Publications by authors named "Halvor Rollag"

36 Publications

Parvovirus B19 DNAemia in pregnant women in relation to perinatal death: A nested case-control study within a large population-based pregnancy cohort.

Acta Obstet Gynecol Scand 2020 07 28;99(7):856-864. Epub 2020 Jan 28.

Department of Microbiology, Oslo University Hospital, Oslo, Norway.

Introduction: Parvovirus B19 (B19V) is the infectious cause of exanthema infectiosum. In Europe around 40% of pregnant women are susceptible to infection. Having small children at home is the main risk factor for contracting an infection during pregnancy. The association between B19V-infection and perinatal death is not yet settled. The aims of the study were to estimate the association between maternal parvovirus B19 infection in pregnancy and perinatal death, and to assess the significance of a positive B19V PCR in pregnancy.

Material And Methods: The study population consists of women included in the Norwegian Mother and Child Cohort Study, a prospective population-based pregnancy cohort of nearly 100 000 women. Blood samples were obtained during weeks 17-18 in pregnancy (M1), at birth, and in umbilical cord blood. Within participants in the pregnancy cohort, 138 cases of perinatal death and 1350 controls with live-born children were included in a nested case-control study. Samples were analyzed with B19V serology and B19V PCR according to a predefined test algorithm. For cases, medical records and laboratory results from hospitals were combined with the results of B19V serology and PCR. The reported causes of perinatal death were categorized using the classification system: Causes Of Death and Associated Conditions (CODAC).

Results: The B19V seroconversion rates were 9.8% for cases and 6.8% for control mothers. The odds ratio for maternal B19V infection in cases compared with controls was 1.28 (95% CI 0.35-4.70), adjusted for age, parity, body mass index and tobacco use. B19V-PCR-positive samples were detected at weeks 17-18 of gestation in both cases and controls. The proportion of positive samples was similar in cases and controls, 24% and 28.2%, respectively. Mothers with PCR-positive M1 samples transmitted B19V vertically in 9.1% of cases and in 11.9% of the controls. Of all perinatal deaths, 53% were attributed to placental pathology or unknown causes.

Conclusions: B19V PCR positivity was high and similar in both cases and controls. In our study B19V DNAemia was not seen to be associated with fatal outcome of pregnancy. The clinical significance of B19V DNA detection during pregnancy is uncertain. Caution is needed when diagnosing a B19V infection based only on B19V DNAemia.
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http://dx.doi.org/10.1111/aogs.13801DOI Listing
July 2020

Maternal and congenital cytomegalovirus infections in a population-based pregnancy cohort study.

APMIS 2018 Dec 30;126(12):899-906. Epub 2018 Oct 30.

Department of Microbiology, Oslo University Hospital, University of Oslo, Oslo, Norway.

CMV is the most common cause of congenital infection. During the past few decades, there has been a change in behaviour that possibly has affected the CMV infection rate of mother and child. We investigated 1350 randomly selected pregnant women from the Norwegian Mother and Child Cohort Study using an algorithm for detection of maternal and congenital CMV (cCMV) infection including both serology and nucleic acid amplification assay. The CMV IgG seroprevalence was 54% and 23 (3.7%) mothers seroconverted. Three (0.22%) children had a positive CMV PCR in the umbilical cord blood. The transmission rate was lower than reported in previous studies, probably due to lower sensitivity in plasma compared to saliva and urine. The prevalence of cCMV in the present study was compared with the number registered with the ICD-10 code P.35.1-congenital CMV infection in the Norwegian Patient Register. The number registered was lower than the number of estimated infections. Factors like lower level of education and parity were associated with higher CMV IgG seroprevalence, but no significant difference could be linked to age. In conclusion, in this cohort of pregnant women, a high CMV IgG seroconversion rate was found, while the vertical transmission rate was low.
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http://dx.doi.org/10.1111/apm.12899DOI Listing
December 2018

High incidence of maternal parvovirus B19 infection in a large unselected population-based pregnancy cohort in Norway.

J Clin Virol 2017 09 20;94:57-62. Epub 2017 Jul 20.

Division for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.

Background: Around 40% of pregnant women in Norway are parvovirus B19 (B19V) seronegative and thus at risk for B19 V infection. Studies on samples from women with symptomatic disease or known exposure have shown that nucleic acid amplification assays combined with serology increase the sensitivity and improves the diagnostic procedure.

Objectives: The aim was to investigate the seroprevalence of B19V infection, the occurrence of new infections and vertical transmission in a population-based pregnancy cohort, with special emphasis on the diagnostic methods.

Study Design: We randomly selected 1350 pregnant women from the Norwegian Mother and Child Cohort Study (MoBa), using an algorithm for the detection of B19V infection, including both serology and PCR.

Results: Maternal infection was confirmed in 50 subjects (3.7% of 1349 women), of which 35(70%) were viremic. Of the initially seronegative 33(6.8%) seroconverted. The estimated average annual seroconversion rate was 15.5%, with the highest estimated annual seroconversion rate of 31.6%. The rates of yearly seroconversion followed the pattern found in reports from Norwegian microbiology laboratories. Among all women, 31 (2.3%) had an inconclusive serological profile and 17 (54.8%) had detectable virus. Of the 16 women with virus detectable at gestational week 17-18, seven were still seronegative with absent seroconversion in the second sample taken at birth. All together 10 children were vertically infected.

Conclusions: High incidence of viremic B19V infections and high estimated annual seroconversion rates were found. Lack of seroconversion despite longstanding viremia emphasizes the importance of including PCR when testing for B19V infection during pregnancy.
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http://dx.doi.org/10.1016/j.jcv.2017.07.010DOI Listing
September 2017

Low level of MAp44, an inhibitor of the lectin complement pathway, and long-term graft and patient survival; a cohort study of 382 kidney recipients.

BMC Nephrol 2016 10 18;17(1):148. Epub 2016 Oct 18.

Department of Nephrology, Ullevål Oslo University Hospital, Postbox 4950, Nydalen, 0424, Oslo, Norway.

