The role of pretransplant immunity in protection from cytomegalovirus disease following renal transplantation

To determine the extent to which pretransplant immunity resulting from natural infection protects against cytomegalovirus (CMV) disease, we analyzed CMV serology on 153 kidney donor and recipient pairs and followed transplant patients to determine incidence and severity of CMV disease. The overall incidence of CMV disease was 22%. Significant differences occurred in CMV disease incidence and severity, depending on the immune status of the kidney donor and recipient. Among recipients of kidneys from seropositive donors, immunity offered significant protection from CMV disease, reducing its incidence from 61% in nonimmune to 24% in immune patients (P less than 0.01). Pretransplant immune patients also had fever CMV-related complications. Among recipients of kidneys from seronegative donors, pretransplant immunity conferred a significant risk of CMV disease; immune patients had a 20% incidence of CMV disease compared with 2% in nonimmune patients (P less than 0.02). Disease was generally mild in all patients receiving kidneys from CMV infection had a 3-fold higher incidence of CMV disease than patients with reactivation infection (P less than 0.01). The incidence of CMV disease was similar in immune patients, whether they received a kidney from a seropositive or a seronegative donor. However, an important observation was that disease was significantly more severe in immune patients receiving a kidney from a seropositive donor (P less than 0.05). This indicates that if kidneys from seropositive donors are selected for use only in seropositive recipients, this places the immune patient at a higher risk for severe CMV disease. We conclude that pretransplant immunity offers a significant advantage to patients receiving kidneys from seropositive donors.     

Monitoring of human cytomegalovirus infections in heart transplant recipients by pp65 antigenemia

BACKGROUND: Rapid diagnostic techniques offer the opportunity of early diagnosis of human cytomegalovirus (CMV) infection in immunocompromized patients at risk of developing CMV disease and syndrome. The use of CMV pp65 antigenemia as a predictor of CMV syndrome and disease in heart transplant recipient after induction therapy was studied retrospectively. METHODS: One hundred and nineteen consecutive heart transplant recipients treated with induction therapy who survived more then 14 d were monitored for CMV infection. Ninety-four recipients were seropositive for CMV. Twenty-five recipients were seronegative for CMV and received grafts from seropositive donors. Pre-emptive therapy was used in seropositive patients when CMV pp65 antigenemia was greater than 50 antigen-positive cells per 2 x 10(5) peripheral blood leukocytes (PBL); prophylactic therapy was done only in seronegative recipient matched with seropositive donor. RESULTS: High-level CMV pp65 antigenemia (50 antigen-positive cells 2 x 10(5) PBL) occurred in 34% (41 of 119) of patients at a median of 44 d following transplantation. In seropositive recipients, 16% (15 of 94) of patients developed CMV invasive disease or syndrome, and in seronegative recipients 20% (5 of 25) of patients developed CMV disease or syndrome. Sixty-six per cent (62 of 94) of CMV seropositive patients were identified as not requiring pre-emptive therapy. In seropositive and seronegative recipients, the sensibility and negative predictive value of the cut-off level of 50 antigen positive cell for CMV disease and syndrome was 100%. The specificity was 79% and positive predictive value was 49%. CONCLUSION: Because of the excellent sensibility and negative predictive value of the cut-off level of 50 antigen positive cell per 2 x 10(5) PBL, application of pre-emptive therapy guided by high level of CMV pp65 antigenemia in the context of induction therapy allow to omit antiviral therapy in many at risk patients. In the context of pre-emptive and prophylactic therapy, the cut-off level of 50 antigen positive cell do not allow to predict with accuracy the development of CMV disease or syndrome.     

