Miklos Degré

The Impact of Cytomegalovirus Infection and Disease on Rejection Episodes in Renal Allograft Recipients

Cytomegalovirus (CMV) infection and disease are potential risk factors for acute allograft rejection in renal transplant recipients. The present study specifically addresses this issue. From October 1994 to July 1997, 477 consecutive renal allograft recipients (397 first transplants and 80 retransplants) were included in the study. CMV infection (cytomegalovirus pp65 antigen in leukocytes) and disease (infection and clinical symptoms or signs of disease) were examined prospectively for 3 months. No CMV prophylaxis was given, and CMV disease was treated with intravenous (i.v.) ganciclovir. The retransplantation of four patients transplanted twice during the study and 22 patients receiving kidneys from human leucocyte antigen (HLA)‐identical siblings were excluded from statistical analysis. Rejections were evaluated clinically [277(61%)] and 173 (38%) also had a biopsy verified rejection. CMV infection occurred in 64% of the patients and 24% experienced CMV disease. In a multiple time‐dependent Cox analysis, CMV infection and CMV disease were independent significant predictors for clinical acute rejections, RR = 1.6 (1.1–2.5, p = 0.02) and RR = 2.5 (1.2–5.1, p = 0.01), respectively. Among 173 patients with biopsy verified rejection, 72% of the patients had tubulointerstitial rejection whereas 28% had a vascular rejection. CMV disease, but not CMV infection was a predictor of tubulointerstitial rejection, RR = 3.1 (1.1–9.3, p = 0.04). CMV infection and disease are independent risk factors for clinical acute rejection in kidney allograft recipients. CMV disease is an independent risk factor for biopsy verified acute tubulointerstitial rejection in kidney allograft recipients.

A prospective study of the natural course of cytomegalovirus infection and disease in renal allograft recipients.

Background. Cytomegalovirus (CMV) infection is the single most frequent infectious complication inrenal transplant recipients. Because no CMV-prophylaxis is given and ganciclovir is used only as deferred therapy for CMV disease at our center, we have been able to study the natural course of CMV infections. The aim was to assess risk factors for CMV infection and disease and thus identify subgroups of patients likely to benefit from CMV prophylaxis or preemptive therapy. Methods. Between October 1994 and July 1997, 477 consecutive renal transplant recipients (397 first transplants and 80 retransplants) were included in the study. The patients were followed prospectively for 3 months with serial measurements of CMV pp65 antigen for monitoring activity of CMV infections. Results. The incidence of CMV infections in first transplants was 68% in D+R− and D±R+ serostatus groups, whereas the incidence of CMV disease was higher in D+R− (56%) than in D±R+ (20%, P <0.001). No difference in severity of CMV disease in D+R− and D±R+ was seen except for an increased incidence of hepatitis in primary infections. One of 14 deaths could be associated with CMV disease in a seropositive recipient. Cox regression analysis showed that rejection (RR 2.5, P <0.01) and serostatus group D+R− (RR 3.9, P <0.001) were significant risk factors for development of CMV disease. The maximum CMV pp65 antigen count had significant correlation to disease only in CMV seropositive recipients, P <0.001. Conclusion. Renal transplant recipients can safely be given deferred ganciclovir therapy for CMV disease if they are intensively monitored for CMV infection. Patients with primary CMV infection (D+R−), CMV infected patients undergoing anti-rejection therapy and R+ patients with high CMV pp65 counts seem to have a particular potential for benefit from preemptive anti-CMV-therapy.

