Respiratory Tract Infections
Conditions
Brief summary
To assess the impact of rapid diagnostic testing of patients with Acute Respiratory Tract Infection (ARTI) at the emergency department, on (1) hospital admission rates and (2) antimicrobial prescriptions (days of treatment) and (3) the non-inferiority in terms of clinical outcome. Geographical and seasonal variation will be assessed on a real time basis including pathogens of public health interest. The impact will be stratified within age groups and risk factors in order to determine the long-term clinical, public health and economic determinants for the integration of diagnostics in a global and sustainable perspective.
Detailed description
Objective: To assess the impact of rapid diagnostic testing of patients with Acute Respiratory Tract Infection (ARTI) at the emergency department, on (1) hospital admission rates and (2) antibiotic prescriptions (days of treatment) and (3) the non-inferiority in terms of clinical outcome. Geographical and seasonal variation will be assessed on a real time basis including pathogens of public health interest. The impact will be stratified within age groups and risk factors in order to determine the long-term clinical, public health and economic determinants for the integration of diagnostics in a global and sustainable perspective. Study design: Prospective, multi-center, individually randomised, controlled trial. Study population: Adults (≥18 years old) consulting in selected participating sites with CA-ARTI. Study Intervention: The diagnostic intervention is rapid syndromic testing with: * BioFire FilmArray Pneumonia Panel plus (PP): Sputum (and/or ETA or BAL sample) * BioFire FilmArray Respiratory Panel 2.1 plus (RP2.1plus): Nasopharyngeal swab Main study parameters/endpoints: * Days alive out of hospital (superiority endpoint), within 14 days * Days on Therapy (DOT) with antibiotics (superiority endpoint), within 14 days * Adverse outcome (non-inferiority safety endpoint) * For initially non-admitted patients: any admission or death within 30 days * For initially hospitalised patients: i) any readmission, ii) ICU admission ≥ 24 hours after hospitalisation, or iii) death within 30 days Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participation in the study involves collection of data that can be obtained from medical charts and follow up questionnaires and interviews. Respiratory samples (e.g. nasopharyngeal swab, sputum) will be obtained as standard of care and diagnostic intervention (Biofire FilmArray) will be used only for participants randomised to the intervention,Based on the results of diagnostic testing (BioFire FilmArray) antibiotics may be withheld when deemed unnecessary, or a different antibiotic class may be selected when certain bacterial pathogens are detected. The risks and benefits of management decisions, complemented with adequate training, are subject to the current investigation.
Interventions
DIAGNOSTIC_TESTBioFire
A molecular rapid syndromic testing platform, using the following panels: * BioFire FilmArray Respiratory Panel 2.1 plus (RP2.1plus) * BioFire FilmArray Pneumonia Panel plus (PP)
Sponsors
BioMérieux
UMC Utrecht
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults (≥18 years old) presenting to the Emergency Room with an acute illness (present for 14 days or less) with cough, and with at least 1 other lower respiratory tract symptom or clinical sign at physical examination: * Sputum production, * Breathlessness, * Chest discomfort or chest pain, * Wheeze, * Crackles, * Self-reported dystermia or documented fever; * Documented hypoxemia (adjusting definition for chronic oxygen therapy users, method of measurement) and no alternative explanation (infection, such as sinusitis; other, such as asthma). 2\. Managing medical team considers: 1. to treat patient with antibiotics and/or to hospitalize patient AND 2. that the rapid syndromic diagnostic test result can be awaited up to a maximum of 4 hours before the decision to discharge the patient or to initiate antibiotic therapy.
