Human herpesvirus 6 reactivation is associated with cytomegalovirus infection and syndromes in kidney transplant recipients at risk for primary cytomegalovirus infection

A potential association between human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) following kidney transplantation was explored by retrospectively testing serial serum specimens for HHV-6 IgG and IgM antibody. HHV-6 reactivation occurred in 35 (66%) of 53 transplant recipients. Fungal or parasitic opportunistic infections, graft rejection or loss, and mortality were not associated with HHV-6 reactivation. HHV-6 reactivation was associated with primary CMV infection (P=.001) and CMV syndrome (P=.003) and with trends for CMV-related hepatitis (P=.095), CMV-related neutropenia (P=.104), and serious CMV disease (P=.085). After controlling for CMV immune globulin (CMVIG) prophylaxis, the association between HHV-6 reactivation and primary CMV infection and syndrome remained significant (P=.002 and 0.006, respectively). The reduction in CMV syndrome among those receiving CMVIG prophylaxis remained significant (P=.007) after controlling for HHV-6 reactivation. HHV-6 reactivation in kidney transplant recipients at risk for primary CMV infection is associated with CMV infection and CMV-related disease, and these effects are independent of CMVIG prophylaxis.     

The correlation between symptomatic CMV infection and CMV antigenemia in heart allograft recipients

Previous studies have demonstrated that CMV-specific antigens detected from peripheral blood leukocytes correlate with active CMV infection in transplant patients. However, the clinical diagnosis of CMV infection is difficult, and the significance of a positive blood finding is unclear, while CMV antigenemia and viremia may also occur in asymptomatic patients. To investigate the clinical significance of CMV antigenemia after heart transplantation, 68 heart allograft recipients were monitored weekly. Altogether 501 blood specimens were analyzed. CMV was demonstrated in blood leukocytes by a monoclonal antibody and immunoperoxidase staining, and the antigenemia level was expressed as CMV positive cells/50,000 leukocytes. CMV antigenemia occurred in 28/68 patients, and 12 of them developed a symptomatic infection. Of all blood specimens 88/501 were CMV positive, and 30 of them related to the clinical manifestation of CMV. When antigenemia level exceeded > 100/50,000, a significant correlation between antigenemia and CMV-related clinical manifestation was reached (P < 0.001). Of the 28 antigenemia positive patients 16 never developed any clinical signs of CMV infection. Their maximal antigenemia level was low (median 23, range 30-90) compared with those with clinical manifestation (median 500, range 30-1000) (P < 0.002). In conclusion, high antigenemia levels (> 100/50,000) correlate with clinical manifestations of CMV infection. Patients with lower levels (< 100/50,000) do not necessarily ever develop a symptomatic infection. Quantitative monitoring of CMV antigenemia may, thus, be helpful in the clinical diagnosis of CMV infection in heart transplant patients.     

Elevated serum cytokines are associated with cytomegalovirus infection and disease in bone marrow transplant recipients

To assess the relationship between serum cytokines and cytomegalovirus (CMV) reactivation, 75 allogeneic bone marrow transplant patients underwent weekly measurements of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha, CMV blood cultures, and antigenemia tests. Of the patients, 44 (58.7%) developed CMV infection, and 19 (25.3%) developed clinical CMV disease. The mean maximum levels of all three cytokines were significantly increased in patients with CMV infection compared with levels in those without. Maximum levels of IL-6 were significantly higher in patients with active CMV disease than in those who did not develop CMV disease (281.2+/-85.5 vs. 95.7+/-15.0 pg/mL; P=.034). Levels of IL-8 and TNF-alpha were also elevated in patients who developed active disease. In a multivariate logistic regression model, IL-6 levels were independently associated with CMV disease (odds ratio=1.70 per 100-pg/mL increase in IL-6; P=.009). Cytokines may play an important role in the pathogenesis of CMV after bone marrow transplantation and may be a useful predictor for CMV.     