Measles virus antibodies in serum and cerebrospinal fluid in patients with multiple sclerosis and other neurological disorders, with special reference to measles antibody synthesis within the central nervous system ☆

Measles virus hemagglutination-inhibiting (HI) and gel precipitating (GP) antibodies were determined in sera and cerebrospinal fluids (CSF) from 65 patinets with multiple sclerosis (MS) and 65 patients with other neurological diseases. The serological results were correlated to content of immunoglobulin-G (IgG) and electrophoretic patterns of sera and CSF. Measles GP antibodies, identified as directed against measles virus ribonucleoprotein antigens, were detected in sera and in CSF from a significantly higher proportion of MS than of non-MS patients. No significant difference between the 2 groups of patients was found for measles HI antibodies. Reduced serum/CSF HI and/or GP antibody ratios were found in about one half of the MS patients and in 2 patients with chronic myelopathy. All patients with reduced antibody ratios had evidence of IgG synthesis within the central nervous system (CNS), as inferred from oligoclonal IgG patterns of the CSF. Reduced ratios of measles GP antibodies were 3 times as common as reduced ratios of HI antibodies. Immunoelectrophoretic assays indicated that the CSF GP antibodies were electrophoretically restricted in a number of MS patients. The results indicate that measles virus may be an active immunogen within the CNS in many MS patients and in some patients with chronic myelopathy, giving rise to an oligoclonal IgG antibody response.

The Role of Viral Infection in Acute Peripheral Facial Palsy

Thirty-three patients with acute non-traumatic peripheral facial palsy were studied. In one patient, varicella-zoster virus was isolated from CSF. Antibody against the same virus was present in CSF, and rising titre was demonstrated in serum. In two cases, herpes virus hominis was isolated from the nasopharynx. CF-antibody tests indicated recent viral infection in 7 other cases. One additional patient had clinical signs of herpes zoster oticus. In most of these 11 patients, but also in the majority of the remaining 22 patients, an acute phase reaction was present, and serum and CSF immunoglobulins were increased. Thus, an active or recent infection (probably viral) seemed to precede or coincide with the facial palsy in most cases in both groups.

INTERFERON IN the SERUM and CEREBROSPINAL FLUID IN PATIENTS WITH MULTIPLE SCLEROSIS and OTHER NEUROLOGICAL DISORDERS

The presence of interferon (IF) was investigated in serum an cerebrospinal fluid (CSF) from neurological patients. Significant titres of IF were found both in the serum and in the CSF in about half of the patients suffering from acute encephalitis and from multiple sclerosis (MS), but not in patients suffering from various non‐inflammatory disorders in the central nervous system (CNS) or in the peripheral nervous system (PNS), and not in the serum of healthy blood donors. Significant IF titres in the CSF were regularly associated with significant titres in the serum, but the converse was not true. Interferon levels were not correlated to cell counts in the CSF; nor to concentration of IgG and albumin in serum and CSF; nor to presence of electrophoretically oligoclonal IgG patterns; nor to hemagglutinating and gel‐precipitation antibodies against measles. IF levels were lower in the serum of patients having reduced serum/CSF ratios for measle antibody than those with normal ratios. the data may indicate that MS is linked to factors which induce IF production in the CNS.

Diagnosis of cytomegalovirus infection in kidney transplant recipients by a quantitative RNA-DNA hybrid capture assay for cytomegalovirus DNA in leukocytes.

The clinical value of a new RNA-DNA hybridization assay for quantification of Cytomegalovirus (CMV) DNA in leukocytes [Hybrid Capture CMV DNA Assay (HCA); Murex Biotech, UK] was evaluated. The HCA was compared with an assay for CMV pp65 antigen in leukocytes and an in-house CMV polymerase chain reaction PCR (CMV-PCR) on parallel blood samples. The HCA and the CMV-PCR were less sensitive than the CMV pp65 assay, but the positive predictive value of all three methods for CMV disease was 50% or less. However, when quantitation of viral load by HCA and CMV pp65 assay was taken into consideration, both assays were superior to CMV-PCR in predicting CMV disease.

Prevalence of antibodies against parvovirus B19 in Norwegians with congenital coagulation factor defects treated with plasma products from small donor pools.

