CAP-NEXT: DiagNostic intervention study of low-dose CT and MultipleX PCR on antibiotic Treatment and outcome of Community-Acquired Pneumonia

The aim of this project is to determine the added value of low-dose chest computed tomography (low-dose CT) and point-of-care multiplex polymerase chain reaction (PoC-PCR) in the diagnostic workup of patients with community-acquired pneumonia (CAP) hospitalised to non-intensive care unit (ICU) wards in minimizing selective antibiotic pressure while maintaining patient safety. Uncertainty in the clinical and etiological diagnosis of CAP often leads to incorrect treatment and unnecessary use of broad-spectrum antibiotics. In current routine care practice of adults, CAP is diagnosed through patient history, physical exam, and a chest radiograph. Establishing the clinical diagnosis of CAP is hampered by the suboptimal sensitivity of chest radiograph to detect pulmonary infiltrates (~70%). Therefore, a “negative” chest X-ray in a patient with a suggestive clinical presentation may well be interpreted as CAP, while the actual underlying disease is not directly recognised. Obviously, absence of an infiltrate on chest radiograph may also lead to a missed CAP diagnosis, also resulting in insufficient treatment. Establishing the etiological diagnosis is also hampered, mainly because of the inevitable diagnostic delays. Samples for microbiological diagnosis are collected but hardly impact empirical treatment. Current national and international guidelines recommend to always include coverage of Streptococcus pneumoniae in the empirical antibiotic treatment of CAP. Recommendations for additional coverage of atypical pathogens vary across guidelines. There are currently no recommendations to withhold antibiotics in case of detected viral pathogens, simply because the data supporting such an approach are lacking. In this study, we will quantify the effects of low-dose CT performed within 24 hours of hospital admission and PoC-PCR of respiratory samples targeting atypical and viral pathogens performed at the ER on antibiotic use and patient safety in patients hospitalized with a clinical suspicion of CAP. The domain of our study are those patients initially hospitalized in non-ICU wards. Through cluster randomisation, hospitals will be randomised to either (1) standard care (control); (2) addition of PoC-PCR testing; or (3) addition of low-dose CT to the diagnostic work-up. Treatment recommendations will be based on the results of these tests, such as discontinuation of antibiotics if only a virus is detected and the patient is clinically stable, or if the CT-scan reveals a non-infectious diagnosis that explains the signs and symptoms. In each study arm we will enrol 1,250 patients in 2-3 years. As reductions in antibiotic use are only justified if the clinical outcome is not compromised, the two primary outcome measures will be non-inferiority for 90-day all-cause mortality (using a non-inferiority margin of 3%) and days of therapy of broad-spectrum antibiotics. Secondary outcomes will be 30-day mortality, length of hospital stay, adverse outcomes (including ICU admission), cost-effectiveness, and changes in diagnosis or treatment by CT or PCR results. We will also determine which patient and disease characteristics are associated with changes in patient management following CT or PCR results. This trial will directly follow an ongoing study in 11 hospitals in which adherence to the Dutch CAP guidelines is optimised with respect to the use of narrow-spectrum antibiotics, using a step-wedged design. Patients included in the intervention arm in that study will form the pre-intervention control group of the currently proposed study. This optimizes efficiency for study execution and allows for accounting differences between hospitals. The study will generate increased knowledge on the (cost) effectiveness of optimised CAP diagnostics on antibiotic consumption and patient outcome, and implementation of the results could start directly after completion of the study and be realised within 3 years.