The impact of donor cytokine gene polymorphisms on the incidence of cytomegalovirus infection after kidney transplantation

Cytomegalovirus (CMV) seronegative recipients of kidneys from CMV seropositive donors are at a high risk of CMV infection after transplantation since viruses in the allograft may reactivate in patients without prior immunity. We hypothesized that the genetic background of the graft has an influence on the incidence of infection. Effects of IL10, IL6 and IFNG gene polymorphisms, known to affect CMV infectivity, were investigated in 71 CMV seronegative recipients of grafts from CMV seropositive cadaver donors. Donor IL10(-1082 AA) genotype reduced the incidence of CMV infection (p=0.031) and CMV episodes in these patients tended to occur later (AA: median 83 days, AG/GG: median 45 days, p=0.072). In multivariate analysis, other explaining factors than the donor IL10(-1082 AA) genotype alone did not improve Cox hazard model (HR=0.3, 95% CI=0.09-0.96, p=0.043). Recipient polymorphisms did not reduce the incidence of CMV infection. We conclude that donor IL10 gene polymorphisms may influence the likelihood of CMV infection in the high risk patients investigated.     

Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3.

A prospective study to investigate risk factors for CMV disease was conducted in 94 renal transplant recipients. CMV disease was defined as either unexplained fever for greater than 3 days with viremia or unexplained fever for greater than 3 days with isolation of CMV from the urine or throat wash and at least one of the following: leukopenia, elevated serum alanine aminotransferase, or biopsy-proved invasive tissue infection of the lung or gastrointestinal tract. Fifty-three patients received immunosuppressive regimens consisting of prednisone and cyclosporine, with or without azathioprine. The remaining 41 patients were treated with these agents plus OKT3 (21 received OKT3 to treat rejection, 20 received OKT3 prophylactically). Thirty-seven patients were at minimal risk of CMV disease (donor and recipient seronegative for CMV); 12 patients were at risk of primary disease (donor seropositive, recipient seronegative), and 45 were at risk of reactivation disease (recipient seropositive at the time of transplantation). The incidences of CMV disease in the 3 groups were 0%, 58%, and 36%, respectively. Although the incidence of CMV disease in patients at risk of primary disease was not influenced by the immunosuppressive regimen, immunosuppression had a profound effect on the occurrence of CMV disease in CMV-seropositive transplant recipients. The incidence of CMV disease in those receiving OKT3 was 59%; but only 21% in those who did not receive OKT3. OKT3 increased the risk of CMV disease five-fold (odds ratio 5.2 (95% confidence limits 1.4-17.5)). In the CMV-seropositive patient, OKT3 was also the most important predictor of CMV disease by multivariate analysis (P less than 0.002). A pilot study of preemptive therapy with ganciclovir (2.5 mg/kg daily during OKT3 therapy) in 17 patients decreased the incidence of CMV disease without appreciable toxicity.     

Primary and reactivated HHV8 infection and disease after liver transplantation: a prospective study

Human herpesvirus 8 (HHV8) is pathogenic in humans, especially in cases of immunosuppression. We evaluated the risk of HHV8 transmission from liver donors, and its clinical impact in southern Italy, where its seroprevalence in the general population is reported to be as high as 18.3%. We tested 179 liver transplant recipients and their donors for HHV8 antibodies at the time of transplantation, and implemented in all recipients a 12-month posttransplant surveillance program for HHV8 infection. Of the 179 liver transplant recipients enrolled, 10.6% were HHV8 seropositive before transplantation, whereas the organ donor's seroprevalence was 4.4%. Eight seronegative patients received a liver from a seropositive donor, and four of them developed primary HHV8 infection. Two of these patients had lethal nonmalignant illness with systemic involvement and multiorgan failure. Among the 19 HHV8 seropositive recipients, two had viral reactivation after liver transplantation. In addition, an HHV8 seronegative recipient of a seronegative donor developed primary HHV8 infection and multicentric Castleman's disease. In conclusion, primary HHV8 infection transmitted from a seropositive donor to a seronegative liver transplant recipient can cause a severe nonmalignant illness associated with high mortality. Donor screening for HHV8 should be considered in geographic areas with a high prevalence of such infection.     