The seroprevalence of antibodies against parvovirus B19 in 308 Norwegians with coagulation factor defects of different types and severities was assessed by an IgG antibody capture radioimmunoassay (GACRIA). The overall seroprevalence was 62%. The seroprevalence among subjects with different types of coagulation factor defects was related to the type and severity of the coagulation factor defect: severe hemophilia A 64%, moderate and mild hemophilia A 58%, severe hemophilia B 88%, moderate and mild hemophilia B 73%, and von Willebrands disease 52%. The prevalence of parvovirus B19 antibodies among household contacts and blood donors was 49% and 42% respectively. This study confirms that replacement therapy with coagulation factors is accompanied by an increased risk for acquiring parvovirus B19 infection. However, the prevalence of parvovirus B19 antibodies among Norwegian hemophiliacs is well below the prevalence reported from other countries and probably reflects the small numbers of donors in plasma pools used for the preparation of coagulation factor concentrates.

Detection of latent varicella zoster virus DNA and human gene sequences in human trigeminal ganglia by in situ amplification combined with in situ hybridization.

SummaryVaricella zoster virus (VZV) establishes latency in sensory ganglia following primary infection (chickenpox) and may reactivate decades later to produce zoster (shingles). The presence of VZV DNA in latently infected ganglia has been demonstrated by Southern blot hybridization as well as by polymerase chain reaction of DNA extracted from latently infected ganglia. Conflicting results have been obtained by in situ hybridization studies to determine the cell type in the ganglia harboring the latent VZV. To address this controversy we have utilized a more sensitive method than the previous studies. We have applied the technique of polymerase chain reaction to sections of ganglia from latently infected individuals and combined this with in situ hybridization to detect the amplified product. Primers specific for VZV were used to amplify VZV DNA in latently infected human trigeminal ganglia and demonstrated the presence of VZV DNA in neurons only. Sections from human kidney and ganglia from neonates as well as monkey ganglia served as controls and did not show amplification of VZV sequences. Amplification using primers for human genes, alpha tubulin and the oncogene Bcl-2, demonstrated the presence of these sequences in nearly all cells in the human tissues while only weak signals were seen in the monkey tissue. This is the first report where in situ amplification has been utilized to detect latent VZV in human ganglia.

The human polyomavirus BK T antigen induces gene expression in human cytomegalovirus.

Co-infections or co-habitations of cells by two or more viruses may occur in the human organism. Human cytomegalovirus (HCMV) and the human polyomavirus BK (BKV) have common host cells and may both establish lifelong latency/persistence following primary infection. Both viruses may become reactivated by immunosuppression or other conditions which upset host-virus balance, and they encode gene products with the inherent potential of acting as heterologous transacting factors for expression of cellular or viral genes. It has been shown that HCMV induces gene expression and replication of primate polyomaviruses. We now demonstrate that BKV is able to enhance the expression of HCMV immediate early (IE1 and 2) as well as the early (E) protein pp65 during double infections in semi-permissive cells. By transfection experiments it was established that the phenomenon is due to heterologous transcriptional transactivation of the HCMV major IE promoter (MIEP) by the BKV large T antigen, without contribution from the small t antigen.

Human cytomegalovirus productively infects porcine endothelial cells in vitro.

BACKGROUND The possibility that human cytomegalovirus (HCMV) may infect porcine endothelial cells (ECs) was investigated. This may be relevant during xenotransplantation of porcine cells or organs into human recipients. METHODS HCMV was inoculated into low-passage porcine ECs. Replication of virus was detected by development of characteristic cytopathogenic effect. Appearance of immediate early, early, and late antigens was studied by immunocytochemical staining. Infectious virus was detected in human fibroblast cells. Presence of HCMV RNA was studied by Northern Blot and reverse transcriptase polymerase chain reaction. RESULTS All parameters indicated that a fresh clinical HCMV isolate productively infects porcine ECs. The same cells do not fully support replication of the laboratory strain Ad 169. CONCLUSION Our results may indicate the possibility of cross-species infectivity of HCMV to porcine cells.