Quantitative Polymerase Chain Reaction for Improved Detection of Pneumococci in CAP CAPTAIN

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the added diagnostic value of a quantitative polymerase chain reaction targeting the lytA gene in detecting pneumococci in patients with community-acquired pneumonia.

Official Title
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Community-Acquired Pneumonia: lytA TArgeted Real Time Quantitative Polymerase chaIN Reaction for Improved Detection of Pneumococci (CAPTAIN)

Conditions
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Pneumonia, Pneumococcal, Community-acquired Pneumonia

Intervention / Treatment
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* Diagnostic Test: LytA targeted quantitative polymerase chain reaction (qPCR)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients: Age 18 years or above; Presentation at the emergency department (ED); Working diagnosis of CAP at the ED with the presence of at least two of the following criteria: New or worsened coughing; Production of purulent sputum or change in sputum colour; Temperature >38.0 ⁰C or ≤36.0 ⁰C (tympanic); Auscultatory findings consistent with pneumonia, including rales, evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds, rales, or egophony), or both; White blood cell count of >10x10^9 cells/L or <4x10^9 cells/L or >15% bands; C-reactive protein level ≥30mg/L; Dyspnea, tachypnea, (>20 breaths per minute), or hypoxemia (arterial pO2 <60mmHg or peripheral O2 saturation <90%). New consolidation(s) on the chest radiograph or computed tomography (CT); No other explanation for the signs and symptoms; Control group 1 - Related controls Being aged 18 years or above; Close relative of the patient: relative defined as living in the same house as the CAP patient or daily contact; Is at the hospital at the moment of inclusion of the CAP patient or is willing to come for testing within 7 days; Control group 2 - Unrelated healthy individuals Being aged 18 years or above; Subject with a preoperative appointment with the anaesthiologist for a planned surgical procedure; Age matched to a included CAP patient (+-10 years); Time matched to a included CAP patient (up to 14 days after inclusion of the CAP patient); Gender matched to a included CAP patient. Control group 3 - Patients with stable COPD Being aged 18 years or above; Diagnosis of COPD confirmed with spirometry (GOLD criteria 2017)(76); Stable disease. Control group 4 - Patients with exacerbation of COPD Being aged 18 years or above; Diagnosis of COPD confirmed with spirometry (GOLD criteria 2017)(76); Diagnosis of exacerbation of COPD: defined as an acute event characterised by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication (76). Presentation at emergency department with the suspicion of an exacerbation. Exclusion Criteria: In general: Recent pneumonia (< 1 month) or pneumonia in last 3 months with known pneumococcal aetiology with one of current diagnostics; Was included in the study group before; Not capable of understanding information needed to sign informed consent. Patients: Aspiration pneumonia; Hospitalisation for two or more days in the last 14 days; History of cystic fibrosis. For all control groups: Fits inclusion criteria for patient group; Present or recent hospitalisation (14 days); Fits inclusion criteria for patient group; Use of antibiotics in the last 14 days, including maintenance antibiotic therapy. Control group 1 and 2 - Related healthy controls and unrelated healthy individuals Active infectious respiratory complaints defined as defined as two or more respiratory symptoms (cough, nasal congestion, runny nose, sore throat or sneezes); Temperature >38.0 ⁰C; Fits inclusion criteria for control group 3 or 4; Chronic pulmonary disease: COPD, asthma, cystic fibrosis, bronchiectasis. Control group 3 - Patients with stable COPD Temperature >38.0 ⁰C; Stable disease; Fits inclusion criteria for control group 4; Recent exacerbation (<1 month) defined as increased respiratory symptoms with need of antibiotic and/or corticosteroid therapy; History of cystic fibrosis. Control group 4 - Patients with exacerbation of COPD Current pneumonia; Recent exacerbation (<1 month) defined as increased respiratory symptoms with need of antibiotic and/or corticosteroid therapy; Fits inclusion criteria for control group 3; History of cystic fibrosis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with CAP<br>Patients with a diagnosis of radiographically-confirmed CAP at the emergency department will undergo the usual diagnostics. For the study an extra nasopharynx sample, saliva sample and blood sample will be collected. A questionnaire will be filled in. LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva, sputum if available) | Diagnostic Test: LytA targeted quantitative polymerase chain reaction (qPCR)<br>* LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva, sputum if available)<br>|
| Related controls<br>Of related controls a nasopharynx sample, oropharynx sample and saliva sample will be collected. A questionnaire will be filled in. LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva) | Diagnostic Test: LytA targeted quantitative polymerase chain reaction (qPCR)<br>* LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva, sputum if available)<br>|
| Unrelated controls<br>Of unrelated controls a nasopharynx sample, oropharynx sample and saliva sample will be collected. A questionnaire will be filled in. LytA PCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva) | Diagnostic Test: LytA targeted quantitative polymerase chain reaction (qPCR)<br>* LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva, sputum if available)<br>|
| Patients with stable COPD<br>Of stable COPD patients a nasopharynx sample, oropharynx sample and saliva sample will be collected. And if available also a sputum sample. A questionnaire will be filled in. LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva, sputum if available) | Diagnostic Test: LytA targeted quantitative polymerase chain reaction (qPCR)<br>* LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva, sputum if available)<br>|
| Patients with exacerbation of COPD<br>Of patients with a diagnosis of an exacerbation of COPD at the emergency department a nasopharynx sample, oropharynx sample and saliva sample will be collected apart from the usual diagnostics. If available also a sputum sample will be collected. A questionnaire will be filled in. LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva, sputum if available) | Diagnostic Test: LytA targeted quantitative polymerase chain reaction (qPCR)<br>* LytA qPCR and cultures will be performed on samples of the upper respiratory tract (nasopahrynx, oropharynx, saliva, sputum if available)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| qPCR diagnosed pneumococcal pneumonia | Occurrence of qPCR proven pneumococcal pneumonia (CAP with S. pneumoniae detected by qPCR in at least one of the samples with a positive lytA qPCR and a DNA copy number above the determined cut-off value) using the cut-off value in at least one of the specimens at inclusion. The cut-off value will be determined in this study, see secondary objective. | 1 day, day of inclusion | 
| Pneumococcal pneumonia with usual tests | Occurrence of pneumococcal pneumonia proven by at least one of the routine microbiological tests (urine antigen test, blood culture and/or sputum culture). The difference between outcome measure 1 and 2 is the added diagnostic value. | 1 day, day of inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of DNA copies of S. pneumoniae in all lytA qPCR positive study subjects | The number of DNA copies of every study subject with a positive qPCR will be determined. The optimal cut-off value will be determined to distinguish between colonisation and infection by comparing the number of DNA copies of controls with a positive lytA PCR and patients with a pneumococcal pneumonia proven by routine microbiological tests. This cut-off value will be used for outcome measure 1 to determine the amount of patients with an qPCR proven pneumococcal pneumonia. | 1 day, day of inclusion | 
| Occurrence of positive lytA qPCR at 30 days after inclusion in CAP patients | Occurrence of positive lytA qPCR at 30 days after inclusion in CAP patients in the different samples: oropharynx, nasopharynx, saliva and sputum. | 30 days | 
| CURB-65 scores | CURB-65 scores will be determined in CAP patients at moment of inclusion. | 1 day, day of inclusion | 
| Procalcitonin | Procalcitonin levels will be determined in CAP patients at moment of inclusion. | 1 day, day of inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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qPCR, quantitative polymerase chain reaction, autolysin, lytA, Pneumococcal pneumonia, Diagnostics, Community-acquired Pneumonia, Antibiotic resistance