Procalcitonin and Lung Ultrasonography Guided Antibiotherapy in Emergency Departments

Lower Respiratory Tract Infection Clinical Trial

— PLUS-IS-LESS  

Official title:

Procalcitonin and Lung Ultrasonography Based Antibiotherapy in Patients With Lower Respiratory Tract Infection in Swiss Emergency Departments: Pragmatic Stepped-wedge Cluster-randomized Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05463406
• Other study ID #: PLUS-IS-LESS
• Secondary ID: SNSF 33IC30_2013
• Status: Recruiting
• Phase: N/A
• Start date: December 5, 2022
• Est. completion date: May 16, 2025

Study information

• Verified date: May 2024
• Source: Centre Hospitalier Universitaire Vaudois
• Contact: Noémie Boillat Blanco, MD
• Phone: +41 21 314 88 30
• Email: noemie.boillat[@]chuv.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Acute respiratory infections are a common reason of attendance at emergency departments. It is also the main reason of unnecessary antibiotic prescription. Antibiotics save lives, but can also directly harm patients by causing antibiotic-associated adverse events. Antibiotic use is directly related to resistance, which is one of the major threats of our century. In addition, some microorganisms live in and on the human body and promote many aspects of our health. Antibiotic treatment can disturb those microorganisms and therefore have long-lasting negative effects on our health.

Unfortunately, it is difficult to differentiate between viral infections, which usually heal spontaneously, and bacterial pneumonia, which needs antibiotics treatment. This is one of the reasons of this over-prescribing of antibiotics.

This project aims to reduce widespread use of antibiotics in the emergency department through a new diagnostic strategy of bacterial pneumonia. This strategy includes sequential use of well-known techniques: a clinical score, lung ultrasound and finally a biomarker, procalcitonin. The latter tends to be higher in bacterial infections. The combination of these different tests improves the diagnostic process and allows improved use of targeted antibiotics, with the ultimate goal of better patient management.

The study will compare the antibiotic prescription rate and the clinical course of patients managed using this new diagnostic approach with those managed as usual. The project will also evaluate the acceptability and feasibility of this strategy and its cost-effectiveness. These two aspects are essential for a wider implementation of this innovative diagnostic approach and decrease antibiotic resistance.

Description:

Background Community-acquired lower respiratory tract infections (LRTI) are one of the most common motivations for emergency department (ED) consultations and stands as the leading cause of inappropriate antibiotic prescription. Besides the side effects, antibiotic overuse alters the microbiome and generates antibiotic resistance. When assessing patients with LRTIs, the challenge for ED physicians is to identify those with community-acquired pneumonia (CAP) of bacterial origin, who will most likely benefit from antibiotics. The low diagnostic accuracy of existing tools, as well as the poor adherence of clinicians to test guidance are leading causes of inappropriate antibiotic use.

Several diagnostic tests can assist in identifying patients with LRTI who require antibiotics. Clinical prediction score can refine the probability of CAP. Lung ultrasound (LUS) has a better diagnostic performance than chest X-ray, the historic reference imaging modality to consolidation in ED. LUS is performed quickly at the bedside without radiation. Procalcitonin (PCT) is a host inflammatory biomarker which tends to be higher in bacterial infections. PCT can be used safely to guide antibiotics use, while its impact on prescription is controversial. None of these tools on its own is sufficient to optimize antibiotic prescription, while a combined approach could better guide clinicians.

Rationale The investigators propose to evaluate the use of a decision support tool to guide antibiotics use in the ED as the summative value of LUS with PCT remains unknown in this setting.

Pragmatic stepped-wedge cluster-randomized controlled clinical trial investigating a new algorithm combining a clinical score, LUS and PCT results (The PLUS algorithm) for the management of LRTIs among adults in EDs. The unit of randomization will be the ED.

Primary safety objective To demonstrate non-inferiority of the intervention in terms of clinical failure by day 28.

Co-primary efficacy objective To show a 15% reduction in the proportion of patients with LRTIs prescribed an antibiotic by day 28 in the intervention group compared with the usual care group.

Secondary objectives

1. To compare the quality of life (bothersomeness of CAP-related symptoms) on day 7, day 28 and day 90 between patients in the intervention and control groups.

2. To evaluate the acceptability and feasibility of the intervention through the identification of barriers and facilitators in patients and physicians.

3. To assess the incremental cost-effectiveness of the intervention as compared to usual care using a within-trial (short-term), and a model-based (long-term) economic evaluation.

4. To develop an advanced automatic LUS image analysis method using machine learning to assist in LUS diagnosis and risk stratification.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1440
• Est. completion date: May 16, 2025
• Est. primary completion date: March 15, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed informed consent

• Patients aged 18 years or more

• Acute LRTI (acute illness, less than 21 days, with at least one lower respiratory tract symptom, i.e. cough, sputum, dyspnea, chest pain and no alternative explanation)

• At least one of the following clinical criteria:

• Focal abnormal auscultation (decreased breath sounds, crackles, bronchial breath sounds)

• Fever (documented temperature = 38°C in the last 24 hours, including self-measured temperature = 38°C)

• Tachypnea (respiratory rate = 22/minute)

• Tachycardia (heart rate = 100/minute)

Exclusion Criteria:

