce long standing donor-specific immunologic hyporesponsiveness. Other strategies are expected to induce immunotolerance.     

Können CMV-Infekte nach Herztransplantation durch dreimonatige antivirale Prophylaxe reduziert werden? 7 Jahre Erfahrung mit Ganciclovir

BACKGROUND: In the early phase after heart transplantation (HTX) patients are at high risk for infection because of intensified immunosuppression. This retrospective study evaluates the efficacy of a three-month antiviral cytomegalovirus (CMV) prophylaxis. Patients and methods: 133 patients received a three-month combined intravenous and oral CMV prophylaxis with Ganciclovir (Cymevene after HTX between 1997 and April 2003 (group II). They were compared to a historical group consisting of 40 patients, who had undergone HTX between 1995 and 1996 (group I; CMV-prophylaxis: hyperimmune globuline (Cytotect) for the first post-operative month in combination with orally administered aciclovir (Zovirax) for 6 months). Demographic data of organ recipients and donors in both groups were comparable, except for underlying cardiac diseases (p = 0.016). All patients had identical postoperative immunosuppressive regimes. RESULTS: Group II had a significantly lower mortality rate (GI: 37.5%, GII: 9.8%; p < 0.001); one year survival (p = 0.001) and overall survival (p = 0.001) were significantly better than in group I. Patients of group II had fewer rejection episodes > or = grade II ISHLT requiring treatment (p < 0.001). Group II presented significantly fewer positive CMV blood samples (p = 0.005) and CMV infections (26% versus 47,5% in GI; p = 0.008), and a later onset of infections after HTX than group I (group I with a mean interval of 5.8 weeks after HTX, group II: 24.8 weeks after HTX; p < 0.001). CONCLUSION: Incidence of CMV infection was significantly lowered under ganciclovir prophylaxis, infections occurred at a later time point after HTX, when patients were immunologically more competent. The proportion of higher grade rejection episodes was markedly reduced and survival was improved.     

Bilateral cytomegalovirus retinitis in a patient with systemic lupus erythematosus and end-stage renal disease

Rheumatic diseases are not commonly associated with cytomegalovirus (CMV) retinitis. We report a case of bilateral CMV retinitis in a human immunodeficiency virus-seronegative patient with systemic lupus erythematosus (SLE) who was undergoing hemodialysis for end-stage renal disease. The CMV retinitis in this patient was associated with combined azathioprine and low-dose corticosteroid therapy for lupus flare. This association may have important clinical implications because this drug combination is used routinely to treat active SLE. Our patient responded to discontinuation of azathioprine, reduction of the corticosteroid dose, and systemic administration of ganciclovir. We recommend that clinicians maintain heightened awareness of the possibility of CMV retinitis in patients with SLE and end-stage renal disease who are receiving azathioprine and low-dose corticosteroids.     

Prophylactic use of hyperimmunoglobulin for cytomegalovirus infection in heart transplantation

Cytomegalovirus (CMV) infection in solid organ recipients can endanger the immunosuppressed patient and increase vulnerability to secondary infections and the high risk of rejection triggered by the viral disease. The effect of passive immunization against CMV was examined in 69 heart transplant patients. The patients received weekly administrations of 1 ml/kg of CMV hyperimmunoglobulin from the day of transplantation until the 30th postoperative day. Forty-four of the patients were monitored clinically and serologically up to the 120th postoperative day. Nine patients showed clinical and serologic signs of CMV infection; in 15 the only evidence of CMV infection was a rise in antibody titers. The remaining 20 patients showed no clinical or serologic signs of CMV infection. Three patients who were seronegative preoperatively remained seronegative until the end of the observation period. The results indicate a potential therapeutic benefit of hyperimmunoglobulin prophylaxis to prevent infectious complications due to CMV in heart transplant patients.     

