Sequential anti-cytomegalovirus response monitoring may allow prediction of cytomegalovirus reactivation after allogeneic stem cell transplantation

Background: Reconstitution of cytomegalovirus-specific CD3+CD8+ T cells (CMV-CTLs) after allogeneic hematopoietic stem cell transplantation (HSCT) is necessary to bring cytomegalovirus (CMV) reactivation under control. However, the parameters determining protective CMV-CTL reconstitution remain unclear to date. Design and Methods: In a prospective tri-center study, CMV-CTL reconstitution was analyzed in the peripheral blood from 278 patients during the year following HSCT using 7 commercially available tetrameric HLA-CMV epitope complexes. All patients included could be monitored with at least CMV-specific tetramer. Results: CMV-CTL reconstitution was detected in 198 patients (71%) after allogeneic HSCT. Most importantly, reconstitution with 1 CMV-CTL per µl blood between day +50 and day +75 post-HSCT discriminated between patients with and without CMV reactivation in the R+/D+ patient group, independent of the CMV-epitope recognized. In addition, CMV-CTLs expanded more daramtaically in patients experiencing only one CMV-reactivation than those without or those with multiple CMV reactivations. Monitoring using at least 2 tetramers was possible in 63% (n = 176) of the patients. The combinations of particular HLA molecules influenced the numbers of CMV-CTLs detected. The highest CMV-CTL count obtained for an individual tetramer also changed over time in 11% of these patients (n = 19) resulting in higher levels of HLA-B*0801 (IE-1) recognizing CMV-CTLs in 14 patients. Conclusions: Our results indicate that 1 CMV-CTL per µl blood between day +50 to +75 marks the beginning of an immune response against CMV in the R+/D+ group. Detection of CMV-CTL expansion thereafter indicates successful resolution of the CMV reactivation. Thus, sequential monitoring of CMV-CTL reconstitution can be used to predict patients at risk for recurrent CMV reactivation

Cytomegalovirus infection of the upper gastrointestinal tract following liver transplantation—incidence, location, and severity in cyclosporine- and FK506-treated patients

One hundred and forty randomly selected liver transplant recipients were studied before and after primary orthotopic liver transplantation for the presence or absence of CMV enteritis. Following OLTx, 65 patients were treated with cyclosporine A and 75 were treated with FK506. The two groups were similar with regard to the incidence, location, and outcome of their upper gastrointestinal CMV infection. Prior to OLTx, only one patient had evidence of enteric CMV infection. The incidence of CMV enteritis post-OLTx was 27.7% in the CsA-treated group and 20% in the FK-treated group. During the first posttransplant month, no patient in the FK-treated group developed CMV enteritis, compared with 11.5% of the patients who were treated with CsA (P<0.05). Gastric CMV was found in over 80% of those positive for any organ in either group. In addition to CMV infection of the upper gastrointestinal tract, clinically evident CMV disease involved more nonenteric organs in the CsA-treated group than in the FK-treated group. In the CsA-treated group, CMV-negative patients had a statistically higher 1-year survival rate (100%) than CMV-positive patients (77.8%) (P<0.05). In the FK-treated group, no difference in survival was observed between CMV-positive or CMV-negative cases at 1 year. Of the patients on CsA, 20% received OKT3 for persistent rejection, as compared with 13% in the FK-treated group. The patients receiving both CsA and OKT3 had a higher rate of upper gastrointestinal CMV infection than did FK-treated patients who also received OKT3 therapy (38.5% versus 20%, respectively). Based upon these data, it can be concluded that (1) patients receiving FK have a lower incidence of enteric CMV infection; (2) following OLTx, upper gastrointestinal CMV infection presents later in FK-treated patients; (3) the stomach is the most frequently involved organ in the UGIT; (4) FK-treated liver recipients have less severe enteric CMV infection than do CsA-treated patients; (5) enteric CMV is not a major cause of mortality in liver trans lant recipients; and (6) in patients receiving FK, those who require OKT3 therapy do not appear to be at a greater risk for the development of CMV enteritis than those who do not. © 1992 by Williams & Wilkins

Impact of IFN lambda 3/4 single nucleotide polymorphisms on the cytomegalovirus reactivation in autologous stem cell transplant patients

Cytomegalovirus (CMV) infection represents one of the main cause mortality after Stem Cell Transplantation. Recently, a protective effect of the T allele of rs12979860 IL28B Single Nucleotide Polymorphisms (SNPs) against CMV infection in the allogenic stem cell transplantation was suggested. We investigate whether the rs12979860 IL28B SNP and the relative rs368234815 (IFNλ4) genotype may affect the incidence of active CMV infection in Autologous stem cell transplantation (Auto-SCT) setting. The study included 99 patients who underwent to Auto-SCT. IL28 and IFNΔ4 SNPs were correlated with CMV reactivation along with other clinical and treatment parameters. CMV reactivation by CMV DNAemia was evaluated once a week until day 100 from Auto-SCT. CMV reactivation was documented in 50% (TT-ΔG/ΔG), 35% (CC-TT/TT) and 29.2% (CT-TT/ΔG) of the patients respectively. No differences in CMV copies number were recorded at reactivation between different IL28/IFNλ4 genotypes. The analysis of patients older than 60 years showed a significantly higher incidence of active CMV infection in the TT-ΔG/ΔG (83%) population with respect to CC-TT/TT (21%) and CT-TT/ΔG (40%) patients. Our data suggest a negative role of TT-ΔG/ΔG genotype in the CMV reactivation in Auto-SCT. The exposure to rituximab and the pre-infusion presence of anti CMV IgG also significantly influenced CMV reactivation

