Role Of Cytomegalovirus Research Articles

174: The role of cytomegalovirus in the development and progression of pre-transplant ischaemic heart disease

Up to 25% of individuals with newly diagnosed ischaemic heart disease (IHD) have no recognised risk factors. This has prompted the investigation of other “potential” risks factors. The role of infection in the development of ischaemic heart disease remains controversial. Associations between CMV seropositivity and endothelial dysfunction have been described, along with myocardial infarction at a young age. Using a cohort of cardiac transplant recipients we investigated the putative role of CMV in the development of ischaemic heart disease.

Cytomegalovirus and Schizophrenia

Several lines of evidence suggest that cytomegalovirus (CMV) may play an aetiological role in schizophrenia. Epidemiologically, both have a worldwide distribution and an increased prevalence in lower socioeconomic groups. Studies have reported that some patients experiencing initial episodes of schizophrenia have increased levels of IgG antibodies against CMV, but not other herpes viruses, in their sera and CSF. Treatment with antipsychotic medications may result in a decrease in CMV antibodies, while treatment with anti-herpes virus and anti-inflammatory medications may reduce symptoms in some individuals with schizophrenia. There is also some overlap in the genes that are thought to operate in CMV infections and schizophrenia. The strongest argument against the role of CMV in schizophrenia is the absence of the traditional CMV neuropathological changes in the brains of individuals with schizophrenia; however, neuropathological studies of CMV have mostly been conducted in immune-compromised individuals. Further studies on CMV and schizophrenia are needed and may lead to improved treatments for schizophrenia.

Influence of Cytomegalovirus Disease on Early and Late Renal Graft Function

The role of cytomegalovirus (CMV) disease to induce chronic nephropathy using new immunosuppressive regimens is debated. This study sought to assess the influence of CMV disease on early and late graft function in relation to immunosuppressive therapy. Among 456 renal recipients transplanted from 1997 to 2003, 95 were diagnosed with CMV disease on the basis of clinical symptoms and the presence of pp65 protein. The patients were divided into 2 groups according to their immunosuppressive regimen: group I included 43 patients treated with cyclosporine (CsA), azathioprine (AZA), and prednisone (P); group II, 52 patients treated with calcineurin inhibitor (CI), mycophenolate mofetil (MMF), and P. A control group of 90 CMV disease-free renal recipients were transplanted in 2001. CMV disease occurred in 20.8% of renal recipients: 14.8% from group I and 25.5% from group II. CMV disease was diagnosed in 73 patients (76.8%) before the third month after transplantation. An acute rejection episode (ARE) appeared in 42 patients, of whom 31 had CMV disease diagnosed within 1 month after ARE, while 5 before an ARE. In six patients ARE was not time related to CMV disease. The serum creatinine values at 6 months after transplantation were significantly higher among the CMV versus control groups: 1.69 and 1.76 vs 1.49 ( P < .05). In patients with ARE and CMV disease, the serum creatinine value was also higher at 6 and 12 months after transplantation compared with patients without an ARE ( P < .03). One- and 3-year graft survival rates were 95.1% and 83.7% in group I versus 93.4% and 86.5% in group II versus 95.4% and 90.2% in the control group. In conclusion, CMV disease showed a negative impact on early graft function independent of the immunosuppressive regimen, an effect that was emphasized by an ARE.

New-Onset Posttransplantation Diabetes Mellitus: Insulin Resistance or Insulinopenia? Impact of Immunosuppressive Drugs, Cytomegalovirus and Hepatitis C Virus Infection

