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Fetal intracranial hemorrhage (ICH) may result from a wide array of causes, either associated with maternal or fetal risk factors. In the last decade, monogenic causes of susceptibility to fetal ICH have been described, in particular in association with COL4A1 and COL4A2 genes. A peculiar form of ICH is acute necrotizing encephalitis (ANE), which is characterized by a rapid‐onset severe encephalopathy following an abnormal inflammatory response to an otherwise banal infection. It usually affects healthy children and it is thought to be multifactorial, with a genetic predisposition. RANBP2 gene has been extensively associated with ANE susceptibility. We hereby present a unique case of a 42‐year‐old secundigravida with intrauterine fetal demise at 35 weeks of gestation. Trio‐based whole‐exome sequencing performed on both parents and fetal DNA showed a de novo likely pathogenic variant in the RANBP2 gene on 2q13. At the fetal autopsy, subtentorial hematoma and cerebral intraparenchymal hemorrhage were present. We speculate that this might be a new phenotypic presentation of RANBP2‐associated disease. However, more similar fetal cases need to be reported in order to reinforce this hypothesis. [ABSTRACT FROM AUTHOR]

Slow cytomegalovirus-specific CD4+ and CD8+ T-cell differentiation: 10-year follow-up of primary infection in a small number of immunocompetent hosts. Human cytomegalovirus, memory inflation, memory T cells, primary infection, T cells. [Extracted from the article]

Ruxolitinib is effective in myeloproliferative neoplasms (MPN) but can cause reactivation of silent infections. We aimed at evaluating viral load and T‐cell responses to human cytomegalovirus (HCMV) and Epstein‐Barr virus (EBV) in a cohort of 25 MPN patients treated with ruxolitinib. EBV‐DNA and HCMV‐DNA were quantified monthly using real‐time polimerase chain reaction (PCR) on peripheral blood samples, and T‐cell subsets were analyzed by flowcytometry. HCMV and EBV‐directed T‐cell responses were evaluated using the IFN‐γ ELISPOT assay. Most patients had CD4+ and/or CD8+ T‐cells below the normal range; these reductions were related to the duration of ruxolitinib treatment. In fact, reduced T‐lymphocytes' subsets were found in 93% of patients treated for ≥5 years and in 45% of those treated for <5 years (P =.021). The former also had lower median numbers of CD4+ and CD8+ cells. Subclinical reactivation of EBV and HCMV occurred in 76% and 8% of patients. We observed a trend to an inverse relationship between EBV and CMV‐specific CD4+ and CD8+ T‐cell responses and viral load, and a trend to an inverse correlation with ruxolitinib dose. Therefore, our data suggest that the ruxolitinib treatment may interfere with immunosurveillance against EBV and HCMV. [ABSTRACT FROM AUTHOR]

To discriminate between primary (PI) and remote (RI) human cytomegalovirus (HCMV) infection, several immunological parameters were monitored for a 2-year period in 53 pregnant women with PI, and 33 pregnant women experiencing HCMV PI at least 5 years prior. Cytokine (IFN-γ and IL-2) production by and phenotype (effector/memory CD45RA+) of HCMV-specific CD4+ and CD8+ T-cells as well as the lymphoproliferative responses (LPR) were evaluated, with special reference to the comparison between a group of women transmitting (T) and a group of non-transmitting (NT) the infection to fetus. While HCMV-specific CD4+ T-cells reached at 90 days post-infection (p.i.) values comparable to RI, CD8+ T-cells reached at 60 days p.i. levels significantly higher and persisting throughout the entire follow-up. Instead, IL-2 production and lymphoproliferative responses were lower in PI than RI for the entire follow-up period. Effector memory CD45RA+ CD4+ and CD8+ HCMV-specific T-cells increased until 90 days p.i., reaching and maintaining levels higher than RI. The comparison between T and NT women showed that, at 30 days p.i., in NT women there was a significantly higher IL-2 production by HCMV-specific CD4+ T-cells, and at 60 days p.i. a significantly higher frequency of both specific CD4+ and CD8+ CD45RA+ T-cells. HCMV T-cell response appears to correlate with virus transmission to fetus and some parameters (CD4+ lymphoproliferation, and frequency of HCMV-specific CD8+ IL2+ T-cells) may help in dating PI during pregnancy. J. Med. Virol. 88:1238-1246, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Given the difficulty in establishing the exact time of HCMV transmission from mother to fetus, HCMV intrauterine infection was investigated in 46 infected fetuses/newborns by correlating maternal and fetal parameters with clinical outcome according to the time interval between the onset of maternal infection and prenatal diagnosis. In detail, 17/28 (60.7%) asymptomatic and 18/18 (100%) symptomatic fetuses/newborns were infected as a consequence of a primary maternal HCMV infection acquired ≤8 weeks of gestational age, while 11/28 (39.3%) asymptomatic and 0/18 (0%) symptomatic fetuses/newborns were congenitally infected when maternal infection was acquired >8 weeks' gestation. Symptomatic fetal infections appeared to be associated with a maternal primary infection occurring at ≤ 8 weeks' gestation. Cordocentesis performed at 20 weeks' gestation should be restricted to high risk infected fetuses. J. Med. Virol. 88:120-126, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

