Severe neonatal enterovirus infection in twins with different outcomes:A case report

Enteroviruses are among the most common causes of acute viral illness worldwide, and in neonates, the clinical course of these infections is heterogeneous. Severe complications, such as myocarditis, are associated with high mortality rates. In this case report, we present the clinical course of premature twins born at 35 weeks of gestational age, suffering from a severe neonatal enterovirus infection with cardiac involvement, which proved fatal in one of the twins. This course led to prompt identification in the other twin and facilitated timely transfer to a neonatal intensive care unit with neonatal hemodynamic expertise, and facilitated the timely transfer to a neonatal intensive care nit with hemodynamic expertise and immediate availability of AZCMO would it have been indicated. Early supportive therapy in the other twin contributed to a positive outcome. Therefore, we emphasize the importance of early recognition in averting adverse consequences. As a recommendation, we propose routine screening of enterovirus in viral panels for febrile newborns.</p

Severe neonatal enterovirus infection in twins with different outcomes: A case report

Enteroviruses are among the most common causes of acute viral illness worldwide, and in neonates, the clinical course of these infections is heterogeneous. Severe complications, such as myocarditis, are associated with high mortality rates. In this case report, we present the clinical course of premature twins born at 35 weeks of gestational age, suffering from a severe neonatal enterovirus infection with cardiac involvement, which proved fatal in one of the twins. This course led to prompt identification in the other twin and facilitated timely transfer to a neonatal intensive care unit with neonatal hemodynamic expertise, and facilitated the timely transfer to a neonatal intensive care nit with hemodynamic expertise and immediate availability of AZCMO would it have been indicated. Early supportive therapy in the other twin contributed to a positive outcome. Therefore, we emphasize the importance of early recognition in averting adverse consequences. As a recommendation, we propose routine screening of enterovirus in viral panels for febrile newborns

Neutralising Antibodies against Enterovirus and Parechovirus in IVIG Reflect General Circulation: A Tool for Sero-Surveillance

Non-polio enteroviruses (NPEV) and parechoviruses (PeV) are widespread pathogens that cause significant morbidity. Surveillance is based on culturing or genotyping of virus strains found in clinical samples. Sero-surveillance, by measuring neutralising antibodies (nAb) through virus neutralisation assays (VNA), could provide additional information as it offers a more comprehensive overview of exposure to circulating types in the general population. In our study we evaluated Intravenous immunoglobulins (IVIG) to generate sero-surveillance data. We performed VNA of nineteen NPEV and PeV with Dutch IVIG batches from two different time points (2010 and 2017) and an IVIG batch from Vietnam (2011). We compared our findings with geno- and sero-surveillance data and evaluated changes over time and between the two countries. Our findings show a good correlation with what is known from geno-surveillance data. The highest nAb titres were found against strains from Enterovirus B, while we did not observe nAb titres against strains belonging to Enterovirus C. In conclusion, we demonstrated that sero-surveillance by means of IVIG can be used to obtain insight into circulation of EV and PeV genotypes. This is of particular interest for public health, to evaluate changes over time and population susceptibility to emerging genotypes

Interleukin-15-induced CD56(+) myeloid dendritic cells combine potent tumor antigen presentation with direct tumoricidal potential

\u3cp\u3eDendritic cells (DCs) are the quintessential antigen-presenting cells of the human immune system and play a prime role in coordinating innate and adaptive immune responses, explaining the strong and still growing interest in their application for cancer immunotherapy. Much current research in the field of DC-based immunotherapy focuses on optimizing the culture conditions for in vitro DC generation in order to assure that DCs with the best possible immunogenic qualities are being used for immunotherapy. In this context, monocyte-derived DCs that are alternatively induced by interleukin-15 (IL-15 DCs) have attracted recent attention due to their superior immunostimulatory characteristics. In this study, we show that IL-15 DCs, in addition to potent tumor antigen-presenting function, possess tumoricidal potential and thus qualify for the designation of killer DCs. Notwithstanding marked expression of the natural killer (NK) cell marker CD56 on a subset of IL-15 DCs, we found no evidence of a further phenotypic overlap between IL-15 DCs and NK cells. Allostimulation and antigen presentation assays confirmed that IL-15 DCs should be regarded as bona fide myeloid DCs not only from the phenotypic but also from the functional point of view. Concerning their cytotoxic activity, we demonstrate that IL-15 DCs are able to induce apoptotic cell death of the human K562 tumor cell line, while sparing tumor antigen-specific T cells. The cytotoxicity of IL-15 DCs is predominantly mediated by granzyme B and, to a small extent, by tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand (TRAIL) but is independent of perforin, Fas ligand and TNF-α. In conclusion, our data provide evidence of a previously unappreciated role for IL-15 in the differentiation of human monocytes towards killer DCs. The observation that IL-15 DCs have killer DC capacity lends further support to their implementation in DC-based immunotherapy protocols.\u3c/p\u3