Exclusion criteria
1. Development of ARTI more than 48 hours after hospital admission (hospital acquired); 2. Patients with cystic fibrosis; 3. Less than 14 days since the last episode of respiratory tract infection; 4. Pregnancy (confirmed by pregnancy test) and breastfeeding; 5. Any clinically significant abnormality identified at the time of screening that in the judgment of the Investigator would preclude safe completion of the study or constrain endpoints assessment such as major systemic diseases or patients with short life expectancy; 6. Inability to obtain informed consent from a competent patient. Based on standard of care microbiological diagnosis and thoracic imaging (when indicated): 7. Radiologically confirmed acute lobar pneumonia; 8. Known or suspected Pneumocystis jirovecii pneumonia or active tuberculosis; 9. Alternative noninfectious diagnosis that explains clinical symptoms (pulmonary embolism, alveolar hemorrhage, acute heart failure, lung cancer).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days Alive Out of Hospital (Superiority Endpoint) | Day 1 - Day 14 | Days alive out of hospital (superiority endpoint), within 14 days after study enrolment |
| Days on Therapy (DOT) With Antibiotics (Superiority Endpoint) | Day 1 - Day 14 | Days on Therapy (DOT) with antibiotics (superiority endpoint), within 14 days after study enrolment |
| Adverse Outcome (Non-inferiority Safety Endpoint) | Day 1 - Day 30 | * For initially non-admitted patients: any admission or death * For initially hospitalized patients: any readmission, ICU admission \>= 24 hours after hospitalization, or death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antibiotic Type Switches and De-escalation Based on Antimicrobial Agent Categories | Day 1 - Day 14 | For this report is presented the number of patients where the antimicrobial was switched to narrower spectrum. |
| Direct Costs and Indirect Costs Within 30 Days After Enrolment. | Day 1 - Day 30 | * Cost of healthcare within 30 days after enrolment, including hospital and ICU days, utilisation of non-hospital services and cost of anti-infective and concomitant medication * Cost of workdays lost within 30 days, including days for childcare |
| Impact on Decisions Regarding Isolation Measures Related to Test Result. | Day 1 - Day 30 | Hours in individual or cohort isolation in hospitalised participants comparing the 2 groups |
| Detection of Antimicrobial Resistance (Carriage or Infection) Related to the Diagnostic Intervention Results Compared to Standard of Care and Impact on Antimicrobial Stewardship Guidelines and Prevention of Hospital Acquired Infections. | >7 days after randomisation | Proportion of hospitalised participants with detection of cephalosporin-, carbapenem- or chinolone-resistant Enterobacteriaceae on any standard of care samples \>7 days after randomisation comparing diagnostic intervention arm and standard of care arm. |
| Microbiological Results Obtained as Standard of Care and With the Diagnostic Intervention | Day 1 | Proportion of participants with an identified respiratory pathogen in both study groups on randomisation day samples. Data refers to the number of participants so in case more than one microorganism is detected in the same sample (co-detection) or same result in more than one sample, it is still counted as one participant. |
| Empirical Antibiotics Based on Antimicrobial Agent Categories | Day 1 - Day 14 | Proportion of participants on non-first-line anti-infective regimens (as defined by local guidelines). For this report, results are defined as non first-line if the choice includes a third or fourth generation cephalosporin or a carbapenem but analysis needs to be adjusted to baseline risk factors, comorbidities, local guidelines and time to de escalation. |
Countries
Belgium, Hungary, Serbia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention BioFire: A molecular rapid syndromic testing platform, using the following panels:
* BioFire FilmArray Respiratory Panel 2.1 plus (RP2.1plus)
* BioFire FilmArray Pneumonia Panel plus (PP) | 92 |
| Standard of Care Standard of care diagnostic testing | 93 |
| Total | 185 |
Baseline characteristics
| Characteristic | Intervention | Standard of Care | Total |
|---|---|---|---|
| Age, Continuous | 66.5 years | 67 years | 67 years |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Belgium | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Hungary | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Serbia | 88 participants | 91 participants | 179 participants |
| Sex: Female, Male Female | 46 Participants | 45 Participants | 91 Participants |
| Sex: Female, Male Male | 46 Participants | 48 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 92 | 11 / 93 |
| other Total, other adverse events | 0 / 92 | 3 / 93 |
| serious Total, serious adverse events | 5 / 92 | 14 / 93 |
Outcome results
Primary
Adverse Outcome (Non-inferiority Safety Endpoint)
* For initially non-admitted patients: any admission or death * For initially hospitalized patients: any readmission, ICU admission \>= 24 hours after hospitalization, or death
Time frame: Day 1 - Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Adverse Outcome (Non-inferiority Safety Endpoint) | 9 Participants |
| Standard of Care | Adverse Outcome (Non-inferiority Safety Endpoint) | 18 Participants |
Primary
Days Alive Out of Hospital (Superiority Endpoint)
Days alive out of hospital (superiority endpoint), within 14 days after study enrolment
Time frame: Day 1 - Day 14
Population: Days alive out of hospital
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Days Alive Out of Hospital (Superiority Endpoint) | 10.7 days | Standard Deviation 5.3 |
| Standard of Care | Days Alive Out of Hospital (Superiority Endpoint) | 9.7 days | Standard Deviation 5.9 |
Primary
Days on Therapy (DOT) With Antibiotics (Superiority Endpoint)
Days on Therapy (DOT) with antibiotics (superiority endpoint), within 14 days after study enrolment
Time frame: Day 1 - Day 14
Population: Number of antibiotic treatment days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Days on Therapy (DOT) With Antibiotics (Superiority Endpoint) | 6.7 days | Standard Deviation 4.6 |
| Standard of Care | Days on Therapy (DOT) With Antibiotics (Superiority Endpoint) | 7 days | Standard Deviation 4.7 |
Secondary
Antibiotic Type Switches and De-escalation Based on Antimicrobial Agent Categories
For this report is presented the number of patients where the antimicrobial was switched to narrower spectrum.
