The emergence of enterovirus D68 in a Dutch University Medical Center and the necessity for routinely screening for respiratory viruses

BACKGROUND: Since August 2014, an increase in infections caused by enterovirus D68 (EV-D68) was reported in the USA and Canada, for the most part in children presenting with severe respiratory symptoms.OBJECTIVES: To determine whether an increase in severe EV-D68 respiratory infections was observed in our region.STUDY DESIGN: Samples from patients with respiratory symptoms were screened for viral pathogens, including rhinovirus and enterovirus. Subsequently, samples positive for rhinovirus and enterovirus were routinely sequenced for phylogenetic analysis. Furthermore, an additional method was used to detect EV-D68 specifically.RESULTS: During the first three quarters of the year 2014, 1896 respiratory samples were analyzed; 39 (2%) of them tested positive for enterovirus. Eighteen samples tested positive for EV-D68, obtained from 16 different patients admitted to our hospital. Eleven were children below the age of 18, of whom five children needed intensive care treatment. The remaining five samples were from adults, who all had an underlying disease; three were transplant patients (heart, lung and renal transplantation), the other two had an underlying lung condition (COPD, asthma). Phylogenetic analysis showed a close relationship with the strains circulating currently in the USA, all belonging to the known EV-D68 genetic subtypes.CONCLUSIONS: We observed an increase of EV-D68 infections in our population, both in children as well as in adult. In 2014 there have been 16 cases so far, compared to none in 2011 and 2013 and a single case in 2012. Phylogenetic analysis identified two similar clusters as shown in the USA and Canada.</p

Immunomodulatory effects of intravenous BIS-1 F(ab')2 administration in renal cell cancer patients.

We report the immunomodulatory effects of an intravenous treatment with F(ab')2 fragments of the bispecific monoclonal antibody BIS-1 during subcutaneous recombinant interleukin 2 (rIL-2) therapy of renal cell cancer (RCC) patients. BIS-1 is directed against both the CD3 antigen on T cells and the EGP-2 molecule on carcinoma cells and some normal epithelia. The amount of BIS-1 F(ab')2 bound to peripheral blood lymphocytes (PBLs) increased dose-dependently. This occupation degree was highest at the end of the 2 h infusion and rapidly decreased subsequently. During the first hour of BIS-1 F(ab')2 infusion the number of PBLs decreased slowly. This was followed by an increase in serum tumour necrosis factor alpha (TNF-alpha) concentrations and a rapid decrease in the numbers of peripheral blood lymphocytes, monocytes and eosinophils. In our view, the most likely explanation for the observed decrease in occupation degree of BIS-1 F(ab')2 and the rise in TNF-alpha levels is based on the assumption that BIS-1-carrying T cells leave the circulation. The CD3 antigens on these extravasated T cells become cross-linked by EGP-2 antigens, inducing TNF-alpha secretion. This results in an enhanced decrease in the numbers of PBLs, monocytes and eosinophils. These preliminary results suggest that BIS-1 F(ab')2 treatment during IL-2 therapy may induce local T-cell activation

Phase I study of intravenously applied bispecific antibody in renal cell cancer patients receiving subcutaneous interleukin 2.

In a phase I trial the toxicity and immunomodulatory effects of combined treatment with intravenous (i.v.) bispecific monoclonal antibody BIS-1 and subcutaneous (s.c.) interleukin 2 (IL-2) was studied in renal cell cancer patients. BIS-1 combines a specificity against CD3 on T lymphocytes with a specificity against a 40 kDa pancarcinoma-associated antigen, EGP-2. Patients received BIS-1 F(ab')2 fragments intravenously at doses of 1, 3 and 5 micrograms kg-1 body weight during a concomitantly given standard s.c. IL-2 treatment. For each dose, four patients were treated with a 2 h BIS-1 infusion in the second and fourth week of IL-2 therapy. Acute BIS-1 F(ab')2-related toxicity with symptoms of chills, peripheral vasoconstriction and temporary dyspnoea was observed in 2/4 and 5/5 patients at the 3 and 5 micrograms kg-1 dose level respectively. The maximum tolerated dose (MTD) of BIS-1 F(ab')2 was 5 micrograms kg-1. Elevated plasma levels of tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were detected at the MTD. Flow cytometric analysis showed a dose-dependent binding of BIS-1 F(ab')2 to circulating T lymphocytes. Peripheral blood mononuclear cells (PBMCs), isolated after treatment with 3 and 5 micrograms kg-1 BIS-1, showed increased specific cytolytic capacity against EGP-2+ tumour cells as tested in an ex vivo performed assay. Maximal killing capacity of the PBMCs, as assessed by adding excess BIS-1 to the assay, was shown to be decreased after BIS-1 infusion at 5 micrograms kg-1 BIS-1 F(ab')2. A BIS-1 F(ab')2 dose-dependent disappearance of circulating mononuclear cells from the peripheral blood was observed. Within the circulating CD3+ CD8+ lymphocyte population. LFA-1 alpha-bright and HLA-DR+ T-cell numbers decreased preferentially. It is concluded that i.v. BIS-1 F(ab')2, when combined with s.c. IL-2, has a MTD of 5 micrograms kg-1. The treatment endows the T lymphocytes with a specific anti-EGP-2-directed cytotoxic potential