Comparison of PCR and pp65 antigenemia assay with quantitative shell vial culture for detection of cytomegalovirus in blood leukocytes from solid-organ transplant recipients

This study compared PCR and an assay for cytomegalovirus (CMV) pp65 antigenemia (CMV-vue; INCSTAR Corp.) with a quantitative shell vial culture (QSVC) technique for the detection of CMV in serial blood specimens from 46 solid-organ transplant recipients. In a comparison based on 535 specimens tested by PCR and QSVC, CMV was detected by PCR in 41 and by QSVC in 37 of 43 recipients at risk of CMV infection. The mean number of days after transplantation of initial detection of CMV was 29.9 for PCR and 34.0 for QSVC (P = 0.01). The antigenemia assay was performed on 395 specimens, including 304 of those also tested by PCR. In these specimens, CMV was detected by the antigenemia assay, QSVC, and PCR in 30, 32, and 35 (respectively) of 38 patients at risk, with no statistically significant difference in the time to detection. Each of the assays detected CMV in similar proportions of patients with and without clinically significant CMV infection. PCR stayed positive longer after transplantation than the other assays but frequently returned to negative when more than 6 months had elapsed after transplantation. The antigenemia assay and PCR stayed positive longer after institution of antiviral therapy than QSVC. PCR can provide highly sensitive detection of CMV viremia, but a PCR assay for CMV is not yet available in kit form. The pp65 antigenemia assay and shell vial culture are quantifiable and comparable in sensitivity. Either is recommended for rapid detection of CMV in blood specimens from solid-organ transplant recipients.     

Human cytomegalovirus (HCMV) encephalitis in an immunocompetent young person and diagnostic reliability of HCMV DNA PCR using cerebrospinal fluid of nonimmunosuppressed patients

Human cytomegalovirus (HCMV) encephalitis in adult nonimmunosuppressed patients has rarely been reported. We have diagnosed HCMV encephalitis in an anti-HCMV immunoglobulin G-negative, nonimmunosuppressed young woman by HCMV DNA PCR and virus isolation from cerebrospinal fluid (CSF). At the same time, HCMV antigen and HCMV DNA could be demonstrated in peripheral blood leukocytes, and the virus was isolated in fibroblast cultures. After 22 days of acute illness, the virus disappeared from the CSF. Remarkably, the patient did not generate detectable anti-HCMV antibodies within 5 months after the beginning of illness. To investigate the significance of HCMV DNA detection in CSF, samples of CSF, blood cells, and serum from 35 nonimmunosuppressed patients with various neurological disorders (but no herpes simplex virus central nervous system [CNS] disease) were tested for HCMV DNA, antigen, and antibodies. Eleven of these patients were found to be positive for virus DNA and/or antigen in peripheral blood leukocytes. Additionally, HCMV DNA was detected in the CSF of two patients with noninflammatory CNS diseases. A causative role of HCMV in the CNS diseases of these two patients was not evident. In summary, HCMV DNA amplification from CSF samples is a very suitable method to verify HCMV-associated encephalitis, but it should be taken into consideration that there are few cases of positive PCR with DNA from CSF without any known clinical correlative.     

Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin)

BACKGROUND: Sirolimus is an interesting immunosuppressive drug that does not seem to cause nephrotoxicity, neurotoxicity, or diabetogenicity, as commonly seen in patients treated with cyclosporine or tacrolimus. In this report, we describe a possible association between sirolimus and observed hyperlipidemia. METHODS: Serum levels of triglycerides and cholesterol were analyzed in 11 patients who participated in a pilot study evaluating the effect of oral sirolimus or placebo combined with cyclosporine and corticosteroids on the occurrence of acute renal transplant rejection. RESULTS: In four of nine patients given sirolimus, significantly increased serum triglyceride levels were seen, with peak levels occurring 2-4 months after transplantation and ranging between 11.7 and 42.0 mmol/L (reference value <2.2 mmol/L). In two patients given placebo, the serum triglyceride levels remained below 5.0 mmol/L. After reduction or discontinuation of sirolimus, the serum triglyceride levels decreased within 1-2 months and after 1-8 months levels had returned to their pretransplant values. A significant increase in serum cholesterol levels was seen in one of nine patients given sirolimus. CONCLUSION: It seems that long-term treatment with sirolimus in combination with cyclosporine and corticosteroids may increase the risk of hypertriglyceridemia.     

