The Effect of a Point-of-care Sputum Specimen Assay at the Emergency Department for Patients Suspected of Pneumonia

The Effect of a Point-of-care Sputum Specimen Assay on Antibiotic Treatment of Patients Admitted Acutely With Suspected Pneumonia: A Multicenter Randomized Controlled Trial

Antibiotic resistance has been identified by the WHO as one of the biggest threats to the health of the world population. In Denmark, there has been an increasing focus on optimizing antibiotic consumption in recent years, but despite significant efforts, total consumption has increased in the hospital sector, especially regarding consumption and in the use of broad-spectrum antibiotics. Currently, a pneumonia diagnosis is primarily based on clinical symptoms such as cough, shortness of breath, chest pain, fever and sputum production, combined with X-ray of the lungs, relevant blood tests and microbiological analysis of sputum samples. X-ray is however an imprecise diagnostic tool, and sputum assays responses are available after 2 days. Sputum can be cultivated to determine the bacterial agent. However, the sputum samples are often of poor quality and many patients cannot deliver a sample. A recently published Danish study shows, that only half of the patients at the ED have sputum samples collected for culturing and none of them had the antibiotic treatment adjusted based on the microbiological results of the sputum.

This study's hypothesis is that point-of-care-polymerase chain reaction (POC-PCR) is superior to standard care on the prescription of targeted pneumonia treatment.

Study Overview

• Status: Completed
• Conditions: Pneumonia, Bacterial
• Intervention / Treatment: Diagnostic test: POC-PCR

Detailed Description

The diagnosis of pneumonia is challenged by nonspecific symptoms, uncertain diagnostic methods, poor prognostic tools and waiting time for test results up to several days. A patient's length of stay in a Danish Emergency Department rarely exceeds 48 hours. Within this period the patient is examined, treated and discharged either home or to another department. Therefore, rapid molecular detection of respiratory pathogens is needed to add value to the management of the diagnostics of pneumonia and could reduce the initial use of antibiotics. Molecular diagnostic tests based on polymerase chain reaction (PCR) assays generate high sensitive analyses in one hour from specimen collection. The Biofire® FilmArray® Pneumonia Panel plus (Biomérieux) can identify 18 bacterial agents including 3 atypical pathogens 9 viruses and 7 antimicrobial resistance genes. This point-of-care (POC) test is promising, as bacterial pathogens often coexist with viruses or are identified with mixed infections. However, the high specificity of molecular diagnostics can challenge the interpretation of clinically significant agents and demands interpretation by highly qualified specialists. Therefore, the POC-PCR combined with advice from a microbiologist has the potential to optimize therapeutic regimens and reduce prescriptions of inappropriate broad-spectrum antibiotics in the initial management of pneumonia.

This study aims to

• investigate how effective the addition of POC-PCR analysis of sputum is to the diagnostic set-up for community-acquired pneumonia on antibiotic prescription at 4 hours after admission without consequent adverse advents
• to identify the effect of POC-PCR on prescribed antibiotic treatment 48 hours after admission and 24 hours after discharge
• to investigate the agreement between POC-PCR and sputum culture on microbiological analysis

• Study Type: Interventional
• Enrollment (Actual): 290
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aabenraa, Denmark
    • Hospital of Southern Jutland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Emergency department patients suspected of pneumonia by the attending physician and with at least one of the following symptoms: dyspnea, cough, expectoration, chest tightness or fever and indication for chest x-ray

Exclusion Criteria:

• If the attending physician considers that participation will delay a life-saving treatment or patient needs direct transfer to the intensive care unit.
• Admission within the last 14 days
• Verified COVID-19 disease within 14 days before admission
• Pregnant women
• Severe immunodeficiencies: Primary immunodeficiencies and secondary immunodeficiencies (HIV positive CD4 <200, Patients receiving immunosuppressive treatment (ATC L04A), Corticosteroid treatment (>20 mg/day prednisone or equivalent for >14 days within the last 30 days), Chemotherapy within 30 days)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard care; A treating physician must perform a clinical assessment within half an hour of patient arrival. This assessment includes the decision whether the patient is suspected of having pneumonia and if this is the case, a sputum specimen and chest x-ray will be ordered. Patients with suspected pneumonia who can deliver a sputum specimen will be randomly allocated with a 1:1 computer-generated randomization schedule with permuting blocks in relation to optimal therapeutical intervention strategy. All standard care sputum samples will be cultured and analysed according to the sites' standard procedures. Under standard care, the treating physician alone decides on the optimal therapeutical intervention.
Active Comparator: POC-PCR analysis supplied with a recommended action list developed by a microbiologist; Along with standard analyses, the specimens will be analysed with POC-PCR and the treating physician will receive an action-list with the results from POC-PCR.	Diagnostic test: POC-PCR; The result of the POC-PCR will be presented by the study assistant to the treating physician within four hours upon admission. The treating physician will along with the result receive a recommended action list, developed by microbiologists.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antibiotic treatment at 4-hour plan	The primary outcome is to determine the effectiveness of POC-PCR sputum analysis on antibiotic prescription, the treatment will either be registered as targeted or non-targeted antibiotic treatment at four hours after admission. This is a binary outcome.	4 hours after admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-days mortality	Mortality within 30 days from admission to the Emergency Department	30 days from the admission to the emergency department
Readmission	If a subject is admitted over a 30 day period after the current hospitalization discharge measured as a binary outcome Re-admissions/not re-admissions.	within 30 days from the discharge to the hospital
In-hospital mortality	Patient mortality during the current hospitalization. Binary outcome - Died/ Not died	within 60 days from admission to the emergency department
Intensive care unit (ICU) treatment	Transfer to the intensive care unit will be recorded during the current hospitalization as a binary variable (transferred/not-transferred)	within 60 days from admission to the emergency department
Length of hospital stay	Defined as the time (in days) spent in hospital during the current admission. Measured in days from admission to hospital discharge. Discharge date minus admission date.	within 60 days from current admission to the emergency department
Antibiotic treatment at 48 hour	The treatment will either be registered as targeted or non-targeted antibiotic treatment 48 hours after admission. This is a binary outcome.	48 hours after admission
Antibiotic treatment at discharge from hospital	The treatment will either be registered as a targeted or non-targeted antibiotic treatment after the patient is discharged from the hospital. This is a binary outcome.	24 hours after hospital discharge
Bacterial agents and viruses from the microbiological results	The bacterial agents and viruses from the Biofire® FilmArray® Pneumonia Panel plus (Biomérieux) and standard sputum culture for the two microbiological analysis will be presented as descriptive statistics.	Within the first 7 days from specimen collection