Changes in enterovirus epidemiology after easing of lockdown measures

INTRODUCTION: Public health measures aimed at controlling transmission of SARS-CoV-2, otherwise known as "lockdown" measures, had profound effects on circulation of non-SARS viruses, many of which decreased to very low levels. The interrupted transmission of these viruses may have lasting effects. Some of the influenza clades seem to have disappeared during this period, a phenomenon which is described as a "funnel effect". It is currently unknown if the lockdown measures had any effect on the diversity of circulating viruses, other than influenza. Enteroviruses are especially interesting in this context, as the clinical presentation of an infection with a particular enterovirus-type may be clade-dependent.METHODS AND MATERIALS: Enteroviruses were detected in clinical materials using a 5'UTR-based detection PCR, and partial VP-1 sequences were obtained, using methods described before. All samples with EV detections from a large part of the Netherlands were included in the study. The samples originated from general practitioners, general hospitals, university hospitals and public health offices.RESULTS: Five EV-genotypes circulated in significant numbers before and after the lockdown, EV-D68, E-11, CV-A6, CV-B5 and CV-A2. All five genotypes showed decreased genetic diversity after the lockdown, and four indicate a significant number of sequences clustering together with a very high sequence homology. Moreover, children with E-11 and CV-B5 detections were significantly older after the lockdown than before.CONCLUSIONS: The reduced enterovirus transmission in the Netherlands during the pandemic, seems to have led to a decrease in genetic diversity in the five most commonly detected enterovirus serotypes.</p

Use of TNF-α-antagonists and systemic steroids is associated with attenuated imunogenicity against SARS-CoV-2 in fully vaccinated patients with Inflammatory Bowel Disease

BackgroundPatients with Inflammatory Bowel Disease (IBD) frequently use immunomodulating treatment, which may render them at increased risk of attenuated immunogenicity after vaccination. Immunosuppressive drugs, such as TNF-α-antagonists, have shown an attenuating effect on serological response after SARS-CoV-2 infection. Here we assessed the effects of different types of immunosuppressive medications on the serological response after vaccination against SARS-CoV-2 in patients with IBD.MethodsThis was a prospective observational cohort study in patients with IBD of whom IgG antibody titers were measured after 2–10 weeks after full vaccination against SARS-CoV-2. Patient demographics, clinical characteristics as well as a previous history of SARS-Cov-2 infection, type of vaccine (mRNA or vector), and medication use were recorded at time of sampling. The primary study outcome was the anti-SARS-CoV-2 spike (S) antibody concentrations, measured using chemiluminescence microparticle immunoassay (CMIA) after full vaccination.Results312 IBD patients were included (172 Crohn’s disease [CD] and 140 ulcerative colitis [UC]). Seroconversion (defined as titer of &gt;50 AU/ml) was achieved in 98,3% of patients. Antibody concentrations were significantly lower in patients treated with TNF-α-antagonists vs. non-users of TNF-α-antagonists (geometric mean [95% confidence interval]: 2204 [1655–2935] vs. 5002 [4089–6116] AU/ml, P&lt;0.001). In multivariable models, use of TNF-α-antagonists (percentage decrease -88%, P&lt;0.001), age (&gt;50 years) (-54%, P&lt;0.01) and CD (vs. UC) (-39%, P&lt;0.05) were independently associated with anti-SARS-CoV-2 antibody titers. In patients who received mRNA vaccines, users of systemic steroids demonstrated significantly lower antibody titers compared to patients who were steroid-free (geometric mean [95% CI]: 3410 [2233;5210] vs. 5553 [4686–6580], P&lt;0.05).ConclusionTNF-α-antagonist use is strongly associated with an attenuated serological response after vaccination, independent of the type of vaccination (mRNA/vector), the time interval between vaccination and sampling, prior SARS-CoV-2 infection and patient age. Patients treated with systemic steroids who received mRNA vaccines demonstrated lower anti-SARS-CoV-2 antibody titers compared with patients who were steroid-free at time of serology