Minimal Rank Decoupling of Full-Lattice CMV Operators with Scalar- and Matrix-Valued Verblunsky Coefficients

Relations between half- and full-lattice CMV operators with scalar- and matrix-valued Verblunsky coefficients are investigated. In particular, the decoupling of full-lattice CMV operators into a direct sum of two half-lattice CMV operators by a perturbation of minimal rank is studied. Contrary to the Jacobi case, decoupling a full-lattice CMV matrix by changing one of the Verblunsky coefficients results in a perturbation of twice the minimal rank. The explicit form for the minimal rank perturbation and the resulting two half-lattice CMV matrices are obtained. In addition, formulas relating the Weyl--Titchmarsh $m$-functions (resp., matrices) associated with the involved CMV operators and their Green's functions (resp., matrices) are derived.Comment: 30 page

Cytomegalovirus is associated with depression and anxiety in older adults

Infection with cytomegalovirus (CMV), a β-herpesvirus, is common within the population. Although asymptomatic, infection is associated with increased serum concentrations of cytokines such as TNFα and IL-6, which are also related to mood and wellbeing. The present study examined whether infection with CMV was associated with mood in a community-based sample of olderadults. Blood samples and scores on the General Health Questionnaire were available for 137 participants. Serum was analysed for the presence of CMV-specific IgG and the antibody titre was used as an indirect measure of viral load. The majority of the participants (66%) were CMV-seropositive and seropositive status was not associated with psychological morbidity. However, within the CMV-positive group, individuals with higher CMV-specific antibody titres were more likely to be depressed, anxious, and suffer more overall psychological morbidity. This association could be mediated by the impact of affect-moderating cytokines secreted through the CMV-specific immune response.\ud \u

The Conditions of Primary Infection Define the Load of Latent Viral Genome in Organs and the Risk of Recurrent Cytomegalovirus Disease

Recurrence of cytomegalovirus (CMV) from latency is a frequent cause of disease in immunocompromised patients. To date, there is no explanation for the diversity in the clinical manifestations. Primary infection can occur perinatally or later in life, and inevitably results in latent infection. Seropositivity for antibodies against CMV is indicative of latent infection, but is insufficient as a predictor for the risk of recurrence. As a model for this important medical problem, we compared the risks of murine CMV recurrence from latency established after neonatal primary infection and after infection at adult age. The risk of CMV recurrence was high only after neonatal infection. The copy number of latent viral genome in tissues was identified as the key parameter that determines the overall and organ-specific risks of recurrence. Latent CMV burden and risk of recurrence were related to the extent of virus multiplication during primary infection. The presence of latent CMV in multiple organs provides the molecular basis for stochastic events of recurrence in single organs or in any combination thereof. These findings are discussed as a concept of multifocal CMV latency and recurrence. It provides a rationale for the diversity in the clinical outcome of CMV disease

CMV in the gut: a critical review of CMV detection in the immunocompetent host with colitis.

As scientific techniques for the detection of cytomegalovirus (CMV) improve, we are able to detect small amounts of CMV in the mucosal wall. As clinicians, we are unsure how to interpret the results of this novel test. There is controversy in the literature as to the significance of the detection of CMV in the gut. Whilst the importance of CMV and reactivation of the virus is clear in those patients such as allograft recipients with established immune compromise, the role is less clear in patients with less damaged immune systems. We explore whether the detection of CMV in such cases influences outcome and how it should be optimally managed. We discuss the optimal management of such cases, according to current guidelines, with a review of the literature

The role of IgG avidity in diagnosis of cytomegalovirus infection in newborns and infants [Uloga IgG aviditeta u dijagnostici infekcije citomegalovirusom u novorođenčadi i dojenčadi]

To evaluate the value of IgG avidity in diagnosis of congenital cytomegalovirus (CMV) infection in newborns and infants we collected serum samples from 40 infants under 12 months of age with suspected congenital CMV infection. Sera were tested for IgM, IgG and IgG avidity. For 25 of them, virus isolation and/or polymerase chain reaction (PCR) on urine specimens were performed. Thirteen (32.5%) patients showed the presence of CMV IgM antibodies, 3 (7.5%) had equivocal IgM result, and 24 (60.0%) patients had IgG antibodies only. Using IgG avidity, CMV infection (low avidity index-AI) was documented in 61.5% IgM positive and 54.2% IgM negative patients. Eight of nine (88.8%) IgM positive patients were positive either on virus isolation or PCR. In IgM negative patients, 46.6% urine cultures were positive for CMV and 66.6% were PCR positive. According to age, IgG avidity demonstrated acute/recent primary CMV infection in 58.8% patients younger than three months compared with 91.7% and 81.8% in 3-6 and 6-12 months old babies, respectively. In conclusion, IgG avidity is useful in diagnosis of CMV infection either in IgM positive or IgM negative children older than 3 months of age. In infants less than 3 months, transplacentally derived maternal IgG antibodies of high avidity influence on the IgG avidity result. In these children, CMV infection should be confirmed by direct virologic methods such as virus isolation or PCR