Impact of high-dose oral acyclovir prophylaxis on cytomegalovirus (CMV) disease in CMV high-risk renal transplant recipients

Recent studies showed contradictory results concerning the efficacy of oral acyclovir in the prevention or amelioration of cytomegalovirus (CMV) disease after renal transplantation (TX). This study evaluated the incidence and severity of CMV disease within the first year after TX in high-risk renal transplant recipients (CMV-seropositive donor, seronegative recipient) treated prophylactically with oral acyclovir (800 to 3200 mg/day) over a period of 12 wk (ACY, N = 22), compared with high-risk patients randomly assigned as controls (CO, N = 10). Follow-up for CMV infection included serological determination of CMV-specific immunoglobulin G and immunoglobulin M antibodies, antigen detection in peripheral blood leukocytes (PP 65), shell vial culture (blood), and virus isolation/early antigen detection (urine). Severity of CMV disease was quantified by a scoring system for CMV-related symptoms. Nine patients (40.1%) in the acyclovir group and four patients (40%) in the control group developed CMV disease. Neither severity (ACY, 11.4 versus CO; 12.5 points score), nor duration of disease (ACY, 21 days; CO, 22 days), nor transplant function at the end of the observation period differed significantly. The onst of CMV disease was not delayed significantly in acyclovir-treated patients compared with controls (ACY, 47 +/- 34 days versus CO, 27 +/- 14 days after TX, not significant). Our results show no beneficial effect of oral acyclovir prophylaxis in CMV high-risk renal transplant recipients.     

Pharmacokinetics of tacrolimus (FK506) in primary orthotopic heart transplant patients

STUDY OBJECTIVES: Local recurrence is high when sublobar resection is chosen as primary management of stage I non-small cell lung carcinoma. Postoperative external-beam radiotherapy may reduce this local recurrence problem. A technique of intraoperative brachyradiotherapy following thoracoscopic wedge resection is described as an alternative to adjuvant external-beam radiotherapy for high-risk patients who are not candidates for pulmonary lobectomy. PATIENTS: Fourteen patients with significant impairment in cardiopulmonary function having small peripheral solitary pulmonary nodules underwent video-assisted thoracoscopic (VATS) wedge resection and were found to have non-small cell cancer. Surgical margins were pathologically clear and mediastinal nodes were benign-stage I (T1NO). INTERVENTIONS: A custom polyglyconate mesh (Vicryl) containing 125I seeds was applied to pulmonary resection margins following wedge resection of peripheral lung cancers. A total dose of 100 to 120 Gy at 1 cm was applied to the target area. RESULTS: All patients had histologically clear surgical margins. Postoperative dosimetry confirmed adequate resection margin coverage. There was neither operative mortality nor morbidity related to the VATS wedge resection or the brachytherapy implants. Implants did not migrate, and there were no cases of significant radiation pneumonitis or local recurrence at mean follow-up of 7 months (range, 2 to 12 months). CONCLUSIONS: Intraoperative brachytherapy appears to be a safe and efficient alternative to external-beam radiation therapy when adjuvant radiotherapy is considered following therapeutic wedge resection of stage I (T1NO) lung cancers. The impact on local recurrence, disease-free interval, and survival will require additional follow-up.     

Hyperhomocyst(e)inemia in renal transplant recipients with and without cyclosporine

A reversed-phase high-performance liquid chromatographic method for the determination of quercetin in human plasma following intravenous infusion is described. Quercetin in plasma was extracted with methanol-dimethyl sulphoxide (4:1 v/v) and separated on a C18 Hypersil-BDS column with 44% (v/v) methanol in 0.1 M ammonium acetate (pH 5.15) containing 0.27 mM EDTA as the mobile phase. The drug was detected specifically and sensitively at its absorption maximum of 375 nm, or electrochemically, with a detection limit of 80 ng/mL and 2 ng/mL, respectively.     