Restoration of renal function may ameliorate uremia induced insulin resistance. Therefore it seems a paradox that new-onset posttransplantation diabetes mellitus (PTDM) is a frequently observed complication after renal transplantation. The incidence varies between 2 and 50% depending on the population under study, criteria for the diagnosis of diabetes and the time of follow up. This review addresses recent findings on transplant specific risk factors and pathogenesis of PTDM after solid organ transplantation, and we focus on the following issues: 1. The relative impact of insulin resistance and insulinopenia in the pathogenesis of PTDM. 2. The role of immunosuppressive drugs with special emphasis on calcineurin inhibitors (cyclosporine A, tacrolimus) and steroids. 3. The possible roles of cytomegalovirus and hepatitis C infections. New-onset PTDM is characterized by a variety of clinical manifestations, ranging from predominantly insulin resistance which can be handled with lifestyle intervention, to beta-cell failure requiring insulin treatment. The etiology is multi-factorial, but diabetogenic immunosuppressive drugs are of major importance. Future studies should therefore address the effects of different immunosuppressive regimens on the incidence of PTDM. In addition, the impact of cytomegalovirus infection and hepatitis C on PTDM needs further evaluation.

Hunting for the owl's eye in acute severe colitis: the role of cytomegalovirus

Acute severe colitis fortunately occurs in only a minority of patients with inflammatory bowel disease (IBD), but its onset heralds a difficult disease course. With the institution of the ‘Oxford regimen’ several decades ago, the mortality of acute severe ulcerative colitis (UC) has fallen to 2% or less in high-volume centres [1–3]. The two main pillars of this approach were administration of intravenous corticosteroids and a willingness to proceed with colectomy if the patient was not clinically improving within 5–10 days of admission.

Role of cytomegalovirus, Epstein-Barr virus, and human herpes virus-8 in benign lymphoepithelial cysts of the parotid gland.

To provide background and evaluate the role of herpesviruses in benign lymphoepithelial cysts (BLC) of the parotid gland. Case series derived from review of pathology specimens. Radiolabeled polymerase chain reaction (PCR) analysis was used to detect for the presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpes virus 8 (HHV-8) DNA sequences in 14 paraffin embedded specimens and 1 freshly aspirated BLC specimen. Thirteen normal parotid tissue specimens obtained from paraffin embedded blocks were used as a control group. CMV was detected with nearly equal frequency between the two groups (23% of normal vs. 20% in BLC). HHV-8 was found in 13% of the BLC group and in none of the normal group (P =.4841). There was significant difference in EBV detection between the normal (0%) and the BLC (33%) groups (P =.0437). CMV and HHV-8 does not appear to be associated with BLCs. Although EBV is found more frequently in BLC than in normal parotid controls, further studies are needed to elucidate the role of this virus in BLC pathogenesis.

Pathogenesis and outcome of biliary atresia: current concepts.

Neonatal cholestatic disorders are a group of hepatobiliary diseases occurring within the first 3 months of life. Bile flow is impaired, and patients have conjugated hyperbilirubinemia, acholic stools, and hepatomegaly. Overall, 1 in 2,500 live births is affected with a neonatal cholestatic disorder (1). The two most common causes of neonatal cholestasis are biliary atresia and idiopathic neonatal hepatitis, accounting for up to 50% to 70% of cases. Other causes include a variety of neonatal infections (viral, toxoplasmosis, syphilis, bacterial), metabolic and genetic diseases, progressive familial intrahepatic cholestatic disorders (PFIC), paucity of interlobular bile duct disorders (e.g., Alagille syndrome), choledochal cyst, ischemia–reperfusion injury, association with parenteral nutrition administration, and other conditions (Table 1). Despite clinical improvement after the portoenterostomy procedure, approximately 70% to 80% of children with biliary atresia will eventually require liver transplantation; thus, biliary atresia alone accounts for almost 50% of all liver transplants performed in children (1). It should be noted that $77 million is spent each year in the United States on liver transplantation for children and the ensuing hospitalizations (2). This sum of money covers 0.2% of total health care expenditures related to children, even though these children represent 0.0006% of the total pediatric population. Importantly, this disproportionate expenditure for liver transplantation in children could be cut in half if improved therapies for biliary atresia were developed that could abrogate or further delay the need for liver transplantation. Remarkably, little is known about the etiopathogenesis of biliary atresia; consequently, there has been slow progress in developing improved therapies or preventative strategies during the past decade. The purpose of this review is to summarize recent advances in the diagnosis and management of biliary atresia, examine the clinical outcome, describe the evolving theories of the etiology and pathogenesis of this disorder, and highlight gaps in our current knowledge.