Time frame: Day 1 - Day 14
Population: Final analysis needs to integrate data from both the adult and the pediatric protocol and to adjust to local guidelines per country as well as risk factors and comorbidities. Data collected includes: antibiotics, antivirals and antifungals recording if initial, switch or addition to ongoing therapy as well as route of administration, dosing interval and start and stop date.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Antibiotic Type Switches and De-escalation Based on Antimicrobial Agent Categories | 11 Participants |
| Standard of Care | Antibiotic Type Switches and De-escalation Based on Antimicrobial Agent Categories | 15 Participants |
Secondary
Detection of Antimicrobial Resistance (Carriage or Infection) Related to the Diagnostic Intervention Results Compared to Standard of Care and Impact on Antimicrobial Stewardship Guidelines and Prevention of Hospital Acquired Infections.
Proportion of hospitalised participants with detection of cephalosporin-, carbapenem- or chinolone-resistant Enterobacteriaceae on any standard of care samples \>7 days after randomisation comparing diagnostic intervention arm and standard of care arm.
Time frame: >7 days after randomisation
Population: Hospitalised participants. Samples obtained as standard of care during hospital stay. Detection of multidrug resistant microorganism was recorded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Detection of Antimicrobial Resistance (Carriage or Infection) Related to the Diagnostic Intervention Results Compared to Standard of Care and Impact on Antimicrobial Stewardship Guidelines and Prevention of Hospital Acquired Infections. | 0 Participants |
| Standard of Care | Detection of Antimicrobial Resistance (Carriage or Infection) Related to the Diagnostic Intervention Results Compared to Standard of Care and Impact on Antimicrobial Stewardship Guidelines and Prevention of Hospital Acquired Infections. | 0 Participants |
Secondary
Direct Costs and Indirect Costs Within 30 Days After Enrolment.
* Cost of healthcare within 30 days after enrolment, including hospital and ICU days, utilisation of non-hospital services and cost of anti-infective and concomitant medication * Cost of workdays lost within 30 days, including days for childcare
Time frame: Day 1 - Day 30
Population: This outcome will not be analysed since direct costs and indirect costs could not be properly collected. Cost effective algorithms might change with factors as the disease incidence changes, performance of other diagnostic tests or its combination. As these other factors are also dependent on country and vary over time, the data as collected in the trial is insufficient to reliably report on cost-effectiveness in general
Secondary
Empirical Antibiotics Based on Antimicrobial Agent Categories
Proportion of participants on non-first-line anti-infective regimens (as defined by local guidelines). For this report, results are defined as non first-line if the choice includes a third or fourth generation cephalosporin or a carbapenem but analysis needs to be adjusted to baseline risk factors, comorbidities, local guidelines and time to de escalation.
Time frame: Day 1 - Day 14
Population: Final analysis needs to integrate data from both the adult and the pediatric protocol and to adjust to local guidelines per country as well as risk factors and comorbidities. Data collected includes: antibiotics, antivirals and antifungals recording if initial, switch or addition to ongoing therapy as well as route of administration, dosing interval and start and stop date.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Empirical Antibiotics Based on Antimicrobial Agent Categories | 30 Participants |
| Standard of Care | Empirical Antibiotics Based on Antimicrobial Agent Categories | 33 Participants |
Secondary
Impact on Decisions Regarding Isolation Measures Related to Test Result.
Hours in individual or cohort isolation in hospitalised participants comparing the 2 groups
Time frame: Day 1 - Day 30
Population: Hospitalised participants. Data collected includes start and stop date of individual or cohort isolation. Isolation measures in the current cohort were related to SARS-CoV-2 infection and not to the detection of multidrug resistant bacteria.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Intervention | Impact on Decisions Regarding Isolation Measures Related to Test Result. | 0 hours in isolation | Standard Deviation 0 |
| Standard of Care | Impact on Decisions Regarding Isolation Measures Related to Test Result. | 0 hours in isolation | Standard Deviation 0 |
Secondary
Microbiological Results Obtained as Standard of Care and With the Diagnostic Intervention
Proportion of participants with an identified respiratory pathogen in both study groups on randomisation day samples. Data refers to the number of participants so in case more than one microorganism is detected in the same sample (co-detection) or same result in more than one sample, it is still counted as one participant.
Time frame: Day 1
Population: Data collected includes: sample type (upper and lower respiratory tract samples for diagnostic intervention but also blood cultures and urinary antigen tests for standard of care if applicable), type of diagnostic test, specific results. Data is also collected regarding the time elapsed until the results were received. Results are final for this trial and later on will be compared with pediatric trial results NCT04781530.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Microbiological Results Obtained as Standard of Care and With the Diagnostic Intervention | 58 Participants |
| Standard of Care | Microbiological Results Obtained as Standard of Care and With the Diagnostic Intervention | 31 Participants |