Prevention and management of cytomegalovirus infection in solid-organ transplantation

Cytomegalovirus (CMV) is the most common opportunistic viral infection to occur following solid-organ transplantation. This review will discuss the current strategies of management of CMV in solid-organ transplantation and their challenges. There are two principal approaches for preventing CMV disease in recipients of solid-organ transplants: prophylactic and pre-emptive. Ganciclovir is the most studied and used antiviral for both treatment and prevention, and is the first-line treatment for CMV infection and CMV disease in transplant recipients. There is no consensus regarding the most appropriate prevention method and the approach to CMV disease prevention differs among transplantation centers owing to the paucity of data comparing the two strategies head-to-head. Currently, the recommended treatment for CMV disease is intravenous ganciclovir.     

Red cell antibodies arising from solid organ transplants

RBC antibodies arising from transplanted organs and directed against recipient RBCs represent a well-established immunohematologic complication of solid organ transplantation. In ABO-unmatched organs, the frequency and severity of graft antibodies and hemolysis generally increase with the size (lymphoid content) of the organ, from kidney to liver to heart-lung transplants. In the cases reviewed here, the frequency of hemolysis increased in cyclosporine-treated kidney transplant recipients and O-to-A liver transplant recipients and decreased in group AB liver transplant recipients and kidney transplant recipients receiving azathioprine or low-dose postoperative graft irradiation. Available data cannot otherwise distinguish which cyclosporine-treated recipients of ABO-unmatched kidneys and livers (30-40% of total) will develop graft antibody. There has been no conclusive effect to date of the age, race, or gender of the donor or the recipient, of cadaver versus living kidney donors, or of patients' A2 or secretor status. In a few cases of living-donor kidney grafts, the donor was the patient's mother or wife who had been exposed to the recipient's RBC antigens via pregnancy. The ABO antibodies are typically IgG, appear 7 to 10 days after transplantation, and last for about a month. If immediate-spin crossmatching is done routinely, DATs are recommended in compatibility testing after ABO-unmatched transplants. Changes in the immunosuppressive regimen, such as a change from cyclosporine therapy, have not affected the duration of these antibodies. Most patients require only transfusions for this self-limited process, but six cases of hemolysis-induced acute renal failure have been reported, and one death was attributed to complications of hemolysis. RBC or plasma exchange has been performed in a few fulminant cases. RBCs of the donor's blood type are given when antibody appears. Some workers recommend such transfusion as prophylaxis at the time of surgery, although in liver transplants, the plasma accompanying a large amount of group O RBCs given perioperatively might be problematic. In several other centers, ABO-unmatched liver transplants have equivalent overall graft survivals, but the Pittsburgh adult patients with hemolysis have had reduced early graft survival. In the cases reviewed here, nine IgG Rh antibodies from kidney grafts directed against recipient RBCs have been observed, usually beginning 2 to 3 weeks after a cyclosporine-treated transplant, lasting for 2 to 6 months after operation, and causing mild hemolysis. One case represented a primary immune response from a previously unsensitized donor.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cytomegalovirus infection

Interest has focused on cytomegalovirus (CMV) infections during recent years for two reasons: First, the number of immunocompromised patients with CMV infections has risen continuously and, secondly, recent advances in basic research have clarified some of the mechanisms of persistent and recurrent CMV infection. Three different clinical pictures can arise with CMV infection. In healthy individuals most of the CMV infections are not clinically apparent. In immunocompromised patients CMV causes a wide spectrum of diseases and is one of the predominant causes of death in AIDS patients and bone marrow transplant recipients. The most important problem for public health associated with CMV are connatal and perinatal CMV infections. Progress has been made with treatment of CMV infection in immunocompromised patients with inhibitors of viral replication.     

Evaluation of eight commercial enzyme-linked immunosorbent assays for detecting CMV-specific IgM antibodies in organ transplant recipients

Eight commercially available enzyme-linked immunosorbent assays (ELISAs) for detecting cytomegalovirus (CMV) IgM antibodies were evaluated with 152 serum samples collected from 36 organ transplant recipients with evidence of CMV infection. A further 32 samples collected from patients with other virus infections and 11 sera containing rheumatoid factor were also included in the evaluation. The sensitivities of the assays ranged from 57.9–95.6% and the specificities from 80.0–100.0% when the results obtained with the samples collected from transplant recipients were assessed. When samples collected from patients with other infections and the rheumatoid factor positive samples were tested the specificities of the ELISAs ranged from 68.3–95.5%.     

