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.

(1,3)-ß-D-glucan-based diagnosis of invasive Candida infection versus culture-based diagnosis in patients with sepsis and with an increased risk of invasive Candida infection (CandiSep): study protocol for a randomized controlled trial.

BACKGROUND: The time to diagnosis of invasive Candida infection (ICI) is often too long to initiate timely antifungal therapy in patients with sepsis. Elevated serum (1,3)-ß-D-glucan (BDG) concentrations have a high diagnostic sensitivity for detecting ICI. However, the clinical significance of elevated BDG concentrations is unclear in critically ill patients. The goal of this study is to investigate whether measurement of BDG in patients with sepsis and a high risk for ICI can be used to decrease the time to empiric antifungal therapy and thus, increase survival. METHODS/DESIGN: This prospective multicenter open randomized controlled trial is being conducted in 19 German intensive care units. All adult patients with severe sepsis or septic shock and an increased risk for ICI are eligible for enrolment. Risk factors are total parenteral nutrition, previous abdominal surgery, previous antimicrobial therapy, and renal replacement therapy. Patients with proven ICI or those already treated with systemic antifungal substances are excluded. Patients are allocated to a BDG or standard care group. The standard care group receives targeted antifungal therapy as necessary. In the BDG group, BDG serum samples are taken after randomization and 24 h later. Antifungal therapy is initiated if BDG is ≥80 pg/ml in at least one sample. We plan to enroll 312 patients. The primary outcome is 28-day mortality. Other outcomes include antifungal-free survival within 28 days after enrolment, time to antifungal therapy, and the diagnostic performance of BDG compared to other laboratory tests for early ICI diagnosis. The statistical analysis will be performed according to the intent-to-treat principle. DISCUSSION: Because of the high risk of death, American guidelines recommend empiric antifungal therapy in sepsis patients with a high risk of ICI despite the limited evidence for such a recommendation. In contrast, empiric antifungal therapy is not recommended by European guidelines. BDG may offer a way out of this dilemma since BDG potentially identifies patients in need of early antifungals. However, the evidence for such an approach is inconclusive. This clinical study will generate solid evidence for health-care providers and authors of guidelines for the use of BDG in critically ill patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02734550 . Registered 12 April 2016.