Cytomegalovirus infection after liver transplantation in children

Post-liver transplant cytomegalovirus (CMV) infection (seroconversion or virus isolation) and CMV disease (infection plus clinical signs and symptoms) were studied in relation to pretransplant recipient and donor serology, age, nutritional status and the effect of paediatric versus adult (reduced size) grafts. Of 70 children receiving 79 transplants, 26 (37%) had evidence of CMV infection, and eight (11.5%) had evidence of CMV disease, four of whom died. The primary infection rate (where the recipients were CMV negative) was 71% with mortality of 7% with most receiving a CMV-positive graft. The active secondary infection rate (reactivation or reinfection, where the recipients were CMV positive) was 60% with mortality of 12.5%. No significant differences in infection on disease rates were found comparing malnourished versus well-nourished patients, or between those who received whole or reduced-size grafts. The high prevalence of CMV infections supports the view that clinical signs alone are inadequate to direct investigations for CMV. Both primary and active secondary CMV infection can result in serious morbidity and mortality in children receiving liver transplants. These data do not support the strategy of providing immunoprophylaxis to seronegative recipients only, at least in paediatric liver transplantation.

PP65 antigenemia in the diagnosis of cytomegalovirus infection in AIDS patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Interferon γ-Dependent Migration of Microglial Cells in the Retina after Systemic Cytomegalovirus Infection

Microglial cells are the resident macrophages of the central nervous system and participate in both innate and adaptive immune responses but can also lead to exacerbation of neurodegenerative pathologies after viral infections. Microglia in the outer layers of the retina and the subretinal space are thought to be involved in retinal diseases where low-grade chronic inflammation and oxidative stress play a role. This study investigated the effect of systemic infection with murine cytomegalovirus on the distribution and dynamics of retinal microglia cells. Systemic infection with murine cytomegalovirus elicited a significant increase in the number of microglia in the subretinal space and an accumulation of iris macrophages, along with morphological signs of activation. Interferon γ (IFN-γ)-deficient mice failed to induce changes in microglia distribution. Bone marrow chimera experiments confirmed that microglial cells in the subretinal space were not recruited from the circulating monocyte pool, but rather represented an accumulation of resident microglial cells from within the retina. Our results demonstrate that a systemic viral infection can lead to IFN-γ-mediated accumulation of microglia into the outer retinal layers and offer proof of concept that systemic viral infections alter the ocular microenvironment and therefore, may influence the course of diseases such as macular degeneration, diabetic retinopathy, or autoimmune uveitis, where low-grade inflammation is implicated.

Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation

BACKGROUND  Polymorphisms in the interferon-λ (IFNL) 3/4 region have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of CMV infection in solid-organ transplant (SOT) recipients. METHODS  Caucasian patients participating in the Swiss Transplant Cohort Study in 2008-2011 were included. A novel functional TT/-G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated. RESULTS  A total of 840 SOT recipients at risk for CMV were included, among whom 373 (44%) received antiviral prophylaxis. The 12-months cumulative incidence of CMV replication and disease were 0.44 and 0.08, respectively. Patient homozygous for the minor rs368234815 allele (-G/-G) tended to have a higher cumulative incidence of CMV replication (SHR=1.30 [95%CI 0.97-1.74], P=0.07) compared to other patients (TT/TT or TT/-G). The association was significant among patients followed by a preemptive approach (SHR=1.46 [1.01-2.12], P=0.047), especially in patients receiving an organ from a seropositive donor (D+, SHR=1.92 [95%CI 1.30-2.85], P=0.001), but not among those who received antiviral prophylaxis (SHR=1.13 [95%CI 0.70-1.83], P=0.6). These associations remained significant in multivariate competing risk regression models. CONCLUSIONS  Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in SOT recipients, particularly in patients not receiving antiviral prophylaxis.

Cytomegalovirus infection and disease reduce 10-year cardiac allograft vasculopathy-free survival in heart transplant recipients.