Background: Higher incidence of malignancy and infectious diseases in kidney transplant recipients is related to immunosuppressive treatment after transplantation and the recipient's native immune system. The complement system is an essential component of the innate immunity. The aim of the present study was to investigate the association of effector molecules of the lectin complement pathway with graft and patient survival after kidney transplantation.

Methods: Two mannan-binding lectin (MBL) associated proteases, MASP-2 and MASP-3 (activators of the lectin pathway) and two MBL-associated proteins, MAp44 and MAp19 (inhibitors of the lectin pathway) were measured at the time of transplantation in 382 patients (≥17 years old) transplanted in 2000-2001. The cohort was followed until December 31, 2014. Data on patient and graft survival were obtained from the Norwegian Renal Registry. Cox proportional hazard regression models were performed for survival analyses.

Results: Low MAp44 level (1st versus 2-4 quartile) was significantly associated with overall mortality; HR 1.52, 95 % CI 1.08-2.14, p = 0.017. In the sub analyses in groups below and above median age (51.7 years), low MAp44 as a predictor of overall mortality was statistically significant only in recipients of ≤51.7 years; HR 2.57, 95 % CI 1.42-4.66, p = 0.002. Furthermore, low MAp44 was associated with mortality due to infectious diseases; HR 2.22, 95 % CI 1.11-4.41, p = 0.023. There was no association between MASP-2, MASP-3 or MAp19 levels and patient mortality. No association between any measured biomarkers and death censored graft loss was found.

Conclusions: Low MAp44 level at the time of transplantation was associated with increased overall mortality in kidney recipients of median age of 51.7 years or below and with mortality due to infectious diseases in the whole patient cohort after nearly 14-years of follow up after transplantation. No associations between other effector molecules; MASP-2, MASP-3 or MAp19 and recipient mortality were found, as well as no association of any biomarker with death censored graft loss.
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http://dx.doi.org/10.1186/s12882-016-0373-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070230PMC
October 2016

Lessons Learned From a Randomized Study of Oral Valganciclovir Versus Parenteral Ganciclovir Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients: The VICTOR Trial.

Clin Infect Dis 2016 May 16;62(9):1154-60. Epub 2016 Feb 16.

Department of Transplant Medicine, Section of Nephrology Institute of Clinical Medicine, University of Oslo, Norway.

The VICTOR study showed comparable efficacy of treatment with intravenous ganciclovir and oral valganciclovir for cytomegalovirus (CMV) disease in solid organ transplant recipients. Oral therapy is now recommended treatment in clinical practice and guidelines. The VICTOR biobank was used in a series of post hoc analyses that yielded unique and clinically valuable insights into CMV treatment and pathogenesis. For example, the importance of tailoring therapy to initial viral load, the effect of immunosuppression on outcomes, and the need to continue therapy until undetectable viral load to prevent recurrence and emergence of resistant strains. Data were also used to validate the use of international units (IU) in quantitative measurements of CMV DNAemia, which may help future studies to define relevant cutoffs for treatment guidance. The analyses also showed the importance of inflammation on viral outcomes and identified potential targets for future studies. Here we summarize the valuable lessons learned from analysis of the VICTOR data set and sample repository.
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http://dx.doi.org/10.1093/cid/ciw084DOI Listing
May 2016

Polyclonal Expansion of NKG2C(+) NK Cells in TAP-Deficient Patients.

Front Immunol 2015 6;6:507. Epub 2015 Oct 6.

Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet , Stockholm , Sweden ; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital , Oslo , Norway ; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo , Oslo , Norway.

Adaptive natural killer (NK) cell responses to human cytomegalovirus infection are characterized by the expansion of NKG2C(+) NK cells expressing self-specific inhibitory killer-cell immunoglobulin-like receptors (KIRs). Here, we set out to study the HLA class I dependency of such NKG2C(+) NK cell expansions. We demonstrate the expansion of NKG2C(+) NK cells in patients with transporter associated with antigen presentation (TAP) deficiency, who express less than 10% of normal HLA class I levels. In contrast to normal individuals, expanded NKG2C(+) NK cell populations in TAP-deficient patients display a polyclonal KIR profile and remain hyporesponsive to HLA class I-negative target cells. Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production. Thus, while interactions with self-HLA class I molecules likely shape the KIR repertoire of expanding NKG2C(+) NK cells during adaptive NK cell responses in normal individuals, they are not a prerequisite for NKG2C(+) NK cell expansions to occur. The emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to antiviral immunity and potentially explain these patients' low incidence of severe viral infections.
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http://dx.doi.org/10.3389/fimmu.2015.00507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594010PMC
October 2015

[Re: Hearing loss in children in Östfold county 2000-09].

Tidsskr Nor Laegeforen 2015 Mar 24;135(6):513. Epub 2015 Mar 24.

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http://dx.doi.org/10.4045/tidsskr.15.0262DOI Listing
March 2015

Viral infection in placenta relevant cells--a morphological and immunohistochemical cell culture study.

APMIS 2015 Jan 22;123(1):60-4. Epub 2014 Sep 22.

Department of Pathology, Oslo University Hospital (OUS), Oslo, Norway.

Viral infections in pregnancy are known to cause fetal malformation, growth restriction, and even fetal death. Macroscopic placental examination usually shows slight and unspecific changes. Histology may show secondary, non-specific tissue reaction, i.e. villitis with lymphocytic invasion. Primary specific morphology characteristics are known for some virus, like cytomegalovirus, parvovirus, and herpes simplex, however many viral infections show non-specific changes. Placenta relevant cells as human first trimester trophoblasts HTR8/SVneo, primary human umbilical vein endothelial cells (HUVEC), and primary human embryonic fibroblasts were examined following infection with commonly occurring virus like adenovirus and enterovirus. Morphology in routine stained sections and virus-specific immunostains were studied 4, 8, 24, 48, 72 h after infection. Nuclear enlargement was seen in the infected cells. A specific diagnosis of adenovirus or enterovirus infection, however, was not possible without specific immunostains.
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http://dx.doi.org/10.1111/apm.12307DOI Listing
January 2015

High ficolin-3 level at the time of transplantation is an independent risk factor for graft loss in kidney transplant recipients.