Treatment of cytomegalovirus infections beyond acute disease to improve human health

Human cytomegalovirus is a common virus that establishes latency and persistence after a primary infection in 50–90% of populations worldwide. In otherwise healthy persons, the infection is generally mild or asymptomatic, although it may cause mononucleosis, prolonged episodes of fever, and hepatitis. However, in AIDS patients and transplant recipients who are immunosuppressed, severe, life-threatening infections may develop. CMV is also the most common congenital infection and may cause birth defects and deafness. Emerging evidence shows a high prevalence of this virus in patients with chronic inflammatory diseases or tumours of different origin, such as breast, colon, and prostate cancer, neuroblastoma, medulloblastoma, and glioblastoma. Several drugs are available to treat CMV infections. This review will highlight the possibility of using anti-CMV therapy to improve outcome not only in patients with acute CMV infections but also in patients with inflammatory diseases and cancer.     

Infection and Immunosuppression: A STUDY OF THE INFECTIVE COMPLICATIONS OF 75 PATIENTS WITH IMMUNOLOGICALLY-MEDIATED DISEASE

We have studied the infective complications in a group of 75patients with immunologically-mediated disease who requiredhigh dose immunosuppression. There were 22 patients with anti-glomerularbasement membrane antibody disease, 19 patients with systemiclupus erythematosus, 18 with Wegener's granulomatosis and 16patients with other forms of systemic vasculitis. The infection rate was 3.69 infections/patient, or 0.74 infections/patient/weekof immunosuppression. Bacteria were the commonest infectingorganisms (76.1 per cent); serious opportunist viral and fungalinfections were less frequent (10.7 per cent) but opportunistpneumonias were an important cause of death. Sixteen patientsdied (21 per cent) and in 10 of these (62.5 per cent) deathwas considered to be primarily due to infection. Analysis of six aspects of host susceptibility to infection(age, renal function, dose of prednisolone, cyclophosphamideand azathioprine, and number of plasma exchanges) revealed nosingle factor as predisposing to infection in the whole group,but in 23 patients who suffered severe infective complications,renal impairment and increasing doses of prednisolone were associatedsignificantly, particularly in combination (p = 0.06). Cyclophosphamidewas associated with infection only in the presence of neutropenia,which was rare (13 infections in nine patients). The durationof plasma exchange was not related to the frequency of infection. Fifty patients needed an arteriovenous shunt to provide vascularaccess for haemodialysis or plasma exchange, and septicaemiaoccurred in 13; only two episodes of septicaemia were seen inpatients without a shunt.     

Donor seropositivity and prednisolone therapy as risk factors for cytomegalovirus infection and disease in cyclosporin-treated renal allograft recipients

We attempted to assess the importance of blood transfusion, donor seropositivity, and prednisolone therapy as risk factors for cytomegalovirus infection in cyclosporin-treated renal allograft recipients. Primary infection was diagnosed in 27 of 86 patients (31 per cent) and recurrent infection in 27 of 79 patients (34 per cent). Receipt of banked blood from unselected donors after transplantation did not increase the incidence of primary infection in the few transfused patients. Kidney donor seropositivity and maintenance prednisolone in addition to cyclosporin were associated with increases in the incidence of primary or recurrent infection, respectively. Cytomegalovirus infection was clinically mild. Presumed bacterial pneumonias occurred in three patients with recurrent cytomegalovirus infection. The absence of severe cytomegalovirus disease probably reflected the minimal use of prednisolone. Matching of seronegative donors with seronegative recipients seemed unjustifiable in cyclosporin-treated renal transplant patients.