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pneumonia severity index (PSI)	Risk classes to predict the severity of pneumonia. Scores are given based on demographics, comorbidity, clinical measurements and physical Exam Findings (<70 = Risk Class II, 71-90 = Risk Class III, 91-130 = Risk Class IV, >130 = Risk Class V)	within 4 hours from admission
CURB-65 score for pneumonia severity	Confusion of new onset, Blood Urea nitrogen greater than 7 mmol/L (19 mg/dL), respiratory rate of 30 breaths per minute or greater, blood pressure less than 90 mmHg systolic or diastolic blood pressure 60 mmHg or less and age 65 or older	within 4 hours from admission
Number of clostridium infections	Identify through patient records if the patient was infected with clostridium difficille, binary outcome yes/no	measured 40 days after discharge from the emergency department
Procalcitonin (PCT), Soluble Urokinase Plasminogen Activator Receptor (suPAR), YKL-40 and Krebs von den Lungen (KL-6)	Measurement of serum PCT and suPAR are collected in connection to routine blood tests within 1 hour from admission	results within 4 hour from admission
90 days mortality	binary	Within 90 days from admission to emergency department

Collaborators and Investigators

• Sponsor: University of Southern Denmark
• Investigators: Study Chair: Christian Backer Mogensen, MD PhD, University Hospital of Southern Denmark

Publications and helpful links

General Publications

• Skjot-Arkil H, Mogensen CB, Lassen AT, Johansen IS, Chen M, Petersen P, Andersen KV, Ellermann-Eriksen S, Moller JM, Ludwig M, Fuglsang-Damgaard D, Nielsen FE, Petersen DB, Jensen US, Rosenvinge FS. Carrier prevalence and risk factors for colonisation of multiresistant bacteria in Danish emergency departments: a cross-sectional survey. BMJ Open. 2019 Jun 27;9(6):e029000. doi: 10.1136/bmjopen-2019-029000.
• Sogaard M, Nielsen RB, Schonheyder HC, Norgaard M, Thomsen RW. Nationwide trends in pneumonia hospitalization rates and mortality, Denmark 1997-2011. Respir Med. 2014 Aug;108(8):1214-22. doi: 10.1016/j.rmed.2014.05.004. Epub 2014 May 20.
• Skjot-Arkil H, Heltborg A, Lorentzen MH, Cartuliares MB, Hertz MA, Graumann O, Rosenvinge FS, Petersen ERB, Ostergaard C, Laursen CB, Skovsted TA, Posth S, Chen M, Mogensen CB. Improved diagnostics of infectious diseases in emergency departments: a protocol of a multifaceted multicentre diagnostic study. BMJ Open. 2021 Sep 30;11(9):e049606. doi: 10.1136/bmjopen-2021-049606.
• Welte T, Torres A, Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax. 2012 Jan;67(1):71-9. doi: 10.1136/thx.2009.129502. Epub 2010 Aug 20.
• van der Eerden MM, Vlaspolder F, de Graaff CS, Groot T, Bronsveld W, Jansen HM, Boersma WG. Comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study. Thorax. 2005 Aug;60(8):672-8. doi: 10.1136/thx.2004.030411.
• Becerra MB, Becerra BJ, Banta JE, Safdar N. Impact of Clostridium difficile infection among pneumonia and urinary tract infection hospitalizations: an analysis of the Nationwide Inpatient Sample. BMC Infect Dis. 2015 Jul 1;15:254. doi: 10.1186/s12879-015-0925-9.
• Ewig S, Schlochtermeier M, Goke N, Niederman MS. Applying sputum as a diagnostic tool in pneumonia: limited yield, minimal impact on treatment decisions. Chest. 2002 May;121(5):1486-92. doi: 10.1378/chest.121.5.1486.
• Roson B, Carratala J, Verdaguer R, Dorca J, Manresa F, Gudiol F. Prospective study of the usefulness of sputum Gram stain in the initial approach to community-acquired pneumonia requiring hospitalization. Clin Infect Dis. 2000 Oct;31(4):869-74. doi: 10.1086/318151. Epub 2000 Oct 12.
• Hadfield J, Bennett L. Determining best outcomes from community-acquired pneumonia and how to achieve them. Respirology. 2018 Feb;23(2):138-147. doi: 10.1111/resp.13218. Epub 2017 Nov 17.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): February 28, 2022
• Study Completion (Actual): June 1, 2022

Study Registration Dates

• First Submitted: November 19, 2020
• First Submitted That Met QC Criteria: November 25, 2020
• First Posted (Actual): December 3, 2020

Study Record Updates

• Last Update Posted (Actual): September 14, 2022
• Last Update Submitted That Met QC Criteria: September 13, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Antibiotics; Emergency department; Sputum
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Pneumonia; Pneumonia, Bacterial
• Other Study ID Numbers: SHS-ED-11c-2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No