Transplantation 2015 Apr;99(4):791-6

1 Department of Nephrology, Ullevål Oslo University Hospital, Oslo, Norway. 2 Department of Transplant Medicine, Rikshospitalet Oslo University Hospital, Oslo, Norway. 3 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. 4 Unit of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway. 5 Department of Microbiology, Rikshospitalet Oslo University Hospital, Oslo, Norway. 6 Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. 7 K.G Jebsen IRC, University of Oslo, Norway. 8 Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, University of Tromsø, Tromsø, Norway. 9 Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Background: Recent studies have shown that activation of the complement system may be associated with long-term graft function. The aim of this retrospective study was to assess the impact of the pattern recognition molecules of the lectin pathway on long-term graft survival after kidney transplantation.

Methods: Patients transplanted in 2000 to 2001 were included. Mannose-binding lectin, Ficolin-1, and Ficolin-3 were measured in serum at the time of transplantation. Data on death-censored graft loss were obtained from the Norwegian Renal Registry. Competing risks regression was used to investigate the association between time to graft loss and the explanatory variables. The variables were: high Ficolin-3 (upper quartile, ≥33.3 μg/mL) versus low Ficolin-3 (<33.3 μg/mL), acute rejection (time-dependent), age, basiliximab induction, sex, donor age, human leukocyte antigen mismatches, human leukocyte antigen antibodies, cold ischemia time, living donor, and preemptive transplantation.

Results: A total of 382 patients with a median follow-up of 9.8 years were included. Sixty-six patients (17%) had death-censored graft loss, and 116 (30%) patients died. In a final competing risks model, high Ficolin-3 (subhazard ratio [SHR] = 1.95, P = 0.009), acute rejection (one vs. none) (SHR = 1.93, P = 0.033), acute rejection (two vs. none) (SHR = 5.45, P < 0.001), and age (SHR = 0.98, P = 0.006) were associated with death-censored graft loss. Basiliximab induction was associated with improved graft survival (SHR = 0.50, P = 0.016). No associations between mannose-binding lectin or Ficolin-1 and graft loss were found.

Conclusion: High Ficolin-3 level at the time of transplantation was an independent significant risk factor for shorter graft survival, even when adjusted for other covariates.
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http://dx.doi.org/10.1097/TP.0000000000000422DOI Listing
April 2015

[Allogeneic stem-cell transplantation in adults 1985-2012: results and development].

Tidsskr Nor Laegeforen 2014 Sep 2;134(16):1569-75. Epub 2014 Sep 2.

Avdeling for blodsykdommer Oslo universitetssykehus, Rikshospitalet.

Background: Allogeneic stem cell transplantation (ASCT) has been a treatment option for patients with serious diseases of the blood and haematopoietic organs in Norway since 1985. Such treatment is potentially curative for selected patients who have a relatively short predicted survival with other treatment modalities. This article summarises the experience and results from ASCT at Oslo University Hospital Rikshospitalet.

Material And Method: The study included all of the 734 adult patients who had undergone allogeneic stem cell transplantation at the Department of Haematology, Rikshospitalet, later Oslo University Hospital Rikshospitalet, from November 1985 to October 2012.

Results: At the time of analysis, altogether 384 patients were alive, and the five and ten-year survival rates were 54% and 48% respectively. The median follow-up time was six years. A total of 339 patients (46%) had developed acute graft-versus-host disease (GvHD), and 250 (73%) of these had GvHD ≥ grade II. Altogether 280 out of 602 patients who lived ≥ 100 days after the transplantation (46.5%) developed chronic GvHD. The most frequent causes of death included recurrence of the initial disease in 116 patients (33.1 %), multi organ failure after transplantation in 88 patients (25.4%), infections in 54 patients (16%) and GvHD in 33 patients (9.4%).

Interpretation: ASCT is a treatment option with a curative potential for patients with serious haematological diseases when other forms of treatment provide few prospects for recovery. The total survival rate in our study is in accordance with international results for the same time period, and the indications have consistently been in line with what is accepted internationally.
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http://dx.doi.org/10.4045/tidsskr.13.1415DOI Listing
September 2014

Increased osteoprotegerin predicts poor virological outcome during anticytomegalovirus therapy in solid organ transplant recipients.

Transplantation 2015 Jan;99(1):100-5

1 Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 2 Department of Microbiology, Oslo University Hospital Rikshospitalet, Oslo, Norway. 3 Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway. 4 Department of Organ Transplantation, Gastroenterology and Nephrology, Section for Nephrology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway. 5 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 6 Faculty of Medicine, University of Oslo, Oslo, Norway. 7 K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway. 8 Institute of Cardiovascular and Medical Sciences University of Glasgow, Glasgow, United Kingdom. 9 Department of Medicine, University of Alberta, Edmonton, Canada. 10 School of Specialization in Hospital Pharmacy, University of Milan, Milan, Italy.

Background: Cytomegalovirus (CMV) infection involves interaction between endothelial cells and leukocyte subsets that may promote vascular inflammation and lead to treatment failure in infected individuals. Osteoprotegerin is a marker of vascular and systemic inflammation but has not been investigated in relation to treatment outcome during CMV infection.

Methods: We investigated whether circulating levels of osteoprotegerin are related to features of CMV disease and treatment outcomes during CMV infection in 291 solid organ transplant recipients receiving valganciclovir or ganciclovir in an international multicenter trial of CMV disease treatment (the VICTOR study).

Results: Elevated plasma osteoprotegerin was associated with (i) certain disease characteristics including presence of tissue invasive disease (P<0.05) and increased viral load at baseline (P<0.05), (ii) poor virological outcome at day 49 after anti-CMV therapy, (iii) increased plasma levels of markers of inflammation (pentraxin 3 and C-reactive protein) and endothelial cell activation (von Willebrand factor) both at baseline and during follow-up.

Conclusion: Our finding indicates that elevated osteoprotegerin levels in solid organ transplant recipients with CMV infection may reflect vascular inflammation and is associated with late virological outcome in these patients.
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http://dx.doi.org/10.1097/TP.0000000000000227DOI Listing
January 2015

The impact of early cytomegalovirus infection after kidney transplantation on long-term graft and patient survival.

Clin Transplant 2014 Jan 18;28(1):120-6. Epub 2013 Dec 18.

