Zoonotic Transmission of Vaccine-Derived Bordetella bronchiseptica.

We describe a unique case of a 43-year-old-female with a Bordetella bronchiseptica infection caused by zoonotic transmission following vaccination of her dog. With this report, we want to raise awareness of potential zoonotic transmission of live attenuated vaccines from animals to patients with impaired immunity.</p

Enterovirus D68-The New Polio?

Enterovirus D68 (EV-D68) has emerged over the recent years, with large outbreaks worldwide. Increased occurrence has coincided with improved clinical awareness and surveillance of non-polio enteroviruses. Studies showing its neurotropic nature and the change in pathogenicity have established EV-D68 as a probable cause of Acute Flaccid Myelitis (AFM). The EV-D68 storyline shows many similarities with poliovirus a century ago, stimulating discussion whether EV-D68 could be ascertaining itself as the "new polio." Increasing awareness amongst clinicians, incorporating proper diagnostics and integrating EV-D68 into accessible surveillance systems in a way that promotes data sharing, will be essential to reveal the burden of disease. This will be a necessary step in preventing EV-D68 from becoming a threat to public health

Therapeutic drug monitoring of ganciclovir:Where are we?

Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps. METHODS: For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened. RESULTS: The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC(50); however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window. CONCLUSIONS: Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted

Effect of school reopening on SARS-CoV-2 incidence in a low-prevalence region:Prospective SARS-CoV-2 testing in healthcare workers with primary school-attending children versus without children living at home

Coronavirus disease 2019 (COVID-19) often presents asymptomatically or milder in children compared to adults. The role of young children in the transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains largely unknown. In the Netherlands, the first action of loosening the partial lockdown that had been implemented to reduce SARS-CoV-2 transmission was the reopening of primary schools on 1 May 2020. We subsequently conducted a prospective cohort study among healthcare workers (HCWs) with primary school-attending children versus HCWs without children living at home. We tested each HCW three times for SARS-CoV-2 from May 20 to June 15 2020 at 1-week intervals. In total, 832 nasopharyngeal swabs were taken from 283 HCWs with primary school-attending children living at home and 864 nasopharyngeal swabs from 285 HCWs without children living at home. All nasopharyngeal swabs tested negative for SARS-CoV-2. In our region with a low population density and low SARS-CoV-2 prevalence, reopening of primary schools did not lead to an increase in infections. The results of this study may serve as an example for the implementation of regional strategies to reduce SARS-CoV-2 transmission in countries with large variations in both population density and SARS-CoV-2 prevalence

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

Shedding a Light on Acyclovir Pharmacodynamics: A Retrospective Analysis on Pharmacokinetic/Pharmacodynamic Modelling of Acyclovir for the Treatment of Varicella Zoster Virus Infection in Immunocompromised Patients: A Pilot Study

BackgroundAcyclovir and valacyclovir are used for the treatment and prophylaxis of infections with herpes simplex virus (HSV) and varicella zoster virus (VZV). The aim of this study is to provide insight into the pharmacodynamics (PD) of (val)acyclovir.MethodsPatients were retrospectively selected, based on therapeutic drug monitoring for acyclovir, to create a population pharmacokinetic (PK) model in Pmetrics. This PK model was used to develop a PK/PD model to study the effect of acyclovir levels on VZV viral load in plasma in immunocompromised patients.ResultsImmunocompromised patients with known VZV viral loads in plasma were included for PK/PD modelling (N = 4, with 23 measure points); they were part of the population of 43 patients used for PK model building. The PK/PD model described the data well (r2 = 0.83). This is a hopeful first step in clarifying the pharmacodynamics of acyclovir; however, the data in this study are limited.ConclusionsOur preliminary PK/PD model can be used in further research to determine the effect of acyclovir levels on VZV viral load

Improved diagnostic policy for respiratory tract infections essential for patient management in the emergency department

Establishing an optimal diagnostic policy for patients with respiratory tract infections, at the emergency department (ED) of a university hospital in The Netherlands. Methods: Adult patients were sampled at admission, during the respiratory season (2014-2015). The FilmArray-RP was implemented at the clinical virology laboratory. Diagnostics were provided from 8 am to 10 pm, weekends included. Results: 436/492 (89%) results were available while patients were still at the ED. Median TAT from admission to test result was 165 min (IQR: 138-214). No antibiotics were prescribed in 94/207 (45%) patients who tested positive for a virus. 185/330 (56%) hospitalized patients did not need admission with isolation measures. The value-based measure, expressed in euro-hour (€h), increased to tenfold compared with previous policy. Conclusion: An optimal policy is essential for patient management, by providing timely, reliable diagnostics

Twenty-nine Cases of Enterovirus-D68-associated Acute Flaccid Myelitis in Europe 2016 A Case Series and Epidemiologic Overview

Background: Enterovirus-D68 (EV-D68) is a respiratory virus within the genus Enterovirus and the family of Picornaviridae. Genetically, it is closely related to rhinovirus that replicates in the respiratory tract and causes respiratory disease. Since 2014, EV-D68 has been associated with the neurologic syndrome of acute flaccid myelitis (AFM). Methods: In October 2016, questionnaires were sent out to a European network including 66 virologists and clinicians, to develop an inventory of EVD68- associated AFM cases in Europe. Clinical and virologic information of case patients was requested. In addition, epidemiologic information on EV testing was collected for the period between March and October 2016. Results: Twenty-nine cases of EV-D68-associated AFM were identified, from 12 different European countries. Five originated from France, 5 from Scotland and 3 each from Sweden, Norway and Spain. Twenty-six were children (median age 3.8 years), 3 were adults. EV-D68 was detected in respiratory materials (n = 27), feces (n = 8) and/or cerebrospinal fluid (n = 2). Common clinical features were asymmetric flaccid limb weakness, cranial nerve deficits and bulbar symptoms. On magnetic resonance imaging, typical findings were hyperintensity of the central cord and/or brainstem; low motor amplitudes with normal conduction velocities were seen on electromyography. Full clinical recovery was rare (n = 3), and 2 patients died. The epidemiologic data from 16 European laboratories showed that of all EV-D68-positive samples, 99% was detected in a respiratory specimen. Conclusions: For 2016, 29 EV-D68-related AFM cases were identified in mostly Western Europe. This is likely an underestimation, because case identification is dependent on awareness among clinicians, adequate viral diagnostics on respiratory samples and the capability of laboratories to type EVs

Comparison of renal histopathology and gene expression profiles between severe COVID-19 and bacterial sepsis in critically ill patients

BACKGROUND: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury. METHODS: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3–4 days for bacterial sepsis patients. RESULTS: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19. CONCLUSIONS: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13054-021-03631-4

Upsurge of Enterovirus D68, the Netherlands, 2016

In June and July 2016, we identified 8 adults and 17 children with respiratory enterovirus D68 infections. Thirteen children required intensive care unit admission because of respiratory insufficiency, and 1 had concomitant acute flaccid myelitis. Phylogenetic analysis showed that all of 20 sequences obtained belong to the recently described clade B3