Relationship Between HLA Tissue Type, CMV Infection, and Acute Graft-vs-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: Single-Center Experience

After allogeneic hematopoietic stem cell transplantation, risk factors for cytomegalovirus (CMV) reactivation include pretransplantation donor and recipient CMV serologic status and posttransplantation development of acute graft-vs-host disease (aGvHD). Human leukocyte antigen (HLA) allele type is an additional factor in CMV infection. The present study included 108 patients who received an allogeneic stem cell graft from an HLA-identical sibling between 1993 and 2004. All recipients and donors were typed for HLA-A, HLA-B, and HLA-DR alleles using serologic or molecular methods. All recipients received grafts because of a hematologic disease from HLA full-matched donors. In pretransplantation seropositive patients with aGvHD, no significant difference was observed in patients who developed CMV infection compared with those without CMV infection. Seropositive patients without aGvHD but with posttransplantation CMV infection demonstrated a higher incidence of HLA-A30, HLA-B40, and HLA-DRB1*15 compared with those without CMV infection. In conclusion, it seems that certain HLA alleles may have either a protective or predisposing role in CMV reactivation, which might be helpful in estimating the risk of aGvHD and designing individualized therapy.     

Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation

Twenty-seven patients received pulmonary transplants during the period since we began routine use of cytomegalovirus-seronegative blood products for CMV-seronegative recipients. Preoperative serologic status of the recipient and the occurrence of cytomegalovirus infection in the postoperative period were correlated with development of obliterative bronchiolitis (OB) as diagnosed by transbronchial biopsy (TBB). Patients included 20 heart-lung and 7 double-lung recipients. OB occurred in 18 of 27 patients. All 3 CMV seronegative recipients receiving lungs from a seropositive donor and 9 of 10 CMV recipients seropositive at the time of transplantation developed OB compared with only 6 of 14 CMV seronegative patients receiving seronegative grafts (P = 0.018). CMV infection occurred in 10/27 patients, of whom 5 were asymptomatic; 90% of these patients developed OB. Donor-specific alloreactivity, based on primed lymphocyte testing (PLT) of bronchoalveolar lavage cells was found at the time of diagnosis of OB in 23 of 27 patients. A positive PLT was significantly associated with the presence of OB (P = 0.017). We conclude that preoperative seropositive status for CMV, grafting of organs from seropositive donors, and postoperative CMV infection are significant risk factors for developing OB. That OB is, in part, an immunologically mediated form of injury and represents chronic rejection is supported by the presence of donor-specific alloreactivity in BAL lymphocytes from all recipients with OB.     

肾移植术后的巨细胞病毒感染及其对急性排斥反应的影响

目的 探讨肾移植受者术后活动性巨细胞病毒（ＣＭＶ）感染的发生率、感染的原因以及ＣＭＶ感染对急性排斥反应的影响。方法 检测１８７例肾移植受者和供者术前血清抗－ＣＭＶ抗体;受者术后定期检测体内ＣＭＶ ＤＮＡ、对ＣＭＶ ＤＮＡ阳性的部分患者给予抗ＣＭＶ治疗,并比较各组排斥反应的发生率。结果 无论是供者还是受者,术前如血清抗－ＣＭＶ抗体阳性,受者术后发生活动性ＣＭＶ感染者明显增多,这些患者急性排斥反应的发     

Cytomegalovirus infection and development of biliary complications after liver transplantation

BACKGROUND: Cytomegalovirus (CMV) infection is known to cause ulceration and mucosal hemorrhage in the gastrointestinal tract. Gastroduodenal and biliary complications were prospectively evaluated in 100 consecutive liver transplant patients in whom CMV was monitored during the first posttransplant year. METHOD: Gastroduodenal biopsy specimens were taken from 36 patients by endoscopies and in 28 patients by endoscopic retrograde cholangiopancreatography, and bile duct specimens were taken from three patients who underwent surgical reconstruction because of biliary complication. CMV was demonstrated from blood by the pp65 antigenemia test and from frozen sections of tissue specimens by immunohistochemistry and in situ hybridization. RESULTS: Symptomatic CMV infection, treated with ganciclovir, developed in 49 recipients: 13 (100%) of CMV seropositive donor (D+) seronegative recipient (R-) cases, 29 (45%) D+/R+ cases, and 7 (32%) D-/R+ cases. Duodenal ulcer developed in three and hemorrhagic gastritis in three recipients. CMV antigens were found from the gastroduodenal mucosa in 37 (69%) of the 54 studied recipients. The biliary complication rate was 24%. Preceding or concomitant CMV antigenemia was demonstrated in 75% of patients with a biliary complication (68% in CMV D+/R+ or D-/R+ and 100% in D+/R- recipients). The biliary complication rate was higher among recipients with CMV antigenemia, compared with recipients without (P<0.05). CMV antigenemia, CMV infection, or both in the duodenal mucosa was found in 96% of patients with a biliary complication. In two patients who underwent surgical reconstruction, CMV antigens and DNA were demonstrated in the bile ducts. CONCLUSIONS: Liver transplant patients are at risk of developing biliary complications after CMV infection, especially those with primary CMV infection.     