Department of Nephrology Ullevål, Oslo University Hospital, Oslo, Norway.

This prospective observational cohort study is an extension of a previous study reporting effects of cytomegalovirus (CMV) on graft and patient survival in 471 patients who underwent kidney transplantation between 1994 and 1997. CMV pp65 antigen was measured every 7-14 d during the first three months after transplantation, given as number of CMV pp65-positive cells per 10(5) leukocytes. A positive test was defined as CMV infection. None of the patients received CMV prophylaxis or preemptive treatment. During a median of 13.7 (7.1-14.9) yr, the number of death-censored graft losses was 118 (25%) and of patient deaths 224 (48%). CMV infection was an independent significant risk factor for mortality in multivariate analysis (HR = 1.453, 95% CI 1.033-2.045, p = 0.032), adjusting for patient and donor age, preemptive transplantation, HLA-DR and -AB mismatches, living donor, acute rejection during the first three months, donor-recipient CMV IgG antibody status and diabetic nephropathy. In univariate analysis, CMV infection was significantly associated with death-censored graft loss but the association was not significant in multivariate model. CMV infection early after kidney transplantation is a predictor of overall mortality but not of death-censored graft loss after a median observation period of 13.7 yr.
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http://dx.doi.org/10.1111/ctr.12288DOI Listing
January 2014

Characterization of cytomegalovirus disease in solid organ transplant recipients by markers of inflammation in plasma.

PLoS One 2013 8;8(4):e60767. Epub 2013 Apr 8.

Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: While several studies have examined the general inflammatory responses in relation to cytomegalovirus infection, the identification of the various inflammatory mediators as well as their relative importance is far from clear.

Patients And Methods: Solid organ recipients enrolled in an international multicenter trial of cytomegalovirus disease treatment (the VICTOR study) were analyzed (n = 289) (ClinicalTrials.gov NCT00431353). Plasma markers of inflammation and endothelial cell activation were assessed at baseline by enzyme immunoassays.

Results: The major findings were: (i) Plasma levels of the CXC-chemokine interferon-inducible protein-10 (P<0.001) and C-reactive protein (P = 0.046) were independently associated with the presence of cytomegalovirus DNAemia above lower level of quantification. (ii) High levels of CC-chemokine ligand 21 (P = 0.027) and pentraxin 3 (P = 0.033) were independently associated with tissue invasive cytomegalovirus disease as opposed to cytomegalovirus syndrome.

Conclusion: Our findings illustrate the complex interaction between cytomegalovirus and the immune system, involving a wide range of inflammatory mediators that could be associated to disease manifestations in cytomegalovirus related disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060767PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620537PMC
November 2013

Virologic suppression measured by a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization international standard is predictive of CMV disease resolution in transplant recipients.

Clin Infect Dis 2013 Jun 15;56(11):1546-53. Epub 2013 Feb 15.

Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905-0002, USA.

Background: Cytomegalovirus (CMV) load measurement is used to assess the efficacy of treatment of CMV disease, but lacks standardization. Using the World Health Organization (WHO) international standard for reporting, we correlated viral load with CMV disease resolution.

Methods: CMV load was quantified in plasma using a test calibrated to the WHO standard. Three predictive rules were predefined to determine association between CMV DNAemia and outcome: (1) pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL; (2) viral load declines of 1.0, 1.5, 2.0, and 2.5 log(10) IU/mL from baseline to days 7, 14, and 21 of treatment, respectively; and (3) viral suppression <137 (2.1 log(10)) IU/mL at days 7, 14, and 21. Analysis was performed using Cox proportional hazard models.

Results: Of 267 patients, 251 had CMV disease resolution by day 49 of treatment. Patients with pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL had faster time to disease resolution (adjusted hazard ratio [AHR], 1.56; P = .001). Patients with CMV load suppression (<137 IU/mL [<2.1 log(10)]) at days 7, 14, and 21 had faster times to clinical disease resolution (AHRs, 1.61, 1.73, and 1.64, and P = .005, <.001, and <.001, respectively). Relative CMV load reductions from baseline were not significantly associated with faster resolution of CMV disease.

Conclusions: Patients with pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL are 1.5 times more likely to have CMV disease resolution. CMV suppression (<137 [2.1 log(10)] IU/mL), as measured by a test calibrated to the WHO Standard, is predictive of clinical response to antiviral treatment.

Clinical Trials Registration: NCT00431353.
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http://dx.doi.org/10.1093/cid/cit096DOI Listing
June 2013

Treatment of cytomegalovirus disease in solid organ transplant recipients: markers of inflammation as predictors of outcome.

Transplantation 2012 Nov;94(10):1060-5

Department of Microbiology, Oslo University Hospital, Rikshospitalet, Nydalen, Oslo, Norway.

Background: Treatment failure or relapse is common in solid organ transplant recipients treated for cytomegalovirus (CMV) disease. Because CMV infections induce a vigorous inflammatory response, we investigated whether pretreatment levels of inflammatory markers were associated with virologic and clinical outcomes.

Methods: Solid organ transplant recipients enrolled in an international multicenter trial of CMV disease treatment (the VICTOR study) were studied (n=248). Plasma levels of markers of inflammation and endothelial cell activation were assessed at baseline and during follow-up by enzyme immunoassays.

Results: Baseline values for the chemokine CXCL16 was an independent predictor of clinical outcome (P=0.003) and was a weak independent predictor of suppression of viral load below level of detection (LOD) (P=0.013) at day 21 after initiation of treatment. Baseline levels of the long pentraxin 3 (PTX3) was an independent predictor of suppression of viral load below LOD at day 21 (P=0.002), whereas baseline levels of von Willebrand factor (vWF) was an independent predictor of clinical outcome at day 21 (P=0.008), and vWF levels at day 21 was a weak independent inflammatory predictor of viral recurrence (P=0.018).

Conclusions: The present study shows that the plasma levels of CXCL16, PTX3 and vWF at the start of treatment are independently associated with virologic and clinical treatment failure during anti-CMV therapy in solid organ transplant recipients. These findings suggest a link between CMV infection and inflammation that also may influence the outcome of anti-CMV therapy.
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http://dx.doi.org/10.1097/TP.0b013e31826c39deDOI Listing
November 2012

Cytomegalovirus viremia in dried blood spots is associated with an increased risk of death in HIV-infected patients: a cohort study from rural Tanzania.