Inhibition of CD56⁺ IL-15 DC-mediated cytotoxicity by neutralizing anti-TRAIL mAbs and concanamycin A.

<p>Matured CD56⁺ IL-15 DCs were co-cultured with PKH67-labeled K562 target cells at an E:T ratio of 50:1 in the presence of either anti-TRAIL blocking mAb (left) or the granule exocytosis inhibitor concanamycin A (right). Parallel experiments were performed using TRAIL isotype-matched control mAb and medium control devoid of concanamycin A, respectively. Lysis of target cells was determined after overnight incubation using a flow cytometry-based cytotoxicity assay, as described above. Results are expressed as mean (± SEM) percentages of specific target cell lysis. Data are from 5 (for TRAIL) and 10 (for concanamycin) independent experiments. *, <i>P</i><0.05; **, <i>P</i><0.01.</p

Phenotypic characteristics of CD56⁺ IL-15 DCs.

<p>(A) CD14⁺ monocytes were cultured for 24–36 hr in the presence of GM-CSF and IL-15 (IL-15 DCs) and analyzed by flow cytometry for expression of CD11c/CD56 (left). The percentage between parentheses indicates the mean (± SEM) percentage of CD56⁺ cells among the total IL-15 DC population (<i>n</i> = 17). These CD56⁺ cells were then immunomagnetically separated, cultured for another 16–20 hr in the presence of DC maturation cocktail and analyzed for co-expression of CD11c/BDCA-1 (middle) and CD56/CD7 (right). Quadrant gates were set using corresponding isotype controls. (B) Matured CD56⁺ IL-15 DCs were further analyzed by flow cytometry for expression of the indicated NK cell-associated (CD56, CD7, CD16, CD69, NKG2D, NKp46), NKDC-associated (CD11c, B220, NKR-P1A) and DC-related surface antigens. Histogram overlays show expression of the indicated markers (solid line histograms) compared to their respective isotype controls (filled grey histograms). All plots are representative of at least 4 independent experiments.</p

Lysis of K562 cells but not of a WT1-specific CTL clone by IL-15 DCs.

<p>PKH67-labeled target cells were mixed at varying E:T ratios with mature CD56⁺ and CD56⁻ IL-15 DCs or, where indicated, with conventionally generated IL-4 DCs and then subjected to PI/Annexin-V staining after overnight incubation. Target cell viability was defined as the percentage of PI⁻/Annexin-V⁻ cells within the PKH67⁺CD11c⁻ gate. (A) Viability profiles of gated K562 tumor cells cultured alone (control) or with either CD56⁻ or CD56⁺ IL-15 DCs at an E:T ratio of 50:1. One representative experiment out of five is shown. Percentages of viable K562 cells are displayed in the lower left quadrants and expressed as mean (± SEM) of 5 independent experiments. (B) Graph depicting the specific lysis of K562 tumor cells by CD56⁺ IL-15 DCs (solid black line, ▪; <i>n</i> = 5), CD56⁻ IL-15 DCs (solid grey line, □; <i>n</i> = 5) and IL-4 DCs (dashed grey line, ○; <i>n</i> = 3) at the indicated E:T ratios. Results are expressed as mean (± SEM) percentages of specific lysis. Asterisks refer to a statistically significant difference in cytotoxic activity at the indicated E:T ratio between CD56⁺ and CD56⁻ IL-15 DCs. (C) Bar graphs showing the viability of a WT1_126–134-specific CTL clone after overnight culture in the absence or presence of either CD56⁻ (□) or CD56⁺ (▪) IL-15 DCs at an E:T ratio of 50:1. Data are presented as mean (± SEM) percentages of viable T cells from three experiments.</p