The impact of cytomegalovirus infections and acute rejection episodes on the development of vascular changes in 6-month protocol biopsy specimens of cadaveric kidney allograft recipients.

The role of cytomegalovirus (CMV) in chronic kidney allograft rejection remains controversial. The purpose of this study was to examine the impact of CMV infection on histopathologic changes in 6-month protocol biopsy specimens of kidney allografts. Altogether, 52 renal allograft recipients were studied. CMV infection was diagnosed by CMV antigenemia test, viral cultures from blood and urine, or both. CMV was demonstrated in the biopsy specimens by antigen detection and hybridization in situ. Acute rejections were diagnosed by biopsy histology, and biopsy specimens were graded according to the Banff '97 classification. CMV infection was diagnosed in 41 patients. The 11 patients in whom CMV infection was not detected were used as controls. Acute rejection was diagnosed in 22 of 41 CMV patients and in 6 of 11 control patients. CMV was demonstrated in the biopsy specimens of 19 of 41 CMV patients. CMV was not associated with increased glomerular, tubular, or interstitial changes. However, the arteriosclerotic changes in small arterioles were significantly increased in the subgroup of patients where CMV was demonstrated in the graft as compared with controls (P<0.01). Analysis of the impact of acute rejection on arteriolar thickening showed that only a positive history of both acute rejection and CMV found in the graft was associated with significantly increased vascular changes compared with CMV-free recipients (P<0.05). Neither CMV nor acute rejection alone was associated with increased vascular or other histopathologic changes in 6-month protocol biopsy specimens of kidney allografts, but a previous history of both acute rejection and the presence of CMV in the graft was associated with increased vascular changes.

Role of cytomegalovirus and asymmetric dimethylarginine in the derangement of nitric oxide synthase in cardiac allograft recipients

Role of cytomegalovirus and asymmetric dimethylarginine in the derangement of nitric oxide synthase in cardiac allograft recipients

Determinants of Cardiovascular Mortality After Renal Transplantation: A Role For Cytomegalovirus?

Death with a functioning graft (DWF) is now the most common cause of late renal transplant failure, with cardiovascular disease its most frequent etiology. In some populations, infection with cytomegalovirus (CMV) increases risk of coronary disease. Few data exist regarding CMV and cardiovascular mortality after renal transplantation. We reviewed charts of 158 adult patients who died more than 90 days after receiving renal allografts and a matched cohort of 143 (of 2398) surviving patients transplanted at the University of Alabama at Birmingham between 1990 and 1998. Only advancing donor and recipient age increased risk of DWF; CMV infection did not. However, of 50 patients who died of cardiovascular causes, 94% were seropositive for CMV, while only 74% of the other 108 deaths occurred in CMV-seropositive patients (p < 0.05). Risk of cardiovascular death was greatest (p < 0.05) in patients with diabetes, advancing age, and CMV seropositivity. In renal transplant recipients, infection with CMV increases risk of death as a result of cardiovascular causes.

The role of cytomegalovirus in inflammatory bowel disease and gastrointestinal lymphoma

GASTROENTEROLOGY 2002;123:390

Cytomegalovirus in solid organ transplantation.