Int J Infect Dis 2012 Dec 30;16(12):e879-85. Epub 2012 Sep 30.

Department of Infectious Diseases, Oslo University Hospital, POB 4956 Nydalen, N-0424 Oslo, Norway.

Objectives: The objectives of the study were to assess the utility of dried blood spots (DBS) for the detection of cytomegalovirus (CMV) antibody and viremia in a resource-poor setting, to study the prevalence of CMV antibody and viremia in HIV-infected patients with access to antiretroviral therapy (ART) in Tanzania, and to relate CMV viremia to outcome.

Methods: DBS were prepared from 168 ART-naïve patients at baseline. Demographic, clinical, and laboratory data were obtained from patient records. CMV antibody was analyzed by chemiluminescent microparticle immunoassay and viremia by quantitative PCR.

Results: All patients were CMV-seropositive. At baseline 38 (22.6%) had detectable CMV viremia and 14 (8.3%) had a CMV viral load ≥ 200 copies/ml. In 135 patients available for follow-up, CMV ≥ 200 copies/ml was an independent risk factor for death with a hazard ratio of 5.0 (95% confidence interval 2.1-11.9) after adjusting for confounders. Symptoms compatible with CMV disease were common with viremia ≥ 200 copies/ml and CD4+ T cell counts <100 cells/mm(3), but confirmatory diagnostic procedures were unavailable.

Conclusions: DBS are suitable for the detection of CMV antibody and viremia in HIV patients in resource-poor areas. CMV viremia was frequent and associated with an increased risk of death. Improved diagnosis and treatment of CMV may improve the prognosis for HIV-infected patients in developing countries and should be addressed in future studies.
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http://dx.doi.org/10.1016/j.ijid.2012.08.003DOI Listing
December 2012

The chromatin remodeling factor SMARCB1 forms a complex with human cytomegalovirus proteins UL114 and UL44.

PLoS One 2012 27;7(3):e34119. Epub 2012 Mar 27.

Department of Microbiology, University of Oslo and Oslo University Hospital HF, Oslo, Norway.

Background: Human cytomegalovirus (HCMV) uracil DNA glycosylase, UL114, is required for efficient viral DNA replication. Presumably, UL114 functions as a structural partner to other factors of the DNA-replication machinery and not as a DNA repair protein. UL114 binds UL44 (HCMV processivity factor) and UL54 (HCMV-DNA-polymerase). In the present study we have searched for cellular partners of UL114.

Methodology/principal Findings: In a yeast two-hybrid screen SMARCB1, a factor of the SWI/SNF chromatin remodeling complex, was found to be an interacting partner of UL114. This interaction was confirmed in vitro by co-immunoprecipitation and pull-down. Immunofluorescence microscopy revealed that SMARCB1 along with BRG-1, BAF170 and BAF155, which are the core SWI/SNF components required for efficient chromatin remodeling, were present in virus replication foci 24-48 hours post infection (hpi). Furthermore a direct interaction was also demonstrated for SMARCB1 and UL44.

Conclusions/significance: The core SWI/SNF factors required for efficient chromatin remodeling are present in the HCMV replication foci throughout infection. The proteins UL44 and UL114 interact with SMARCB1 and may participate in the recruitment of the SWI/SNF complex to the chromatinized virus DNA. Thus, the presence of the SWI/SNF chromatin remodeling complex in replication foci and its association with UL114 and with UL44 might imply its involvement in different DNA transactions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034119PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313996PMC
November 2012

Differential decay kinetics of human cytomegalovirus glycoprotein B genotypes following antiviral chemotherapy.

J Clin Virol 2012 May 10;54(1):56-60. Epub 2012 Mar 10.

Centre for Virology, Department of Infection, University College Medical School, London, United Kingdom.

Background: The impact of different cytomegalovirus (HCMV) glycoprotein B (gB) genotypes on pathogenesis remains controversial.

Objectives: To investigate the effect of gB genotypes either as single infections or as part of multiple infections on the early kinetics of response to ganciclovir therapy.

Methods: Patients (n=239) enrolled in a study of intravenous ganciclovir or valganciclovir for the treatment of HCMV disease were analysed by a gB genotype specific PCR to quantify the amount of each gB genotype present at initiation of therapy (baseline, day 0) and at days 3, 7, 14 and 21 post therapy.

Results And Conclusions: In all gB groups (individual gB genotype infections and mixed genotype infections) there was a biphasic decline in viral load after therapy. The first phase half life (days 0-3) was ≤1 day and was followed over the next 18 days by a slower second phase decline with half lives ranging from 3.4 to 4.4 days. The 1st phase rapid decline in viral load was dependent upon gB genotype whereas the ultimate viral load reduction at day 21 was relatively insensitive to gB genotype. A strong correlation between 1st phase decline and extent of viral load reduction at day 21 was observed (r=0.37; p=0.002). These data imply that early reductions in HCMV load after therapy may be useful in predicting the duration of drug therapy needed to control HCMV replication.
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http://dx.doi.org/10.1016/j.jcv.2012.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328767PMC
May 2012

Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients.

Transplantation 2011 Jul;92(2):217-23

Section of Nephrology, Medical Department, Oslo University Hospital, Oslo, Norway.

Background: Cytomegalovirus (CMV) infections in kidney transplant recipients are in most cases successfully treated with oral valganciclovir (VGCV). However, in a few percent of patients, mutations in the UL 97 or UL 54 gene lead to drug resistance.

Methods: We investigated the incidence and outcomes of ganciclovir-resistant CMV viremia in all 1244 kidney recipients transplanted at our center from 2004 through 2008. CMV DNAemia was monitored in all patients at least weekly, and patients who were positive were treated preemptively with VGCV (900 mg once daily).