CMV seronegative donors: Effect on clinical severity of CMV infection and reconstitution of CMV-specific immunity

BackgroundCytomegalovirus (CMV)-specific T-cells are crucial to prevent CMV disease. CMV seropositive recipients transplanted with stem cells from a CMV seronegative allogeneic donor (R⁺D⁻) may be at risk for CMV disease due to absence of donor CMV-specific memory T-cells in the graft.MethodsWe analyzed the duration of CMV reactivations and the incidence of CMV disease in R⁺D⁻ and R⁺D⁺ patients after alemtuzumab-based T-cell depleted allogeneic stem cell transplantation (TCD alloSCT). To determine the presence of donor-derived primary CMV-specific T-cell responses we analyzed the origin of CMV-specific T-cells in R⁺D⁻ patients.ResultsThe duration of CMV reactivations (54 versus 38 days, respectively, p = 0.048) and the incidence of CMV disease (0.14 versus 0.02, p = 0.003 at 1 year after alloSCT) were higher in R⁺D⁻ patients compared to R⁺D⁺ patients. In R⁺D⁻ patients, CMV-specific CD4⁺ and CD8⁺ T-cells were mainly of recipient origin. However, in 53% of R⁺D⁻ patients donor-derived CMV-specific T-cells were detected within the first year.ConclusionsIn R⁺D⁻ patients, immunity against CMV was predominantly mediated by recipient T-cells. Nevertheless, donor CMV serostatus significantly influenced the clinical severity of CMV reactivations indicating the role of CMV-specific memory T-cells transferred with the graft, despite the ultimate formation of primary donor-derived CMV-specific T-cell responses in R⁺D⁻ patients.     

Cytomegalovirus infection in the first year after pediatric kidney transplantation

Cytomegalovirus is common in adult recipients (prevalence of 40–90%). Children are typically seronegative but immunosuppression may prone to primary-infection or viral reactivation, with potentially severe consequences. CMV infection incidence in pediatric kidney transplant recipients has seldom been investigated. The aim of our study was to evaluate the incidence and timing of CMV infection during the first year after renal transplantation. We assembled a retrospective cohort of 136 children who had received a kidney transplant between 2003 and 2014 with a year follow-up. The patients were classified regarding CMV infection as high risk (D+/R?), intermediate risk (R+) or low risk (D?/R?). CMV infection was defined by the viral replication remaining asymptomatic whereas CMV disease concerned viral replication with clinical and/or biological symptoms. Oral valganciclovir was used as prophylaxis for high-risk recipients. A total of 38 patients (27.9%) developed CMV infection, 13 (40.6%) of the 32 D+/R?, 24 (45.3%) of the 53 R+ and 1 (2.0%) of the 51 D?/R?. Of these 38 infected patients, 10 developed tissue-invasive disease. During the first year after kidney transplantation, 27.9% of recipients developed CMV infection. This study confirms the influence of donor and recipient CMV status on infection propensity and highlights the importance of adequate follow-up for intermediate risk patients.     

Fatal disseminated toxoplasmosis in a cardiac transplantation with seropositive match for Toxoplasma: should prophylaxis be extended?