Despite substantial advances made in controlling the effects of cytomegalovirus (CMV) infection, it remains the single most important pathogen in solid organ transplantation (SOT). Because CMV shares some characteristics with other human herpesviruses, it is also an important model system for understanding the actions of herpesviruses 6 and 7, Epstein-Barr virus (EBV) and, potentially, hepatitis C and B. As the lessons learned from HIV influenced our thinking about other viral infections (e.g. importance of viral load), so too what is learned about CMV will be applied to other herpesviruses. The pervasive nature of CMV and the common problems posed by this virus prompted the convening of a panel of experts in the field of SOT to discuss issues associated with CMV in transplant recipients. This supplement reflects the presentations and discussions at this symposium, including the clinical implications of CMV drug resistance, economic impact of CMV on transplant programs, the rationale for CMV hyperimmune globulin (CMW-IGIV, CytoGam) in SOT, antibody inhibition of CMV, hypogammaglobulinemia, role of CMV in allograft vasculopathy, and the clinical use of CytoGam therapy in a variety of SOT patients. A number of questions during the general discussion prompted the addition of other material to this Supplement, including the development of CMV-IGIV for clinical use in SOT recipients and resource utilization associated with CMV-related hospital readmissions.

Role of cytomegalovirus infection in transplant arteriosclerosis and chronic rejection

Chronic rejection is a serious limitation to long-term survival of all solid-organ allografts. The common pathologic feature of chronic rejection seen across all allografts is transplant arteriosclerosis (TA), an obliterative and fibrotic process involving the vasculature and other hollow structures. These changes are most apparent in cardiothoracic organ transplants, in which the majority of grafts are lost as a result of TA affecting the coronary artery disease after heart transplantation, and obliterative bronchiolitis (OB) after lung transplantation. Recently, considerable evidence has emerged supporting an important role for microorganisms in the disease process of vascular injury leading to chronic rejection. This evidence is based on epidemiologic and observational data from transplant recipients, as well as native organs, experimental models, and therapeutic trials. The organisms that have been implicated in the pathophysiology of arteriosclerosis, include Helicobacter pylori , chlamydia, and herpes viruses, most notably, cytomegalovirus (CMV). CMV infection has been reported as a risk factor for TA and OB, and patients who develop CMV disease after heart transplantation have been shown to have a higher incidence of TA and death from TA compared with those who remain free from the disease. Endomyocardial biopsies from patients during CMV viremia show endothelial and vascular smooth muscle cell proliferation, as well as endothelialitis, independent of acute rejection. These changes, which are consistent with vascular injury induced by CMV, have been shown to be markers of subsequent diffuse TA. Rodent models of heterotopic heart transplantation infected with rat CMV develop TA at an accelerated rate, and this process is partially inhibited by early, prophylactic treatment with the antiviral drug, ganciclovir. Similarly, patients treated prophylactically with ganciclovir during the initial 28 days after heart transplantation had a lower incidence of TA compared with placebo. However, this benefit was not seen in seronegative patients receiving hearts from seropositive donors, consistent with the high-risk nature of this group (D+/R−) for developing acute CMV disease. Recent studies have addressed the question of whether improved prophylaxis could be achieved with the addition of CMV hyperimmune globulin (CMVIG) in high-risk patients, including all donor or recipient seropositivity at lung transplantation. Using historical controls, these studies suggest that a combined regimen of ganciclovir plus CMVIG reduces the incidence of acute CMV disease, TA, OB, and death from OB. These observations emphasize the need for future, randomized, controlled trials to confirm a causal role for CMV (and other pathogens) in the disease process of TA and chronic rejection.

Pneumocystis carinii pneumonia and cytomegalovirus infection in children with vertically acquired HIV infection.