To investigate retrospectively the prognostic significance of maternal, fetal, and neonatal parameters and clinical outcome in 150 HCMV congenital infections during the period 1995-2009. HCMV fetal infection was investigated in amniotic fluid and fetal blood samples. HCMV congenital infection was confirmed in newborn urine and blood samples. Symptomatic infection was defined in HCMV-infected fetuses and in infected newborns on the basis of physical and instrumental findings. Follow-up at 3, 6, 12 months, and then annually up to school age, included clinical evaluation, funduscopic, audiologic, neurologic, and cognitive assessment. Overall, 122/150 (81.3%) newborns were asymptomatic and 28/150 (18.7%) were symptomatic at birth. The best prognostic maternal parameter of symptomatic infection at birth was gestational age at infection ( P = 0.037). The best fetal virological markers were HCMV DNA levels in amniotic fluid ( P < 0.001), antigenaemia levels ( P = 0.007), HCMV DNA levels in blood ( P = 0.004), and HCMV-specific IgM index values ( P = 0.002). The only significant neonatal parameter was HCMV DNA level in blood [ P = 0.006; OR, 3.62 (95% CI, 1.46-8.97)]. Symptoms at birth correlated significantly with long-term sequelae ( P = 0.021). A trend towards a risk of sequelae in early (n = 15/58 examined) versus late (n = 6/57 examined) maternal infection was documented. The risk of symptomatic congenital infection at birth increased linearly with the number of significant maternal, fetal, and neonatal parameters. J. Med. Virol. 86:2163-2170, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Following primary human cytomegalovirus (HCMV) infection, virus-specific IgG antibody shift from low to high avidity with individual variations in the rate of avidity maturation. The kinetics of the avidity maturation of IgG specific for HCMV nuclear antigen in pregnant women with primary infection was investigated. Absorbance values used for avidity index calculation of 286 sequential sera collected from 69 pregnant women with primary HCMV infection were retrieved. Percent difference in absorbance values of IgG antibody bound to the solid phase after urea treatment (IgG avidity) between early (T1, 0-90, median 31 days) and late (T2, 91-180, median 136 days) serum samples was calculated for each woman. Three groups of women were identified: 24/69 (34.8%) women showed high (>100%) avidity increase between T1 and T2 (pattern H), 29/69 (42%) low (<50%) increase (pattern L), and 16/69 (23.2%) intermediate increase (pattern I). Avidity values in T1 samples were significantly higher in women with pattern L compared to women with pattern H ( P = 0.01). Altogether, 28/69 (40.6%) women transmitted HCMV infection to their fetuses. Fetal infection preferentially occurred ( P < 0.01) in women with pattern H (15/24, 62.5%) compared with women with pattern L (7/29, 24.1%). In conclusion, different patterns of IgG avidity maturation can be detected following primary HCMV infection. Pregnant women with pattern H (rapid IgG avidity increase) appear to be at higher risk for fetal infection, whereas, pregnant women developing early antibody with high avidity appear to be at a lower risk of vertical transmission. J Med. Virol. 85:1960-1967, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Human parechoviruses (HPeVs) infection is associated with a wide range of clinical syndromes such as respiratory, gastrointestinal, neurologic diseases, and neonatal sepsis-like illness. The main objective of this study was to investigate the epidemiology of HPeVs infection in hospitalized patients in a period of 2 years. Respiratory samples from 3,525 patients with respiratory syndrome, cerebrospinal fluid (CSF) from 340 patients with neurologic syndrome as well as CSF and plasma samples from five neonatal patients with sepsis-like illness collected from October 2008 to 2010 were tested retrospectively using HPeV-specific real-time RT-PCR. Phylogenetic analysis of VP3/VP1 region was performed on the positive samples. Fourteen out of 3,525 (0.4%) patients with respiratory syndrome and five out of five patients with sepsis-like illness were positive for HPeV. In 3/5 patients with sepsis-like illness multiple samples (e.g., stool, plasma, CSF, or respiratory samples) were available, and HPeV was found in all specimens. In contrast, no positive CSF was detected among the 340 patients with neurologic syndromes. Eleven patients (57.9%) were infected with HPeV1 strain, 7 (36.8%) with HPeV3, and 1 (5.3%) with HPeV6 strains. Ten of the 14 HPeV patients with respiratory syndrome were co-infected with other respiratory viruses (eight with rhinovirus and two with coronavirus OC43). All five patients with sepsis-like illness were less than 1 month of age and were infected with HPeV3. Although not circulating at high frequency and unlikely to cause respiratory syndrome, HPeV was associated with severe clinical syndromes in a minority of newborns. J. Med. Virol. 84:686-690, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The source of human cytomegalovirus (HCMV) infection was investigated in 29 pregnant women with primary HCMV infection by comparing DNA sequences of UL146, UL144 and a portion of UL55 gene of HCMV strains circulating within each family. Thirteen families were identified in which the pregnant woman, the husband and/or a child were shedding HCMV. In three of these families, both the woman and the husband suffered from a concomitant primary HCMV infection. Phylogenetic analysis of UL146, UL144, and UL55 genes indicated that strains circulating within each family were identical, whereas strains from different families appeared to be distinct. However, identical UL146, UL144, and UL55 DNA sequences were observed sporadically among unrelated strains. A child rather than the husband was the virus source for the great majority of pregnant women. No association was observed between UL144 polymorphisms and intrauterine transmission. J. Med. Virol. 80:1415-1425, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Infections by herpesviruses may have severe complications in liver transplant patients. Although prophylactic varicella zoster virus vaccination is strongly recommended and widely applied, severe infection may still occur. We report the case of systemic chronic varicella, which developed in a liver allograft recipient, unresponsive to antiviral drug treatment, successfully treated by varicella zooster-specific CTL. Graft failure ensued, likely, because of massive cytolysis of infected hepatocytes. The patient, who was re-transplanted in the absence of signs of varicella zooster reactivation, is now well and disease free 3 yr after second liver transplant. [ABSTRACT FROM AUTHOR]