• Previous receipt of a quinolone, macrolide or ceftriaxone or, of more than one dose of any other antibiotic within 72h prior to enrolment (excepted prophylactic antibiotics or antibiotics given for urinary tract infection)

• Previous hospital stay in the last 14 days

• Cystic fibrosis

• Severe COPD (=GOLD 3 or if not available, as a proxy: exacerbation treated with antibiotics during the last 6 months)

• Severe immunodeficiency (drug-induced neutropenia with <500 neutrophils/mm3, HIV infection with CD4<200 cells/mm3, solid organ or bone marrow transplant recipient, prednisone = 20mg/day for >28 days)

• Initial admission of the patient in the intensive care unit

• Microbiologically-documented SARS-CoV-2

• Incapacity of discernment

Related Conditions & MeSH terms

• Emergencies
• Infections
• Lower Respiratory Tract Infection
• Respiratory Tract Infections

Intervention

Other:
• The PLUS algorithm
Combination of a clinical prediction score and LUS, and if needed PCT measurement
• Usual care
Management as usual

Locations

Country	Name	City	State
Switzerland	Cantonal hospital of Baden	Baden	AG
Switzerland	University Hospital of Basel	Basel	BS
Switzerland	Centre hospitalier universitaire vaudois (CHUV)	Lausanne	VD
Switzerland	Kantonsspital Baselland	Liestal	BS
Switzerland	Luzerner Kantonsspital	Luzern	LU
Switzerland	Réseau Hospitalier Neuchâtelois	Neuchâtel	NE
Switzerland	Hôpital Intercantonal de la Broye	Payerne	VD
Switzerland	Hôpital Riviera-Chablais	Rennaz	VD
Switzerland	Cantonal Hospital of St. Gallen	Saint Gallen	SG

Sponsors (10)

Lead Sponsor	Collaborator
Dr Boillat-Blanco Noemie	Cantonal Hospital of St. Gallen, Cantonal Hosptal, Baselland, Hôpital Intercantonal de la Broye, Payerne, Switzerland, Hôpital Riviera-Chablais, Vaud-Valais, Kantonsspital Baden, Luzerner Kantonsspital, Réseau Hospitalier Neuchâtelois, Switzerland, St. Claraspital AG, University Hospital, Basel, Switzerland

Country where clinical trial is conducted

Switzerland, 

References & Publications (3)

Lamping DL, Schroter S, Marquis P, Marrel A, Duprat-Lomon I, Sagnier PP. The community-acquired pneumonia symptom questionnaire: a new, patient-based outcome measure to evaluate symptoms in patients with community-acquired pneumonia. Chest. 2002 Sep;122(3 — View Citation

Lhopitallier L, Kronenberg A, Meuwly JY, Locatelli I, Dubois J, Marti J, Mueller Y, Senn N, D'Acremont V, Boillat-Blanco N. Procalcitonin and lung ultrasonography point-of-care testing to decide on antibiotic prescription in patients with lower respirator — View Citation

Lhopitallier L, Kronenberg A, Meuwly JY, Locatelli I, Mueller Y, Senn N, D'Acremont V, Boillat-Blanco N. Procalcitonin and lung ultrasonography point-of-care testing to determine antibiotic prescription in patients with lower respiratory tract infection i — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety outcome	Proportion of patients with clinical failure (defined as a composite of any of the following: death or secondary ICU admission or secondary admission to hospital or hospital re-admission after index hospital discharge or complications due to the LRTI [empyema, lung abscess])	Day 28
Primary	Efficacy outcome	Proportion of patients prescribed an antibiotic in each intervention group between enrolment and day 28	Day 28
Secondary	Quality of life measured with the community-acquired pneumonia symptom questionnaire	Number of points on the community-acquired pneumonia symptom questionnaire as a surrogate marker of quality of life (range 0 to 90; 90 beeing the worse quality of life)	Day 7, Day 28, Day 90
Secondary	Hospitalisation	Duration of hospitalisation	Day 0 to Day 90
Secondary	Efficacy endpoint	Proportion of patients prescribed an antibiotic in each study group between enrolment and day 28 as well as day 90.	Day 90
Secondary	Antibiotic side effects and C. difficile infection	Proportion of patients with antibiotic-related side effects and C. difficile infections in each study group.	Day 0 to Day 28
Secondary	Emergency department stay	Length of stay in the emergency department in each study group.	Day 0 to Day 28
Secondary	Qualitative evaluation	Acceptability and feasibility of the intervention through extensive identification of barriers and facilitators in patients and physicians conducting qualitative semi-structured interviews	Day 90
Secondary	Machine learning of Lung ultrasonography (LUS) images and videos	Diagnostic performance for pneumonia (sensitivity, specificity, AUROC) of artificial intelligence LUS interpretation using expert interpretation as gold standard	Day 90
Secondary	Economic evaluation	Cost of the intervention as compared to usual care	Day 90
Secondary	Clinical gestalt	Diagnostic performance (sensitivity, specificity, AUROC) of the "Clinical gestalt" of the physician in charge of the patient (probability of pneumonia low/intermediate versus high) versus Van Vugt score (1×absence of runny nose+1×breathlessness+1×crackles+1×diminished vesicular breathing+1×raised pulse (>100/min)+1×fever (temperature >37.8°C: probability of pneumonia low/intermediate (score 0-2 ) versus high (score>=3)) to predict LUS-visualized pneumonia	Day 0