Quantitation of human cytomegalovirus (HCMV) DNA in cerebrospinal fluid by competitive PCR in AIDS patients with different HCMV central nervous system diseases

The current study was designed to quantitate human cytomegalovirus (HCMV) DNA in cerebrospinal fluid (CSF) of persons with AIDS with specific HCMV-related CNS disease. DNA present in CSF obtained from AIDS patients was initially detected by a qualitative PCR procedure and then quantitated using a competitive PCR assay. In a group of 21 AIDS patients with HCMV-related CNS disease, 12 patients with HCMV polyradiculopathy had a mean +/- SEM of 11,982 +/- 4,480 copies/microliters in their CSF compared to 1,747 +/- 929 for 9 patients with HCMV encephalitis p = 0.017). Of the 14 patients with > 1,000 copies/microliters of HCMV DNA in CSF, 11(79%) had HCMV polyradiculopathy including all 3 with > 10,000 copies/microliters. Ganciclovir treatment of 3 patients with HCMV-related CNS disease was associated with a decline in HCMV DNA detectable within CSF. These data indicate that quantities of HCMV DNA in CSF are higher in persons with HCMV-related polyradiculopathy than encephalitis, and that quantitation of HCMV DNA can be useful in monitoring antiviral therapy.     

Late acute rejection and subclinical noncompliance with cyclosporine therapy in heart transplant recipients

BACKGROUND: Although noncompliance with immunosuppressive medication is recognized as a critical behavioral risk factor for late acute rejection episodes and graft loss after transplantation, little is known about the degree of subclinical cyclosporine noncompliance, its associated risk for acute late rejection episodes (>1 year after transplantation), and its determinants in heart transplant recipients. METHODS: The convenience sample of this longitudinal study included 101 European heart transplant recipients (87 men and 14 women), with a median age of 56 (Q1 = 50, Q3 = 61) and a median posttransplantation status of 3 (range 1 to 6) years. Subclinical cyclosporine noncompliance was measured during a 3-month period with electronic event monitoring. Selected sociodemographic, behavioral, cognitive, emotional, health, and treatment-related determinants of medication noncompliance were measured by using instruments with established psychometric properties or by patient interviews. With the use of iterative partitioning methods of cluster analysis, including nonstandardized electronic event monitoring compliance parameters, patients were categorized by degree of subclinical cyclosporine noncompliance into a 3-cluster solution. RESULTS: Overall compliance was high, with a median medication taking compliance of 99.4%. The 3 derived clusters, that is, excellent compliers (84%), minor subclinical noncompliers (7%), and moderate subclinical noncompliers (9%), differed significantly by degree of subclinical noncompliance (p < .0001) and showed a 1.19%, 14.28%, and 22.22% incidence of late acute rejections (p = .01), respectively. The 3 groups also differed in terms of former medication noncompliance (p = .02), appointment noncompliance (p = .03), and perceived self-efficacy with medication taking (p = .04). CONCLUSIONS: Although in absolute numbers cyclosporine compliance in this sample was high, minor deviations from dosing schedule were associated with an increased risk for acute late rejection episodes. This suggests a pivotal role of patient compliance in successful long-term outcome after transplantation.     

Quantitative polymerase chain reaction to predict occurrence of symptomatic cytomegalovirus infection and assess response to ganciclovir therapy in renal transplant recipients

Cytomegalovirus (CMV) DNA levels were measured by quantitative-competitive polymerase chain reaction (PCR) in weekly leukocyte samples from 50 renal transplant recipients, including 23 with symptomatic and 27 with asymptomatic CMV infection. Peak and week 4 CMV DNA levels were higher in symptomatic subjects (P = .07 and .02, respectively). In a logistic regression model, the logarithm of the week 4 level independently predicted symptomatic infection (odds ratio, 1.78 for a 1 log10 increase; 95% confidence interval, 1.14-2.78; P = .01). All subjects whose week 4 level exceeded 1000 copies/100,000 leukocytes developed symptoms. In subjects with adequate samples for analysis, CMV levels declined exponentially with ganciclovir treatment, with an average half-life of 3.3 days. Levels exceeding 10,000 copies were associated with prolonged time to clearing of CMV DNA. Potential clinical applications of quantitative CMV PCR include predicting occurrence of symptomatic first episodes after transplantation and individualizing duration of antiviral therapy.     