The outcome of Pneumocystis carinii pneumonia (PCP) in HIV-infected infants is poor, and the role of cytomegalovirus (CMV) co-infection in the course and outcome of PCP is unclear. This study describes the prevalence, clinical characteristics, management and changes in survival over time of vertically HIV-infected infants developing PCP and/or CMV infection. Data on children with HIV, born in the UK and Ireland and reported to the National Study of HIV in Pregnancy and Childhood, with PCP and/or CMV were combined with clinical information collected from reporting paediatricians. By April 1998, 340 vertically HIV-infected children had been reported, of whom 93 had PCP and/or CMV, as their first AIDS indicator disease; 85 (91%) were infants. Among infants with PCP, 79% were born to mothers not diagnosed as HIV infected, and there was an independent and statistically significant association with breast-feeding, being black African, and developing CMV disease. Median survival after PCP and/or CMV was significantly better in those born between 1993 and 1998 compared with those born before 1993 (P = 0.009), and worse than after other AIDS diagnoses (P = 0.01). Infants with dual infection were more likely to be ventilated (P = 0.003) and receive corticosteroids (P = 0.002) than those with PCP alone. Although survival from PCP and CMV has improved over time, these remain serious and potentially fatal infections among infants in whom maternal HIV status is not recognized in pregnancy. Breast-feeding increases the risk of combined PCP and CMV infection, which is associated with severe disease.

Cytomegalovirus (CMV)–Specific T Cell Immunity after Renal Transplantation Mediates Protection from CMV Disease by Limiting the Systemic Virus Load

The role of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTLs) and T helper cells (Th) in controlling CMV infection, as detected by antigenemia assay and polymerase chain reaction (PCR) in blood leukocytes, and CMV disease was investigated in 20 renal transplant recipients. Within 3 months after transplant, CMV-specific CTL and Th responses were demonstrable in 11 (55%) and 15 (75%) patients, respectively; CMV infection was detected by antigenemia and PCR in 19 (95%) patients each. During the month of first CMV detection, there was an inverse correlation between CTL response and antigenemia at >/=20 positive cells/105 leukocytes (P=.007) but no association with lower antigenemia levels or PCR positivity. CMV disease developed in 7 (35%) patients and was associated with high-level antigenemia but was inversely correlated with detection of CTLs (P=.04). After renal transplantation, CMV-specific CTLs limit the systemic virus load as reflected by antigenemia levels and thereby mediate protection from CMV disease.

Annexin II enhances cytomegalovirus binding and fusion to phospholipid membranes.

A number of studies have suggested that the anionic phospholipid (anPL)-binding protein annexin II may play a role in cytomegalovirus (CMV) infection. Since annexin II has been shown to mediate aggregation and fusion of certain membranes, we investigated whether these properties could be exploited by CMV directly. The experiments showed that purified annexin II, but not the homologous protein annexin V (AnV), can mediate the binding of 35S-CMV (strain AD169) to anPL-coated microtiter wells. This association required Ca2+, could be titrated by varying either annexin II (apparent Kd = 4 x 10(-)8 M) or 35S-CMV, was inhibited by unlabeled CMV, and was observed for the heterotetrameric or monomeric form of annexin II. In experiments utilizing the fluorescence dequenching of octadecyl rhodamine incorporated into the CMV envelope, annexin II was furthermore found to enhance the rate of virus-anPL vesicle fusion. The observed fusion was dependent on the concentration of annexin II, Ca2+, and anPL and was mediated principally by the heterotetramer. Interestingly, AnV was observed to inhibit the effects of annexin II on CMV fusion but not binding to anPL, which indicates that annexin II enhances these processes by distinct mechanisms. The results presented here provide the first direct evidence that annexin II has the capacity to bridge CMV to a phospholipid membrane and to enhance virus-membrane fusion. These observations furthermore suggest that AnV may regulate the fusogenic function of annexin II.

Role of cytomegalovirus in the T cell changes seen in elderly individuals.

The effect of prior cytomegalovirus (CMV) infection on the immune system was evaluated in young and elderly volunteers. Prevalence of IgG antibodies to CMV was higher in the elderly volunteers. In both age groups, there was a strong association with CMV seropositivity and increased number of CD28- CD4 or CD8 T cells, as well as with increased numbers of T cells expressing CD56 or DR. Although these changes have previously been reported to be age-related, they were independent of age when CMV serological status was taken into account. In contrast, both age group and CMV status were important determinants of the total number of T cells, the number of CD8 T cells, and the number of CD8 T cells expressing CD45RA or CD28. These findings indicate that prior infection with CMV, as reflected by CMV serological status, has important effects on T cell subsets and surface markers and must be considered whenever evaluating age-related changes in immunological parameters.

Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts.

It has been suggested that cytomegalovirus (CMV) infection is involved in allograft rejection. In liver transplantation, it has been suggested that CMV is associated with the development of vanishing bile duct syndrome (VBDS), and persistent CMV has been found in liver grafts that develop chronic rejection. In this experimental study, the effect of rat CMV (RCMV) infection on intragraft changes was investigated in a rat model of acute liver allograft rejection. Liver transplantations were performed in a rat strain combination of PVG (RT1c) --> BN (RT1n). No immunosuppression was given. One group of animals was infected with RCMV Maastricht Strain (10(5) plaque-forming units, intraperitoneally), and another group was left uninfected. The grafts were examined histologically after the rats were killed on postoperative days 7 through 9 at the early phase and days 20 through 30 at the late phase of rejection. Immunohistochemical studies were performed to demonstrate the immunological activation markers major histocompatibility complex class II and interleukin 2 receptors, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and their ligands. RCMV infection was demonstrated from the grafts by culture and direct antigen detection. In liver allografts undergoing acute rejection, CMV significantly increased portal inflammation and caused more severe bile duct damage than in the uninfected grafts. CMV was also linked to the induction of VCAM-1 in the endothelial cells. The ongoing infection was found to vary over time in the different structures of the liver grafts, including the vascular endothelium and bile ducts. Our results support an association between CMV infection and the immunological mechanisms of rejection, as well as the role of CMV in the development of bile duct damage in liver allografts.

Patients with diabetes mellitus and atherosclerosis; a role for cytomegalovirus?

Diabetic patients are known to have an impaired immune response to viral antigens and a high incidence of atherosclerosis. This study was initiated to evaluate the association between cytomegalovirus infection and atherosclerosis in patients with diabetes mellitus. Patients with diabetes mellitus type 1 and 2 (> 5 years) with (group A) and without (group B) clinical signs of atherosclerosis were included. Cytomegalovirus cultures were obtained, serum was screened for CMV-antibodies and CMV-IgG and CMV-IgM titers were determined. Cytomegalovirus antibodies were detected more often in diabetic patients with atherosclerosis compared to patients without atherosclerosis (70.7 vs. 45.2%, P = 0.018). In female patients the prevalence of CMV-antibodies was 89.5 vs. 40.0% ( P = 0.0037). CMV IgG titers were twice as high in group A compared to group B. Cytomegalovirus was cultured from four urine samples and two throat swabs in group B and in one urine and one throat swab in group A. The prevalence of cytomegalovirus antibodies was higher in diabetic patients with atherosclerosis compared to diabetic patients without atherosclerosis. This difference was most striking in the female population. CMV-IgG titers were twice as high in the atherosclerosis group. These data suggest that cytomegalovirus may play a role in the development of clinical atherosclerosis in patients with diabetes mellitus.

Long-term prognosis of renal transplantation after preemptive treatment of cytomegalovirus infection.

A role for cytomegalovirus (CMV) infection in the etiologies of acute and chronic rejection in renal allograft recipients has been suggested. We previously reported that preemptive treatment of CMV infection with ganciclovir in kidney transplant patients was safe and effective. We now present a retrospective analysis of 169 consecutive renal transplant patients, of whom 87 (51.5%) received preemptive treatment with ganciclovir (CMV(+) group). No patient died of CMV infection. Actuarial graft and patient survival rates were not different between the CMV(+) and the CMV(-) groups (graft survival: 68% and 69%; patient survival: 89% and 88%, respectively). At the end of the study, the mean plasma creatinine levels were not statistically different between the two groups (185+/-13 and 166+/-12 micromol/L for the CMV(+) group and the CMV(-) group, respectively). These results suggest that preemptive treatment of CMV infection with ganciclovir may prevent the CMV-induced renal injury and graft loss.