In cardiac transplant, toxoplasmosis in the immunocompromised recipient can result either from the transmission of the parasite from a seropositive donor (D+) to a seronegative recipient (R-) with the transplanted organ (more common) or from the reactivation of a pre-transplant latent infection (D-/R+ or D+/R+). In the immunocompromised patient, toxoplasmosis is a life-threatening disease. We report a case of disseminated toxoplasmosis following heart transplantation in a Toxoplasma seropositive recipient before transplantation (R+) (IgG 1:160, IgM negative) who received an organ from a Toxoplasma seropositive donor (D+) (IgG 1:640, IgM negative). No anti-Toxoplasma prophylactic treatment was administered. A number of complications arose in the postoperative period, as well as Enterobacter cloacae and Cytomegalovirus (CMV) (reactivation) infections, but neither serological nor histological toxoplasma recrudescence was evidenced. The patient died on post transplant day 41. Post-autopsy histological examinations revealed an unexpected diffuse toxoplasmosis (lungs, brain, heart).     

Association of Cytomegalovirus Infection and Disease With Death and Graft Loss After Liver Transplant in High‐Risk Recipients

In the era of effective antiviral chemoprophylaxis, cytomegalovirus (CMV) disease has been inconsistently associated with increased mortality in liver transplant (LT) recipients. A retrospective study evaluating the association of CMV infection and disease occurring within 1 year of transplant with the endpoints of death or the combined endpoint of graft loss or death was undertaken in a cohort of 227 CMV donor seropositive, recipient seronegative first LT recipients. Associations were evaluated using Cox proportional hazards regression models. CMV infection and disease occurred in 91 (40%) and 43 (19%) patients, respectively. Forty‐eight (21%) died while 58 (26%) sustained graft loss or death. In multivariable analysis, CMV infection was associated with an increased risk of death (RR: 2.24, p = 0.008) and graft loss or death (RR: 2.85, p < 0.001). CMV disease was also associated with an increased risk of death (RR: 2.73, p = 0.003) and graft loss or death (RR: 3.04, p = 0.001). CMV infection and disease occurring within the first year after LT in high‐risk recipients is associated with increased risk of death and of graft loss or death. Investigation of strategies to further reduce the risk of CMV infection and disease in high‐risk LT recipients is warranted.     

Characterization of cytotoxic function of CMV-pp65-specific CD8+ T-lymphocytes identified by HLA tetramers in recipients and donors of stem-cell transplants

BACKGROUND: Human cytomegalovirus (CMV) is a ubiquitous herpesvirus that is an important complication of bone marrow and allogeneic stem-cell transplant (HSCT). CD8 T-lymphocytes have an important role in immunity against CMV, but correlation between antigen-specific subpopulations of these cells and protection are still unclear. METHODS: Flow analysis with fluorescently-conjugated human leukocyte antigen (HLA) class I tetramers (Tet) was used to investigate levels of CMV-specific CD8 T-lymphocytes in peripheral blood monocyte cells (PBMC) samples from HSCT donors and recipients and their ability to produce interferon (IFN)-gamma on stimulation with either CMV antigenic peptide or nonspecific mitogenic stimulation. Chromium release assays were used to evaluate ex vivo CMV-specific cytotoxicity associated with the PBMC samples. RESULTS: Use of Tet in conjunction with fluorescently conjugated anti-T-cell receptor (TCR) beta-chain variable (Vbeta) monoclonal antibodies indicated that the Vbeta repertoires associated with Tet cells seen in two HSCT recipients were similar to the Vbeta repertoires of the Tet cells in their HSCT donors. Significant ex vivo cytotoxicity against peptide-loaded targets was measured from several recipient samples after transplant. However, PBMC from the HSCT donors, even when containing populations of CMV-specific Tet cells capable of secreting IFN-gamma in response to peptide stimulation, possessed no ex vivo CMV-specific cytotoxicity. CONCLUSIONS: We hypothesize that in the setting of the reconstituting immune system of HSCT recipients, CMV reactivation may stimulate a functional change in CMV-specific CD8 T-lymphocytes, rendering them able to directly lyse target cells presenting CMV antigens without in vitro stimulation. These findings have important implications for development of vaccines designed to induce protective cellular immunity to CMV in transplant recipients.     