Results: Ganciclovir-resistant mutations were detected in 27 patients (2.2%), of which 26 occurred in the 209 CMV IgG-negative recipients receiving a CMV-positive kidney (12.5%). All had UL97 gene mutations, and none had UL54 gene mutations. Mean DNAemia half-life for the first (nonresistance) episode of CMV viremia was 3.8 ± 1.2 days. After established resistance, 25 of 27 patients had their mycophenolate mofetil dose reduced by approximately 50%, and 10 of these were also treated with intravenous foscarnet. The DNAemia half-life was 3.7 ± 1.4 days in the foscarnet-treated patients, significantly shorter than in the other 17 patients, 10.8 ± 6.7 days (P = 0.001). Time to DNAemia eradication was 30 ± 16 and 81 ± 51 days in the two groups, respectively (P = 0.001).

Conclusion: Use of 900 mg VGCV once daily for preemptive CMV treatment is associated with a high incidence of CMV UL97-resistance gene mutations in D+/R- patients. Foscarnet treatment rapidly and safely eradicated CMV DNAemia, and also patients who only reduced the immunosuppression and continued on VGCV treatment eventually cleared the virus.
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http://dx.doi.org/10.1097/TP.0b013e31821fad25DOI Listing
July 2011

The clinical utility of whole blood versus plasma cytomegalovirus viral load assays for monitoring therapeutic response.

Transplantation 2011 Jan;91(2):231-6

Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Background: In patients with cytomegalovirus (CMV) disease, regular monitoring of viral loads and treatment until negative are recommended. However, with more sensitive polymerase chain reaction (PCR) assays and cellular peripheral sample types, detection of low-level viremia is achievable. We compared a whole blood real-time PCR with a plasma PCR assay for monitoring therapeutic response.

Methods: Patients enrolled in a trial to treat CMV disease for 21 days had regular viral load monitoring. The results of a plasma-based PCR assay were compared with a real-time PCR assay of whole blood and assessed for their ability to predict recurrence.

Results: In 219 evaluable patients, viral loads in plasma versus whole blood demonstrated good correlation but significant difference in absolute value and clearance kinetics. Virus was still detectable by day 21 in 154 of 219 (70.3%) patients with the whole blood versus 105 of 219 (52.1%; P<0.001) patients with the plasma assay. The positive predictive value of persistent plasma viremia at day 21 for virologic recurrence was 41.9% vs. 36.3% for the whole blood assay. In the subset of patients with a negative plasma but positive whole blood at day 21 (n = 49), the incidence of virologic recurrence was similar to that of all patients with a negative plasma assay (23.1% vs. 23.6%).

Conclusions: When treating CMV disease, enhanced detection of residual viremia using a whole blood real-time PCR does not seem to offer significant clinical advantages nor allows for better prediction of recurrence of CMV viremia or disease. The treat-to-negative paradigm may not hold true when such assays are used.
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http://dx.doi.org/10.1097/TP.0b013e3181ff8719DOI Listing
January 2011

Valganciclovir for the prevention and treatment of CMV in solid organ transplant recipients.

Expert Opin Pharmacother 2010 May;11(7):1159-66

University of Oslo, School of Pharmacy, PO Box 1068, Blindern, 0316 Oslo, Norway.

Importance Of The Field: Cytomegalovirus (CMV) infection is the most common viral infectious complication after solid organ transplantation (SOT). Ganciclovir is the first-line anti-CMV treatment, but its low oral bioavailability limits its use and generally intravenous treatment has been mandatory. Valganciclovir is a prodrug of ganciclovir with > 60% bioavailability and has become an alternative to intravenous ganciclovir.

Areas Covered In This Review: The review examines the use of valganciclovir both for prophylaxis and treatment of CMV disease in SOT.

What The Reader Will Gain: The reader will be provided an overview of the literature on valganciclovir related to efficacy and safety in SOT recipients. Furthermore, the use of valganciclovir in less well-documented areas, such as patients with potential problems with oral absorption of drugs, pediatric patients and patients with life-threatening CMV disease, is discussed.

Take Home Message: The major take home message is that valganciclovir is a documented option for prevention and treatment of CMV in most SOT recipients. Given the ease of use and clinical efficacy it allows for substituting intravenous treatment in the majority of cases and has resulted in a major change of therapy for CMV in solid organ transplanted patients.
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http://dx.doi.org/10.1517/14656561003742954DOI Listing
May 2010

Impact of genetic polymorphisms in cytomegalovirus glycoprotein B on outcomes in solid-organ transplant recipients with cytomegalovirus disease.

Clin Infect Dis 2009 Oct;49(8):1160-6

Transplant Infectious Diseases and Provincial Laboratory for Public Health (Microbiology), University of Alberta, Edmonton, Alberta, Canada.

Background: It is unknown whether specific viral polymorphisms affect in vivo therapeutic response in patients with cytomegalovirus (CMV) disease. Polymorphisms in the CMV glycoprotein B (gB) gene allow discrimination of 4 distinct genotypes (gB1-gB4). We assessed the influence of gB genotypes on the clinical and virologic outcome of CMV disease.

Methods: Solid-organ transplant recipients enrolled in a multicenter trial of CMV disease treatment (VICTOR study) were included in this study. CMV gB genotyping was performed using quantitative real-time polymerase chain reaction at day 0 (start of antiviral therapy).

Results: Among 239 patients with CMV disease, the prevalence of gB strain types was 26% for gB1, 10% for gB2, 10% for gB3, and 5% for gB4, whereas mixed infections were present in 49%. Donor-seropositive/recipient-seropositive patients were more likely to have mixed gB infection than donor-seropositive/recipient-seronegative patients (40% vs. 12%; P = .001). Median baseline viral loads were higher and time to viral eradication was longer ( P = .006 and P = .026 , respectively) for mixed infection versus infection with a single genotype. In a multivariate model, mixed gB infection was a significant predictor of failure to eradicate virus by day 21 (mixed vs single genotype; odds ratio, 2.66; 95% confidence interval, 1.31-5.38; P = .007 ) after controlling for baseline viral load, CMV serostatus at baseline, ganciclovir resistance, and antiviral treatment. No effect of gB genotype was seen on virologic or clinical CMV recurrence.

Conclusions: No specific gB genotype appears to confer a specific CMV virulence advantage. However, mixed gB genotype infections are associated with higher viral loads and delayed viral clearance.
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http://dx.doi.org/10.1086/605633DOI Listing
October 2009

Cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral valganciclovir.

