Effect of acyclovir therapy on the outcome of mechanically ventilated patients with lower respiratory tract infection and detection of herpes simplex virus in bronchoalveolar lavage: protocol for a multicentre, randomised controlled trial (HerpMV)

Introduction
Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine whether antiviral therapy in HSV-positive patients improves outcome.

Methods and analysis
Prospective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥105 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial.

Ethics and dissemination
The trial was approved by the responsible ethics committee and by Germany’s Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany’s Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers.

Trial registration number
NCT06134492.

Leggi
Aprile 2024

Estimating the incidence of COVID-19, influenza and respiratory syncytial virus infection in three regions of Queensland, Australia, winter 2022: findings from a novel longitudinal testing-based sentinel surveillance programme

Objective
The 2022 Australian winter was the first time that COVID-19, influenza and respiratory syncytial virus (RSV) were circulating in the population together, after two winters of physical distancing, quarantine and borders closed to international travellers. We developed a novel surveillance system to estimate the incidence of COVID-19, influenza and RSV in three regions of Queensland, Australia.

Design
We implemented a longitudinal testing-based sentinel surveillance programme. Participants were provided with self-collection nasal swabs to be dropped off at a safe location at their workplace each week. Swabs were tested for SARS-CoV-2 by PCR. Symptomatic participants attended COVID-19 respiratory clinics to be tested by multiplex PCR for SARS-CoV-2, influenza A and B and RSV. Rapid antigen test (RAT) results reported by participants were included in the analysis.

Setting and participants
Between 4 April 2022 and 3 October 2022, 578 adults were recruited via their workplace. Due to rolling recruitment, withdrawals and completion due to positive COVID-19 results, the maximum number enrolled in any week was 423 people.

Results
A total of 4290 tests were included. Participation rates varied across the period ranging from 25.9% to 72.1% of enrolled participants. The total positivity of COVID-19 was 3.3%, with few influenza or RSV cases detected. Widespread use of RAT may have resulted in few symptomatic participants attending respiratory clinics. The weekly positivity rate of SARS-CoV-2 detected during the programme correlated with the incidence of notified cases in the corresponding communities.

Conclusion
This testing-based surveillance programme could estimate disease trends and be a useful tool in settings where testing is less common or accessible. Difficulties with recruitment meant the study was underpowered. The frontline sentinel nature of workplaces meant participants were not representative of the general population but were high-risk groups providing early warning of disease.

Leggi
Aprile 2024

Rationale and protocol for a prospective cohort study of respiratory viral infections in patients admitted from emergency departments of community hospitals: Effect of respiratory Virus infection on EmeRgencY admission (EVERY) study

Introduction
Respiratory syncytial virus (RSV) is a causative virus for the common cold worldwide and can result in hospitalisations and even death in patients with high-risk conditions and older adults. However, the relationship between RSV or other incidental respiratory infections and acute exacerbations of underlying conditions has not been well investigated. The primary objective of this study is to estimate RSV prevalence, risk factors for adverse outcomes or hospitalisation and their effect on the hospital course of patients with acute respiratory symptoms admitted from emergency departments. Furthermore, we evaluate the prevalence of other respiratory viruses associated with respiratory symptoms.

Methods and analysis
We are conducting a multicentre prospective cohort study in Japan. We plan to enrol 3000 consecutive patients admitted from emergency departments with acute respiratory symptoms or signs from 1 July 2023 to 30 June 2024. A nasopharyngeal swab is obtained within 24 hours of admission and the prevalence of RSV and other respiratory viruses is measured using the FilmArray Respiratory 2.1 panel. Paired serum samples are collected from patients with suspected lower respiratory infections to measure RSV antibodies at admission and 30 days later. Information on patients’ hospital course is retrieved from the electronic medical records at discharge, death or 30 days after admission. Furthermore, information on readmission to the hospital and all-cause mortality is collected 180 days after admission. We assess the differences in clinical outcomes between patients with RSV or other respiratory viruses and those without, adjusting for baseline characteristics. Clinical outcomes include in-hospital mortality, length of hospital stay, disease progression, laboratory tests and management of respiratory symptoms or underlying conditions.

Ethics and dissemination
The study protocol was approved by the institutional review boards of participating hospitals. Our study reports will be published in academic journals as well as international meetings.

Trial registration number
NCT05913700.

Leggi
Aprile 2024

Spatial transcriptomics reveals a low extent of transcriptionally active hepatitis B virus integration in patients with HBsAg loss

Objective
Hepatitis B virus (HBV) can integrate into the chromosomes of infected hepatocytes, contributing to the production of hepatitis B surface antigen (HBsAg) and to hepatocarcinogenesis. In this study, we aimed to explore whether transcriptionally active HBV integration events spread throughout the liver tissue in different phases of chronic HBV infection, especially in patients with HBsAg loss.

Design
We constructed high-resolution spatial transcriptomes of liver biopsies containing 13 059 tissue spots from 18 patients with chronic HBV infection to analyse the occurrence and relative distribution of transcriptionally active viral integration events. Immunohistochemistry was performed to evaluate the expression of HBsAg and HBV core antigen. Intrahepatic covalently closed circular DNA (cccDNA) levels were quantified by real-time qPCR.

Results
Spatial transcriptome sequencing identified the presence of 13 154 virus-host chimeric reads in 7.86% (1026 of 13 059) of liver tissue spots in all patients, including three patients with HBsAg loss. These HBV integration sites were randomly distributed on chromosomes and can localise in host genes involved in hepatocarcinogenesis, such as ALB, CLU and APOB. Patients who were receiving or had received antiviral treatment had a significantly lower percentage of viral integration-containing spots and significantly fewer chimeric reads than treatment-naïve patients. Intrahepatic cccDNA levels correlated well with viral integration events.

Conclusion
Transcriptionally active HBV integration occurred in chronically HBV-infected patients at different phases, including in patients with HBsAg loss. Antiviral treatment was associated with a decreased number and extent of transcriptionally active viral integrations, implying that early treatment intervention may further reduce the number of viral integration events.

Leggi
Aprile 2024