Cytomegalovirus mismatch still negatively affects patient and graft survival in the era of routine prophylactic and preemptive therapy: A paired kidney analysis

The impact of cytomegalovirus (CMV) serostatus on kidney transplant outcomes in an era when CMV prophylactic and preemptive strategies are used routinely is not clearly established. Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, recipients with first deceased donor kidney transplant (≥18 years, 2010‐2015) were stratified into 4 groups in the main cohort: CMV‐seronegative donor (D?)/CMV‐seronegative recipient (R?), CMV‐seropositive donor (D+)/R?, D+/CMV‐seropositive recipient (R+), and D?/R+. In a paired kidney cohort, we identified 2899 pairs of D? kidney transplant with discordance of recipient serostatus (D?/R? vs D?/R+) and 4567 pairs of D+ kidney transplant with discordance of recipient serostatus (D+/R? vs D+/R+). In the main cohort, D+/R? was associated with a higher risk of graft failure (hazard ratio [HR] = 1.17, P = .01), all‐cause mortality (HR = 1.18, P < .001), and infection‐related mortality (HR = 1.38, P = .03) compared with D?/R?. In the paired kidney analysis, D+/R? was an independent risk factor for all‐cause mortality (HR = 1.21, P = .003) and infection‐related mortality (HR = 1.47, P = .04) compared with D+/R+. No difference in graft loss between D+/R? and D+/R+. CMV mismatch is still an independent risk factor for graft loss and patient mortality. The negative impact of D+/R? serostatus on mortality persists after fully matching for donor factors.     

Determinants of the source of cytomegalovirus in murine renal allograft recipients

Cytomegalovirus is present in a latent state in renal allografts and may be reactivated in recipients. While human and murine strains are alike in that a primary infection occurs in seronegative recipients of a kidney from a seropositive donor, they may differ when the recipient is seropositive. In a murine transplant model, superinfection of a seropositive recipient with a second strain is unusual. Reports in human transplantation indicate that superinfection of a seropositive recipient does occur, however the frequency is unknown. Our studies examine the potential importance of specific viral strains in host and recipient, the contribution of prior humoral immunity in the recipient, and the technical ability to identify distinctive strains of virus in the presence of each other. Our results indicate that reversal of the viral strains in donor or recipient animals does not alter our previous observation that reactivation of the endogenous recipient viral strain predominates as the infecting strain in the posttransplant period. Further, the presence of antibody in nearly all donors and recipients confirms that all animals were originally infected prior to transplantation. Finally, we demonstrated the technical ability to detect one virus in the presence of the other, thus excluding this variable as possibly confounding. We conclude that the endogenous, latent recipient strain of cytomegalovirus in the murine model is preferentially reactivated in the posttransplant interval.     

Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis

BACKGROUND: The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined. METHODS: The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models. RESULTS: CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04-0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8-54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R-) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R- status was the only variable significantly associated with CMV disease in multivariate analysis. CONCLUSIONS: Late CMV disease develops in a substantial proportion of D+R- recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R- patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.     

Successful prophylaxis of cytomegalovirus disease after primary CMV exposure in liver transplant recipients.