BACKGROUND Cytomegalovirus (CMV) is associated with an increased risk of cardiac allograft vasculopathy (CAV), the major limiting factor for long-term survival after heart transplantation (HTx). The purpose of this study was to evaluate the impact of CMV infection during long-term follow-up after HTx. METHODS A retrospective, single-centre study analyzed 226 HTx recipients (mean age 45 ± 13 years, 78 % men) who underwent transplantation between January 1988 and December 2000. The incidence and risk factors for CMV infection during the first year after transplantation were studied. Risk factors for CAV were included in an analyses of CAV-free survival within 10 years post-transplant. The effect of CMV infection on the grade of CAV was analyzed. RESULTS Survival to 10 years post-transplant was higher in patients with no CMV infection (69 %) compared with patients with CMV disease (55 %; p = 0.018) or asymptomatic CMV infection (54 %; p = 0.053). CAV-free survival time was higher in patients with no CMV infection (6.7 years; 95 % CI, 6.0-7.4) compared with CMV disease (4.2 years; CI, 3.2-5.2; p < 0.001) or asymptomatic CMV infection (5.4 years; CI, 4.3-6.4; p = 0.013). In univariate analysis, recipient age, donor age, coronary artery disease (CAD), asymptomatic CMV infection and CMV disease were significantly associated with CAV-free survival. In multivariate regression analysis, CMV disease, asymptomatic CMV infection, CAD and donor age remained independent predictors of CAV-free survival at 10 years post-transplant. CONCLUSIONS CAV-free survival was significantly reduced in patients with CMV disease and asymptomatic CMV infection compared to patients without CMV infection. These findings highlight the importance of close monitoring of CMV viral load and appropriate therapeutic strategies for preventing asymptomatic CMV infection.

Use of differential display analysis to assess the effect of human cytomegalovirus infection on the accumulation of cellular RNAs: Induction of interferon-responsive RNAs

We used differential display analysis to identify mRNAs that accumulate to enhanced levels in human cytomegalovirus-infected cells as compared with mock-infected cells. RNAs were compared at 8 hr after infection of primary human fibroblasts. Fifty-seven partial cDNA clones were isolated, representing about 26 differentially expressed mRNAs. Eleven of the mRNAs were virus-coded, and 15 were of cellular origin. Six of the partial cDNA sequences have not been reported previously. All of the cellular mRNAs identified in the screen are induced by interferon α. The induction in virus-infected cells, however, does not involve the action of interferon or other small signaling molecules. Neutralizing antibodies that block virus infection also block the induction. These RNAs accumulate after infection with virus that has been inactivated by treatment with UV light, indicating that the inducer is present in virions. We conclude that human cytomegalovirus induces interferon-responsive mRNAs.

Autoimmune response to U1 small nuclear ribonucleoprotein (U1 snRNP) associated with cytomegalovirus infection

The induction of autoantibodies to U1 small nuclear ribonucleoprotein (U1 snRNP) complexes is not well understood. We present evidence that healthy individuals with cytomegalovirus (CMV) infection have an increased frequency and quantity of antibodies to ribonucleoprotein, directed primarily against the U1-70k protein. A significant association between the presence of antibodies to CMV and antibodies to the total RNP targeted by the immune response to the spliceosome (to both the Sm and RNP; Sm/RNP) was found for patients with systemic lupus erythematosus (SLE) but not those with mixed connective-tissue disease. CMV thus may play a role in inducing autoimmune responses in a subset of patients with systemic lupus erythematosus.

Acute partial Budd-Chiari syndrome and portal vein thrombosis in cytomegalovirus primary infection: a case report

BACKGROUND: Splanchnic vein thrombosis may complicate inherited thrombotic disorders. Acute cytomegalovirus infection is a rare cause of acquired venous thrombosis in the portal or mesenteric territory, but has never been described extending into a main hepatic vein. CASE PRESENTATION: A 36-year-old immunocompetent woman presented with acute primary cytomegalovirus infection in association with extensive thrombosis in the portal and splenic vein. In addition, a fresh thrombus was evident in the right hepatic vein. A thorough evaluation for a hypercoagulable state was negative. The clinical course, biological evolution, radiological and histological findings were consistent with cytomegalovirus hepatitis complicated by a partial acute Budd-Chiari syndrome and portal thrombosis. Therapeutic anticoagulation was associated with a slow clinical improvement and partial vascular recanalization. CONCLUSION: We described in details a new association between cytomegalovirus infection and acute venous thrombosis both in the portal vein and in the right hepatic vein, realizing a partial Budd-Chiari syndrome. One should be aware that this rare thrombotic event may be complicated by partial venous outflow block.

Clozapine associated neutropenia and cytomegalovirus colitis.

Both diarrhea and colitis associated with clozapine have been reported. We present a case of clozapine-associated neutropenia complicated by cytomegalovirus colitis. The definitive diagnosis was suggested on biopsy which showed eosinophilic intranuclear inclusions suggestive of cytomegalovirus infection, and confirmed on immunohistochemistry. Neutropenia or agranulocytosis in association with clozapine treatment may be complicated by colitis. In such cases, investigations for cytomegalovirus may be indicated.