INHALE: the impact of using FilmArray Pneumonia Panel molecular diagnostics for hospital-acquired and ventilator-associated pneumonia on antimicrobial stewardship and patient outcomes in UK Critical Care-study protocol for a multicentre randomised controlled trial.

BACKGROUND: Hospital-acquired and ventilator-associated pneumonias (HAP and VAP) are common in critical care and can be life-threatening. Rapid microbiological diagnostics, linked to an algorithm to translate their results into antibiotic choices, could simultaneously improve patient outcomes and antimicrobial stewardship. METHODS: The INHALE Randomised Controlled Trial is a multi-centre, parallel study exploring the potential of the BioFire FilmArray molecular diagnostic to guide antibiotic treatment of HAP/VAP in intensive care units (ICU); it identifies pathogens and key antibiotic resistance in around 90 min. The comparator is standard care whereby the patient receives empirical antibiotics until microbiological culture results become available, typically after 48-72 h. Adult and paediatric ICU patients are eligible if they are about to receive antibiotics for a suspected lower respiratory infection (including HAP/VAP) for the first time or a change in antibiotic because of a deteriorating clinical condition. Breathing spontaneously or intubated, they must have been hospitalised for 48 h or more. Patients are randomised 1:1 to receive either antibiotics guided by the FilmArray molecular diagnostic and its trial-based prescribing algorithm or standard care, meaning empirical antibiotics based on local policy, adapted subsequently based upon local microbiology culture results. Co-primary outcomes are (i) non-inferiority in clinical cure of pneumonia at 14 days post-randomisation and (ii) superiority in antimicrobial stewardship at 24 h post-randomisation (defined as % of patients on active and proportionate antibiotics). Secondary outcomes include further stewardship reviews; length of ICU stay; co-morbidity indicators, including septic shock, change in sequential organ failure assessment scores, and secondary pneumonias; ventilator-free days; adverse events over 21 days; all-cause mortality; and total antibiotic usage. Both cost-effectiveness of the molecular diagnostic-guided therapy and behavioural aspects determining antibiotic prescribing are being explored. A sample size of 552 will be required to detect clinically significant results with 90% power and 5% significance for the co-primary outcomes. DISCUSSION: This trial will test whether the potential merits of rapid molecular diagnostics for pathogen and resistance detection in HAP/VAP are realised in patient outcomes and/or improved antibiotic stewardship. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16483855 . Retrospectively registered on 15 July 2019.

Rapid and Point-of-Care Testing in Respiratory Tract Infections: An Antibiotic Guardian?

This is a narrative review on the potential of rapid and point-of-care microbiological testing in pneumonia patients, focusing particularly on hospital-acquired and ventilator-associated pneumonia, which have substantial mortality and diverse microbiology. This work is written from a United Kingdom perspective, but much of it is generalizable internationally. In a world where antimicrobial resistance is a major international threat, the use of rapid molecular diagnostics has great potential to improve both the management of pneumonia patients and the stewardship of antibiotics. Rapid tests potentially can distinguish patients with bacterial versus viral infection and can swiftly identify bacterial pathogens and their resistances. We seek to answer the question: "Can such tests be used as an antibiotic guardian?" Their availability at the bedside rather than in the laboratory should best ensure that results are swiftly used to optimize patient management but will raise new challenges, not the least with respect to maintaining quality control and microbiology/infection control input. A further challenge lies in assessing the degree of trust that treating clinicians will place in these molecular diagnostic tests, particularly when early de-escalation of antibiotic therapy is indicated.

Death by antibody.

A 42-year-old woman with a background of psoriatic arthritis presented with a 7-day medical history of fevers of unknown source; she had recently undergone elective shoulder arthroscopy, and her medications included anti-interleukin 17A (anti-IL-17A) drug, secukinumab.She went on to develop sepsis-induced cardiomyopathy, requiring veno-arterial extracorporeal membrane oxygenation (ECMO), from which she was successfully weaned after 12 days. However, she then went on to develop a candidaemia, with new intra-abdominal collections found incidentally on CT; despite appropriate anti-fungal therapy and attempts at drainage, she passed away.Both anti-IL-17A treatment and ECMO have been shown to be significant independent risk factors for Candida infection. The use of monoclonal antibody therapy in the management of autoimmune disease, and the use of ECMO in the intensive care setting are each becoming increasingly widespread. Fungal infection should be screened for early in this critically unwell group of patients, and treatment initiated as indicated.

Zika virus infection in travellers returning to the United Kingdom during the period of the outbreak in the Americas (2016-17): A retrospective analysis.

BACKGROUND: In 2016, Zika virus (ZIKV) spread rapidly throughout the Americas and Caribbean in an explosive outbreak. In the UK, testing for ZIKV infection is performed at Public Health England's Rare and Imported Pathogens Laboratory. Here we present the UK's experience of imported ZIKV during the epidemic. METHOD: A retrospective review was performed on the laboratory computer system searching by orders for ZIKV PCR and/or ELISA serology tests between 1st January 2016 and 31st December 2017. Each individual request form and result was reviewed. RESULTS: Of 6333 symptomatic patients tested for ZIKV, 374 (6%) had molecular or serological evidence consistent with recent infection; most of these had travelled to the Caribbean in 2016. On follow-up of PCR-confirmed cases, ZIKV IgM disappeared within 6 weeks and often didn't appear in patients with previous dengue infection. Rash was the commonest symptom in PCR-confirmed infection (93%). There were only single cases of presumed sexual transmission and of in-utero transmission. CONCLUSIONS: The rise and fall in numbers of imported ZIKV cases largely reflected the temporal course of the outbreak in the Caribbean. ZIKV serology is difficult to interpret but the absence of antibodies to ZIKV 14 days after symptom onset makes infection very unlikely.

Transcript profiling of the murine immune response to invasive aspergillosis.

Invasive aspergillosis is an opportunistic infection for which complex host-pathogen interactions determine infection outcome. In particular, immunosuppressive therapies and other host factors, such as neutropenia, need to be taken into account when modelling the immune response to aspergillosis. Mammalian models have been developed in order to gain a deeper understanding of these biological interactions, which cannot be easily replicated in vitro. In vivo transcript profiling is emerging as a valuable technique to gain an overview of host responses to invasive infections. This approach can be applied to specific tissue sections, whole organs, or peripheral blood leukocyte populations. Here we describe a microarray technique for analyzing transcript profiles from whole lung homogenates in the context of invasive aspergillosis. This approach has the advantage of enabling a broad overview of the immune responses that govern disease outcome. The generic techniques described, however, have wider application to other infectious processes and tissue types.