Quantity of cytomegalovirus viruria is a major risk factor for cytomegalovirus disease after renal transplantation

Abstract

Studies have shown that risk factors for human cytomegalovirus (HCMV) disease after renal transplant include primary infection (virus of donor origin infecting a non-immune individual), re-infection (virus of donor origin infecting a immune individual), and the detection of viraemia (as a marker of virus dissemination). We now report that viral load in the urine is also a significant factor in HCMV disease and is one of the main mechanisms underlying the risk associated with viraemia and donor serostatus. Longitudinal analysis of a group of 196 renal recipient identified 35 recipients who were PCR positive for HCMV in urine. Elevated viral loads were present in symptomatic patients, viraemic patients, and patients experiencing primary HCMV infection. Disease was associated with the peak quantity of virus present in the urine during the post-transplant period (P = 0.0001), with viraemia (P = 0.0003), and with transplantation of a seropositive donor (P = 0.03). Univariate logistic regression analysis showed that increases of 0.25 log10 in viral load were associated with a 179% increased risk of disease (odds ratio = 2.79; 95% C.I. 1.22-6.39; P = 0.02). This effect persisted in a multivariate logistic analysis when viraemia was incorporated (odds ratio = 2.77; 95% C.I. 1.07-7.18; P = 0.04). In contrast, the significant association between viraemia and disease observed in univariate analysis (odds ratio = 23.75; 95% C.I. 3.69-152.90; P = 0.0009) became marginally non-significant in multivariate analysis once viral load had been controlled for (odds ratio = 34.54; 95% C.I. 0.75-1599.00; P = 0.07). The computed probability of disease showed that a rapid transition occurred at viral loads between 10(5.7) and 10(6.5) genomes/ml urine in non-viraemic patients compared to viral loads between 10(5.0) and 10(5.7) genomes/ml urine in patients with concurrent viraemia. The implications of these findings for understanding HCMV pathogenesis, improving patient management, and optimising trials of antiviral treatment are discussed.

Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant patients: relationship between peak virus load, donor/recipient serostatus, acute GVHD and CMV disease

“…In similar studies we have identified threshold viral load levels for disease in the blood of liver transplant recipients, 20 and in the urine of renal transplant patients. 21 In conclusion, the data in this study demonstrate the central role of viral load in the pathogenesis of HCMV in the bone marrow transplant recipient and provide the mechanism by which previously identified risk factors are associated with disease. These data also provide a rational approach to reducing viral loads below critical levels through antiviral chemotherapeutic targeting of patients most at risk of symptomatic infection, as well as monitoring the success of such interventions.…”

“…18 In other patient populations at risk of HCMV disease, quantification of HCMV load has provided another risk factor for HCMV disease. Specifically, cross-sectional and longitudinal studies have indicated the importance of monitoring HCMV load in congenitally infected infants, 19 renal transplant recipients [20][21][22] and HIV infected patients. 23,24 There is, however, a paucity of information on longitudinal fluctuations in cytomegalovirus load in the bone marrow transplant patient.…”

“…25 Previous studies in our laboratory have used a quantitative-competitive PCR assay for HCMV to show that HCMV load in the urine of renal transplant recipients and in the blood of liver-transplant patients is a significant risk factor for HCMV disease independent of other risk factors. 20,21 We were interested to ascertain whether a similar situation exists in the bone marrow transplant patient group and if the previously reported risk factors for disease of recipient seropositivity and acute graft-versus-host disease 26,27 were accounted for by increased viral load.…”

Comparative analysis of a double primer PCR assay with plasma, leukocytes and antigenemia for diagnosis of active human cytomegalovirus infection in bone marrow transplant patients

“…4 Seroepidemiological studies have shown that approximately 60% of adults in developed countries and up to 100% of adults in developing countries are positive for antibodies against HCMV. 5 BMT recipients negative for anti-HCMV antibody are at risk of primary infection. 5 In addition, reactivation of latent HCMV is responsible for significant morbidity and mortality in BMT recipients, and HCMV pneumonia has a high mortality rate in patients who have received an allogeneic marrow transplant.…”

“…5 BMT recipients negative for anti-HCMV antibody are at risk of primary infection. 5 In addition, reactivation of latent HCMV is responsible for significant morbidity and mortality in BMT recipients, and HCMV pneumonia has a high mortality rate in patients who have received an allogeneic marrow transplant. The diagnosis of HCMV disease is complicated because of varying clinical presentations and inherent difficulties in diagnosis.…”