Fludarabine is effective in chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). A major side-effect of this purine analogue is immunosuppression which may favour opportunistic infections. Additionally, impairment of immunosurveillance might promote Epstein-Barr virus (EBV) reactivation and possibly favour transformation to high-grade malignancy. The aim of this study was to evaluate the immunosuppression-related effects of the fludarabine-based combination Flucyd in advanced low-grade NHL or CLL by serially monitoring T-lymphocyte subsets, opportunistic infections, EBV-reactivation, and histologic transformation. 24 patients with advanced NHL (n = 21) or CLL (n = 3) received fludarabine 25 mg/m2/d + cyclophosphamide 350 mg/m2/d + dexamethasone 20 mg/d in 3 d courses for a maximum of six courses. The overall response rate was 79% (eight CR, 11 PR, five failures); 11 patients relapsed or progressed between 3 and 19 months from response, and eight are in CR or PR at 3–27 months. The CD4+ lymphocyte counts decreased significantly during therapy from a median of 484/μl pre-treatment (range 142–1865) to a median of 198/μl (71–367). In 19 responders monitored off therapy every 3 months until relapse/progression, CD4+ counts were persistently low with minimal recovery over time. During treatment, 16 infections occurred in 11/24 patients. No delayed opportunistic infections occurred in responders while off therapy. The circulating EBV DNA load serially measured in 19 patients by a quantitative PCR assay showed an increase in four patients during treatment. A lymph node biopsy performed in two of these was PCR positive for EBV DNA, whereas LMP1 and EBERs were negative. Six NHL patients evolved into high-grade B-cell NHL. In conclusion, fludarabine combined with cyclophosphamide and dexamethasone is an effective therapy for recurrent indolent lymphoma. This combination... [ABSTRACT FROM AUTHOR]