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

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.

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

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.

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.

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.

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

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.

[Allogeneic stem-cell transplantation in adults 1985-2012: results and development]. / Allogen stamcelletransplantasjon hos voksne 1985-2012.

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.

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.

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.

Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management.

BACKGROUND: Following kidney transplantation (KT), cytomegalovirus (CMV) infection remains an important challenge. Both prophylactic and preemptive antiviral protocols are used for CMV high-risk kidney recipients (donor seropositive/recipient seronegative; D+/R-). We performed a nationwide comparison of the 2 strategies in de novo D+/R- KT recipients accessing long-term outcomes. METHODS: A nationwide retrospective study was conducted from 2007 to 2018, with follow-up until February 1, 2022. All adult D+/R- and R+ KT recipients were included. During the first 4 y, D+/R- recipients were managed preemptively, changing to 6 mo of valganciclovir prophylaxis from 2011. To adjust for the 2 time eras, de novo intermediate-risk (R+) recipients, who received preemptive CMV therapy throughout the study period, served as longitudinal controls for possible confounders. RESULTS: A total of 2198 KT recipients (D+/R-, n = 428; R+, n = 1770) were included with a median follow-up of 9.4 (range, 3.1-15.1) y. As expected, a greater proportion experienced a CMV infection in the preemptive era compared with the prophylactic era and with a shorter time from KT to CMV infection ( P < 0.001). However, there were no differences in long-term outcomes such as patient death (47/146 [32%] versus 57/282 [20%]; P = 0.3), graft loss (64/146 [44%] versus 71/282 [25%]; P = 0.5), or death censored graft loss (26/146 [18%] versus 26/282 [9%]; P = 0.9) in the preemptive versus prophylactic era. Long-term outcomes in R+ recipients showed no signs of sequential era-related bias. CONCLUSIONS: There were no significant differences in relevant long-term outcomes between preemptive and prophylactic CMV-preventive strategies in D+/R- kidney transplant recipients.

Maternal cytomegalovirus infection and delayed language development in children at 3 years of age-a nested case-control study in a large population-based pregnancy cohort.

INTRODUCTION: Maternal cytomegalovirus (CMV) infection in pregnancy may result in vertical transmission of CMV to the child. Long-term effects of congenital CMV infection include visual, cognitive as well as neurological impairment. The aim of this study was to estimate the odds ratios for CMV seropositivity and seroconversion in mothers, with and without delayed language development in 3 year old children, nested within a large cohort. MATERIAL AND METHODS: The Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective population-based pregnancy cohort that includes 95 200 mothers and 114 500 children. Blood samples were obtained from mothers during pregnancy weeks 17 or 18 in pregnancy and after birth. We included 300 women from MoBa with children suffering from delayed language development at three years of age, based on validated questionnaires. Within the cohort, 1350 randomly selected women were included as controls to perform a nested case-control study. The cases and controls were tested for CMV IgG antibodies by an enzyme-linked immunosorbent assay. RESULTS: Among mothers of cases, 63.2% were CMV-IgG positive in the sample at birth, as compared to 55.9% among controls; OR 1.36, (95% CI; 1.05 to 1.76). Also, among case mothers, 8/118 (6.8%) initially seronegative cases, seroconverted. Among initially seronegative controls, seroconversion occurred in 23/618 (3.7%) mothers. The OR for seroconversion in cases as compared to control mothers was 1.88 (CI; 0.82 to 4.31), thus not statistically significant different. CONCLUSION: This study shows a higher risk of delayed language development at three years of age in children born by mothers seropositive for CMV, compared to children born from seronegative mothers.

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

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.

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

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.

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

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 (

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

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.

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

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.

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

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

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.

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

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.

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

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.

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

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.

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

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.