During a 38-month period, we studied 320 liver transplants in 283 recipients (202 adults, 81 children). CMV disease was documented in 85 patients (30.0%) The major risk factor for CMV disease was primary CMV exposure (transplanting a seropositive allograft into a seronegative recipient). A total of 42 patients (14.8%) had primary CMV exposure. Twenty-one patients were historical controls, while the next 21 received prophylaxis for CMV infection in a nonrandomized trial of consecutive study groups. The regimen of prophylaxis consisted of intravenous immune globulin (IgG; 0.5 g/kg) at weekly intervals for 6 weeks and acyclovir for 3 months. CMV prophylaxis resulted in a dramatic reduction in the incidence of CMV disease (71.4% vs. 23.8%, (P less than 0.01). All cases of CMV were treated with intravenous ganciclovir (5 mg/kg b.i.d. for 14 days), with 5 patients in the control group developing recurrent CMV disease (33.3% relapse). In the 16 patients receiving prophylaxis who did not develop CMV disease, all developed positive CMV-IgG titers with the passive administration of IgG. However, none developed any evidence of CMV infection or viral shedding as assessed by IgM titers and surveillance viral cultures. Four deaths occurred (all control patients), but none were related to CMV disease. Overall patient and graft survivals after primary CMV exposure were 90.5% and 82.2%, respectively, after a mean follow-up of 14 months. Conclusion: Primary CMV exposure is a major risk factor for CMV disease in liver transplant recipients. Intravenous IgG plus acyclovir is safe and effective in preventing CMV infection and disease in this setting. Because of the scarcity of donor organs, we do not advocate protective matching to avoid primary CMV exposure but rather recommend prophylaxis to prevent CMV disease in this high-risk group.     

The Association of Cytomegalovirus Sero-Pairing with Outcomes and Costs Following Cadaveric Renal Transplantation Prior to the Introduction of Oral Ganciclovir CMV Prophylaxis

Cytomegalovirus (CMV) is an important cause of morbidity, mortality and cost in cadaveric renal transplantation. This study was designed to document the clinical and economic outcomes associated with donor and recipient CMV sero-pairing. Data were drawn from the United States Renal Data System (USRDS) on 17 001 cadaveric renal transplant recipients transplanted between 1995 and 1997 with recorded donor and recipient CMV sero-status. In multivariate analysis, CMV-seropositive recipients were associated with a significantly higher incidence of delayed graft function, a lower incidence of graft loss, and lower costs than CMV-seronegative recipients. CMV-seropositive compared to seronegative donors were associated with significantly higher incidence of CMV disease, graft loss, and higher costs when transplanted into CMV-seronegative recipients. However, CMV-seronegative donors into seropositive recipients had no significant association with outcome beyond a higher incidence of CMV disease compared to CMV-seronegative donor and recipient pairs. The outcomes associated with CMV-seropositive donors and seronegative recipients call for tailored management strategies which may include avoidance of such mismatching, antiviral therapy, immunization, or modified immunosuppression.     

Direct visualization and quantitation of cytomegalovirus-specific CD8+ cytotoxic T-lymphocytes in liver transplant patients

BACKGROUND: CMV infection remains a significant clinical problem in the context of LT. Changes in the magnitude of the CMV-specific CTL response after LT have not previously been assessed but may be important in determining the outcome of CMV infection. METHOD: We used a fluorescent HLA-B*0702-CMV peptide tetrameric complex to directly visualize and quantitate CMV-specific CD8+ CTL both in immunosuppressed patients after LT and in immunocompetent controls. RESULTS: CMV-specific CD8+ CTL, at a frequency ranging from 0.1 to 5.8% of CD8+, were detected in the peripheral blood of 22 of 25 B*0702, CMV immunoglobulin G seropositive individuals, with no difference observed between immunocompetent controls and patients >3 years after LT. In CMV seropositive LT recipients who did not have symptomatic CMV infection during the first 3 months after LT, CMV-specific CD8+ CTL magnitude initially decreased, then increased up to 5 times higher than pre-LT levels within 3 months. Two CMV seronegative recipients of seropositive donors had symptomatic CMV infection in association with high viral load. In both patients, no CD8+ CTL response was detected before the onset of symptoms, and a reduction in viral load was observed during antiviral therapy. However, polymerase chain reaction negativity was achieved only when a demonstrable CMV-specific CD8+ CTL response was generated. Responses were never observed in asymptomatic CMV seronegative patients. CONCLUSIONS: We suggest that the generation of CMV-specific CD8+ CTL may be driven by, and seems to coincide with the suppression of, viral reactivation. Direct monitoring of CMV-specific CD8+ CTL using an HLA-peptide tetramer may prove to be of value in the management of patients after LT.