A natural history study of the prognostic role of coronary arteriography

Coronary cinearteriograms, clinical records, and left ventriculograms of 304 patients studied for evaluation of chest pain were reviewed. Clinical and follow-up data on survival of the normal subjects and the nonoperative group with abnormal arteriograms are presented.Ninety-two per cent of patients with typical angina pectoris had serious coronary occlusive disease. Ninety-eight per cent of patients with relatively normal coronary arteriograms survived for one to 60 or more months (mean follow-up period 24 months).There was a high mortality rate when the left main coronary artery was involved (47 per cent) and when the left coronary anterior descending branch was seriously occluded (28 per cent when arteriographic scores were high and 14 per cent when total scores were low) and a low mortality rate (0 to 7 per cent) when the LAD was normal. Mean follow-up interval in these groups was 19 months.The mortality rate was nearly three times greater when patients had QRS changes on ECG of prior myocardial infarction and six times greater when left ventricular contraction was significantly impaired.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22297/1/0000740.pd

Viral load dynamics in intubated patients with COVID-19 admitted to the intensive care unit

Background: Prolonged viral RNA detection in respiratory samples from patients with COVID-19 has been described, but the clinical relevance remains unclear. We studied the dynamics of SARS-CoV-2 on a group and individual level in intubated ICU patients. Methods: In a cohort of 86 patients, we analysed SARS-CoV-2 RT-PCR results on nasopharyngeal and sputum samples (obtained as part of clinical care twice a week) according to time after intubation. Subsequently, we performed survival analyses. Results: 870 samples were tested by RT-PCR. Overall viral load was highest in the first week (median nasopharynx 3.5. IQR 1.5-4.3; median sputum 4.3. IQR 3.3-5.6) and decreased over time. In 20% of patients a relapsing pattern was observed. Nasopharyngeal and sputum PCR status on day 14 was not significantly associated with survival up to day 60 in this small cohort. Conclusion: In general SARS-CoV-2 RNA levels in respiratory samples in patients with severe COVID-19 decease alter the first week after intubation, but individual SARS-CoV-2 RNA levels can show a relapsing pattern. Larger studies are needed to address the association of clearance of SARS-CoV-2 RNA from respiratory samples with survival, because we observed a trend towards better survival in patients with early clearance from sputum. (C) 2021 The Authors. Published by Elsevier Inc

Searching for converging research using field to field citations

We define converging research as the emergence of an interdisciplinary research area from fields that did not show interdisciplinary connections before. This paper presents a process to search for converging research using journal subject categories as a proxy for fields and citations to measure interdisciplinary connections, as well as an application of this search. The search consists of two phases: a quantitative phase in which pairs of citing and cited fields are located that show a significant change in number of citations, followed by a qualitative phase in which thematic focus is sought in publications associated with located pairs. Applying this search on publications from the Web of Science published between 1995 and 2005, 38 candidate converging pairs were located, 27 of which showed thematic focus, and 20 also showed a similar focus in the other, reciprocal pair

The Development of Intensive Care Unit Acquired Hypernatremia Is Not Explained by Sodium Overload or Water Deficit:A Retrospective Cohort Study on Water Balance and Sodium Handling

Background. ICU acquired hypernatremia (IAH, serum sodium concentration (sNa) ≥ 143 mmol/L) is mainly considered iatrogenic, induced by sodium overload and water deficit. Main goal of the current paper was to answer the following questions: Can the development of IAH indeed be explained by sodium intake and water balance? Or can it be explained by renal cation excretion? Methods. Two retrospective studies were conducted: a balance study in 97 ICU patients with and without IAH and a survey on renal cation excretion in 115 patients with IAH. Results. Sodium intake within the first 48 hours of ICU admission was 12.5 [9.3–17.5] g in patients without IAH (n=50) and 15.8 [9–21.9] g in patients with IAH (n=47), p=0.13. Fluid balance was 2.3 [1–3.7] L and 2.5 [0.8–4.2] L, respectively, p=0.77. Urine cation excretion (urine Na + K) was < sNa in 99 out of 115 patients with IAH. Severity of illness was the only independent variable predicting development of IAH and low cation excretion, respectively. Conclusion. IAH is not explained by sodium intake or fluid balance. Patients with IAH are characterized by low urine cation excretion, despite positive fluid balances. The current paradigm does not seem to explain IAH to the full extent and warrants further studies on sodium handling in ICU patients