Management of posttransplant lymphoproliferative disease in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) after pediatric liver transplantation has been associated with high mortality rates. METHODS: The present study examined 282 consecutive pediatric liver transplant recipients from October 1989 to June 1996 who received primary tacrolimus immunosuppression. The aim was to determine the incidence of PTLD, management strategies, and patient outcome. RESULTS: The incidence of PTLD was 13% (361282) with a mean age of 5.5+/-0.7 years (range 0.6 to 15) at diagnosis. The average time from transplantation to PTLD was 10.1+/-2.1 months. Initial treatment of PTLD consisted of reduction (3 patients) or discontinuation (33 patients) of tacrolimus and initiation of antiviral therapy (intravenous ganciclovir, 14 patients; intravenous acyclovir, 22 patients; or both, 5 patients). Alpha-interferon was used in four patients (two successfully). One patient also received gamma-interferon, chemotherapy, and radiation for a central nervous system lesion. Chemotherapy was also used in one patient with Burkitt's, whereas one patient with a pulmonary lesion received additional radiation therapy. Three patients received supportive surgery for gastrointestinal involvement, and one patient had a splenectomy for hemolysis. Overall mortality was 22% (8/36) with 5 (14%) PTLD-related deaths (disseminated disease, 4 patients; bowel perforation, 1 patient). Of 31 survivors, 23 had acute rejection at a median time of 24 days after PTLD, with 2 patients developing chronic rejection. One patient required retransplantation. Present immunosuppression consists of tacrolimus monotherapy in 14 patients, tacrolimus/prednisone in 8 patients, and none in 6 patients. CONCLUSION: In summary, PTLD can be successfully treated with reduction of immunosuppression and administration of antiviral agents in most patients. The management of rejection after PTLD requires reassessment of disease status and judicious reintroduction of immunosuppression therapy.     

Persistence and clinical outcome of hepatitis G virus infection in pediatric bone marrow transplant recipients and children treated for hematological malignancy

The natural course and the clinical significance of hepatitis G virus (HGV) infection were investigated in 106 pediatric patients who received chemotherapy for hematological malignancy or underwent bone marrow transplantation (BMT) using HGV-RNA and antibodies to the HGV-E2 protein (anti-E2). HGV markers were detected in 21 patients (19.8%; HGV-RNA in 19 and anti-E2 in 2). Longitudinal analysis of these HGV-infected patients showed that 1 had anti-E2 before the initial blood transfusion, 14 had persistent viremia, and 6 became clear of circulating HGV-RNA after completion of therapy, although 5 of the 6 HGV-cleared patients never developed anti-E2. Reactivation of HGV infection during chemotherapy was observed in two anti-E2-positive, HGV-RNA-negative patients; the reappearance of the same HGV strain was confirmed by phylogenetic analysis. Among BMT survivors without other known causes of liver dysfunction, HGV-RNA-positive patients had a higher peak serum alanine amino transferase (ALT) value than negative patients. Contrary to previous reports, immunosuppressed patients can apparently recover from HGV infection without detectable anti-E2 and some patients who supposedly recovered from HGV infection can nonetheless suffer exacerbation when subsequently immunosuppressed.     

Depressive syndromes and symptoms in subjects with human immunodeficiency virus (HIV) infection

The association between the infection produced by the human immunodeficiency virus (HIV) and syndromal or subsyndromal depression has been the topic of several studies in recent years. The results of the WHO Neuropsychiatric AIDS Study, conducted in the five geographical areas predominantly affected by the HIV epidemic, suggest that the symptomatic stages of HIV infection are associated with an increased prevalence of depressive symptoms, and, at least in some contexts in which the spreading of the infection is more recent and the social rejection of HIV-seropositive subjects is harsher, may also be associated with an increased prevalence of a syndromal diagnosis of depression.