Antivir Ther 2009 ;14(5):697-704

Infectious Disease Research Center of the Centre hospitalier universitaire de Québec, Québec City, QC, Canada.

Background: The rate of cytomegalovirus (CMV) mutations conferring ganciclovir resistance was assessed in a trial comparing intravenous ganciclovir and oral valganciclovir for treatment of CMV disease in solid organ transplant (SOT) recipients.

Methods: Viral genes (UL97 and UL54) conferring ganciclovir resistance were amplified and sequenced from blood samples collected at days 0 (before therapy), 21 (end of induction) and 49 (end of maintenance).

Results: The overall risk of developing a confirmed or probable ganciclovir resistance mutation during treatment was similar for patients treated with ganciclovir (2.3%) and valganciclovir (3.6%; P=0.51). A persistent viral load at day 21 was associated with a significant risk of ganciclovir resistance by day 49 (odds ratio 11.83; P=0.022). In multivariate analyses, presence of a confirmed ganciclovir resistance mutation was independently associated with virological failure (viral load > or =600 copies/ml) at days 21 and 49. One-third (3/9) of patients with confirmed CMV resistance mutations had recurrent CMV disease. The plasma half-life of confirmed ganciclovir-resistant UL97 mutants was significantly longer than that of wild-type strains, polymorphic variants and strains with mutations of unknown significance (P=0.045). Multiple UL54 mutations of unknown significance were found in clinical strains. Viral kinetic analysis of these latter strains revealed no effect (negative or positive) on in vivo viral fitness.

Conclusions: Treatment with oral valganciclovir or intravenous ganciclovir results in similar and low rates of resistance mutations in SOT recipients. Patients with drug-resistant CMV strains often have virological failure and might have unfavourable clinical outcomes.
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September 2009

Characterization of human cytomegalovirus uracil DNA glycosylase (UL114) and its interaction with polymerase processivity factor (UL44).

J Mol Biol 2008 Aug 17;381(2):276-88. Epub 2008 May 17.

Department of Virology, Rikshospitalet Medical Centre, N-0027 Oslo, Norway.

Here, we report the molecular characterization of the human cytomegalovirus uracil DNA glycosylase (UNG) UL114. Purified UL114 was shown to be a DNA glycosylase, which removes uracil from double-stranded and single-stranded DNA. However, kinetic analysis has shown that viral UNG removed uracil more slowly compared with the core form of human UNG (Delta84hUNG), which has a catalytic efficiency (k(cat)/K(M)) 350- to 650-fold higher than that of UL114. Furthermore, UL114 showed a maximum level of DNA glycosylase activity at equimolar concentrations of the viral polymerase processivity factor UL44. Next, UL114 was coprecipitated with DNA immobilized to magnetic beads only in the presence of UL44, suggesting that UL44 facilitated the loading of UL114 on DNA. Moreover, mutant analysis demonstrated that the C-terminal part of UL44 (residues 291-433) is important for the interplay with UL114. Immunofluorescence microscopy revealed that UL44 and UL114 colocalized in numerous small punctuate foci at the immediate-early (5 and 8 hpi) phases of infection and that these foci grew in size throughout the infection. Furthermore, coimmunoprecipitation assays with cellular extracts of infected cells confirmed that UL44 associated with UL114. Finally, the nuclear concentration of UL114 was estimated to be 5- to 10-fold higher than that of UL44 in infected cells, which indicated a UL44-independent role of UL114. In summary, our data have demonstrated a catalytically inefficient viral UNG that was highly enriched in viral replication foci, thus supporting an important role of UL114 in replication rather than repair of the viral genome.
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http://dx.doi.org/10.1016/j.jmb.2008.05.028DOI Listing
August 2008

Impact of the complement lectin pathway on cytomegalovirus disease early after kidney transplantation.

Nephrol Dial Transplant 2008 Dec 24;23(12):4054-60. Epub 2008 Jun 24.

Department of Nephrology, Ullevål University Hospital, 0407 Oslo, Norway.

Background: This study retrospectively investigated the association between pre-transplant levels of mannose-binding lectin (MBL) plus the associated serine protease (MASP)-2 and the occurrence of cytomegalovirus (CMV) infection and symptomatic CMV disease during the first 12 weeks after kidney transplantation. Materials and methods. Altogether 159 consecutive single kidney transplant recipients were included. The patients were screened for CMV pp65 antigenaemia every second week. No CMV prophylaxis or pre-emptive treatment was given. MBL and MASP-2 were measured in samples taken at transplantation and 10 weeks later.

Results: CMV infection, defined as at least one positive test, was found in 95 patients (59.8%). MBL and MASP-2 measured at transplantation were similar in patients with and without CMV infection. The incidence of CMV infection was also similar in 36 patients (58.3%) with pre-transplant MBL levels below the reference level (500 microg/L) and in patients with higher MBL levels (60.2%). Symptomatic CMV disease was diagnosed in 35 patients (22%), and MASP-2 levels at transplantation in the lower quartile range (
Conclusion: Pre-transplant MBL levels do not influence the incidence of any CMV infection or symptomatic CMV disease during the first 12 weeks after kidney transplantation. However, low MASP-2 levels may play a role in the development of symptomatic CMV disease.
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http://dx.doi.org/10.1093/ndt/gfn355DOI Listing
December 2008

Reduced incidence of new-onset posttransplantation diabetes mellitus during the last decade.

Transplantation 2007 Nov;84(9):1125-30

Medical Department, Rikshospitalet, University of Oslo, Norway.

Background: A previous study (1995-1996) of 173 nondiabetic renal transplant recipients (historical cohort; HC) revealed a 20% incidence of new-onset posttransplantation diabetes mellitus (PTDM) and 32% with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). We examined whether glucose tolerance has improved after recent changes in our immunosuppressive protocol and a switch from deferred to preemptive cytomegalovirus (CMV) therapy.

Methods: A total of 321 consecutive, nondiabetic patients (new cohort; NC) were examined 10 weeks after kidney transplantation with an oral glucose tolerance test (n=301) between January 2004 and December 2005.

Results: Although recipients in the NC were on average 3 years older [mean (SD): 50.3 (14.6) vs. 47.4 (16.0), P=0.038] and had a higher mean body mass index [24.5 (3.6) vs. 23.5 (3.8) kg/m(2), P=0.003], a significantly lower incidence of both PTDM (13%) and IGT/IFG (18%) was observed in the NC (P<0.001) as compared to the HC. The patients in the NC received a significantly lower mean daily oral prednisolone dose [13.2 (4.7) vs. 15.3 (6.6) mg/day, P<0.001], and had lower frequencies of rejections (36% vs. 57%, P<0.001) and CMV infection (54% vs. 63%, P=0.071). Patients in the NC had significantly lower odds of developing PTDM, even after adjustment for age, prednisolone dose, HLA-B27 status and CMV infection (odds ratio: 0.42, 95% CI: 0.23-0.77, P=0.005).

Conclusions: The odds of developing PTDM are more than halved over the last decade. Possible explanations are changes in immunosuppressive therapy, fewer rejections, and lower doses of steroids.
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http://dx.doi.org/10.1097/01.tp.0000287191.45032.38DOI Listing
November 2007

Pre-transplant Toxoplasma gondii seropositivity among heart transplant recipients is associated with an increased risk of all-cause and cardiac mortality.

J Am Coll Cardiol 2007 Nov 29;50(20):1967-72. Epub 2007 Oct 29.

Department of Cardiology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.

Objectives: We evaluated the risk of mortality, development of cardiac allograft vasculopathy (CAV), and acute cellular rejection among Toxoplasma gondii (T. gondii) seropositive heart transplant (HTx) recipients and the 4 donor/recipient seropairing groups.

Background: Chronic T. gondii infection is known to trigger potentially adverse immunoregulatory changes, but the long-term implication for HTx recipients has not been assessed previously.

Methods: Frozen pre-HTx serum samples of 288 recipients and 246 donors were evaluated for T. gondii serostatus using Platelia immunoglobulin G immunoassay. Patients had undergone prospective serotesting using alternative assays, and results determined by the 2 methods were compared. Data regarding mortality, CAV, and acute cellular rejection were available for all patients.

Results: Overall, 211 recipients (73%) were seronegative and 77 (27%) were seropositive. In total, 82 recipients died, 76 developed CAV, and 82 had 1 or more episode of treated cellular rejection. Recipient seropositivity was associated with a significantly higher risk of all-cause (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.1 to 3.4; p = 0.02) and CAV mortality (HR 4.4, 95% CI 1.3 to 15.6; p = 0.02) and a higher risk of developing advanced CAV (HR 2.7, 95% CI 1.2 to 5.8; p = 0.01). Seropositivity did not influence the number of rejection episodes, and donor/recipient seropairing was not a risk factor for any end point.

Conclusions: T. gondii seropositivity among HTx recipients is associated with an increased risk of all-cause and CAV mortality and of development of advanced CAV. This may be mediated via immunoregulatory changes triggered by chronic T. gondii infection and needs to be explored further.
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http://dx.doi.org/10.1016/j.jacc.2007.07.068DOI Listing
November 2007

Cytomegalovirus infection in renal transplant recipients is associated with impaired survival irrespective of expected mortality risk.

Clin Transplant 2007 May-Jun;21(3):309-13

Department of Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway.

Cytomegalovirus (CMV) infection and CMV disease are associated with increased mortality post-transplantation. We have thus retrospectively examined whether this association is found both in patients with high and low mortality risk. Between 1994 and 1997, 471 kidney transplant recipients were monitored once weekly for CMV pp65 antigenemia and CMV disease the first 100 d after tx and followed prospectively for median 66.6 months. Patients with nephrosclerosis, diabetic nephropathy and amyloidosis were selected as high mortality risk groups (HRG). Overall and cardiovascular mortality beyond 100 d in the low-risk group (n = 372) was 14% and 3.5%, and in the HRG (n = 99) 31% and 16%, respectively. The effects of CMV infection and disease, recipient age and gender, panel-reactive cytotoxic antibodies, acute rejection, HRG, and graft loss in the whole study period were tested on overall mortality beyond 100 d in multiple analysis. HRG was independently associated with overall mortality, RR = 2.03, and still both CMV infection and disease were significant risk factors for mortality, independent of HRG. The same analysis was repeated for HRG (n = 99). Even in this small group CMV disease was independently associated with overall mortality. These data indicate that CMV increase mortality independently both in patients with otherwise high- or low-risk for long-term mortality.
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http://dx.doi.org/10.1111/j.1399-0012.2006.00639.xDOI Listing
July 2007

Plasmacytoid DCs regulate recall responses by rapid induction of IL-10 in memory T cells.

Blood 2007 Apr 7;109(8):3369-76. Epub 2006 Dec 7.

Laboratory for Immunohistochemistry and Immunopathology, Institute of Pathology, University of Oslo, Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway.

Dendritic cells (DCs) are believed to regulate T cell-mediated immunity primarily by directing differentiation of naive T cells. Here, we show that a large fraction of CD4(+) memory cells produce IL-10 within the first hours after interaction with plasmacytoid DCs (PDCs). In contrast, CD11c(+) DCs induce IFN-gamma and little IL-10. IL-10-secreting T cells isolated after 36 hours of culture with PDCs suppressed antigen-induced T-cell proliferation by an IL-10-dependent mechanism, but were distinct from natural and type 1 regulatory T cells. They proliferated strongly and continued to secrete IL-10 during expansion with PDCs, and after restimulation with immature monocyte-derived DCs or CD11c(+) DCs. The IL-10-producing T cells acquired the ability to secrete high levels of IFN-gamma after isolation and subsequent coculture with PDCs or CD11c(+) DCs. Compared to CD11c(+) DCs, PDCs were superior in their ability to selectively expand T cells that produced cytokines on repeated antigenic challenge. The DC-dependent differences in cytokine profiles were observed with viral recall antigen or staphylococcal enterotoxin B and were independent of extracellular type I interferon or IL-10. Our results show that DCs can regulate memory responses and that PDCs rapidly induce regulatory cytokines in effector T cells that can suppress bystander activity.
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http://dx.doi.org/10.1182/blood-2006-06-031484DOI Listing
April 2007