Ignite Creation Date:
2024-05-06 @ 10:21 AM
Last Modification Date:
2024-10-26 @ 12:28 PM
Study NCT ID:
NCT03233516
Status:
COMPLETED
Last Update Posted:
2020-11-23
First Post:
2017-07-26
Brief Title:
Trial of Respiratory Infections in Children for Enhanced Diagnostics
Sponsor:
Karolinska Institutet
Organization:
Karolinska Institutet
Study Overview
Official Title:
Trial of Respiratory Infections in Children for Enhanced Diagnostics
Status:
COMPLETED
Status Verified Date:
2020-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TREND
Brief Summary:
The overall aim of the TREND study is to improve the differential diagnosis of bacterial and viral etiology in children below 5 years of age with clinical community acquired pneumonia
Specific objectives
To assess the diagnostic accuracy of MxA for viral CAP sub-study I
To study etiologies in children with CAP sub-study II
To evaluate sensitivity and specificity for MariPOC Respi test versus PCR for detection of respiratory viruses sub-study III
To assess sensitivity and specificity for a novel RPA-based point-of-care test versus PCR for detection of respiratory viruses sub-study IV
To assess long-term complications in children with CAP sub-study V
The study takes place at Sachs Children and Youth hospital in Stockholm
Specific objectives
To assess the diagnostic accuracy of MxA for viral CAP sub-study I
To study etiologies in children with CAP sub-study II
To evaluate sensitivity and specificity for MariPOC Respi test versus PCR for detection of respiratory viruses sub-study III
To assess sensitivity and specificity for a novel RPA-based point-of-care test versus PCR for detection of respiratory viruses sub-study IV
To assess long-term complications in children with CAP sub-study V
The study takes place at Sachs Children and Youth hospital in Stockholm
Detailed Description:
Background Respiratory viral and bacterial infections are hard to distinguish clinically and many children with viral infections receive unnecessary treatment with antibiotics which contributes to development and spread of antibiotic resistance Therefore there is a need for new point-of-care diagnostic tests that better distinguish viral from antibiotic-requiring bacterial infections particularly in children presenting with suspected clinical community-acquired pneumonia CAP and thus assist health-care workers decision making and improve rational use of antibiotics
Myxovirus resistance protein A MxA is a promising biomarker for viral infection but no studies have investigated MxA in children with CAP Procalcitonin PCT is used as a biomarker for severe bacterial infection as the protein rapidly increases in plasma levels in response to stress and systemic infection PCT has been reported to be more specific for bacterial infection as compared to CRP but there are conflicting data on the clinical utility of PCT in children with CAP
The role of viruses and atypical bacteria in childhood CAP Is increasingly recognized Recent studies have reported an increasing incidence of B pertussis and there have been several deaths in previously healthy infants associated with whooping cough in Sweden over the last ten years Consequently there is a need for new etiologic studies in childhood CAP
Real-time PCR is currently considered gold-standard for detection of respiratory viruses in children with respiratory tract infection Nevertheless the turn-around time is usually long and the test results can rarely be used for decision making regarding treatment There are currently several new antigen-based point-of-care tests of respiratory infections on the market one is Multianalyte Point-of-care Antigen Detection Test System MariPOC Respi The sensitivity for respiratory syncytial virus RSV and influenza virus is as high as 90 as compared to PCR the current gold-standard PCR but the sensitivity for less common respiratory viruses such as metapneumovirus hMPV parainfluenza virus PIV coronavirus and bocavirus have been insufficiently investigated
Recombinase polymerase amplification RPA is a nucleic acid amplification method that doesnt require thermal cycling As the test reaction can be carried out at room temperature it is a particularly interesting method for resource-limited settings where the need for new diagnostic tests is high
Studies on long-term outcomes of radiologically confirmed bacterial CAP have indicated that the disease is associated with later development of asthma and decreased lung-function Given the ongoing change in etiology of pediatric CAP there is a need for new studies of long-term complications in pediatric CAP
Overall Aim
The overall aim of the TREND study is to improve the differential diagnosis of bacterial and viral etiology in children below 5 years of age with clinical CAP
Specific objectives
To assess the diagnostic accuracy of MxA for viral CAP sub-study I
To study etiologies in children with CAP sub-study II
To evaluate sensitivity and specificity for MariPOC Respi test versus PCR for detection of respiratory viruses sub-study III
To assess sensitivity and specificity for a novel RPA-based point-of-care test versus PCR for detection of respiratory viruses sub-study IV
To assess long-term complications in children with CAP sub-study V
Study Design
The TREND study is a hospital-based prospective observational study of children with clinical CAP with asymptomatic controls at the emergency department at Sachs Children and Youth hospital Stockholm
Case definition Children 1-59 months with clinical CAP according to WHO-criteria
Bronchodilator challenge
Inhalation with a rapid acting bronchodilator will be administered to children with wheezing and in-drawings to improve the specificity of the WHO clinical CAP criteria as suggested by the PERCH study team Resolved in-drawings after bronchodilator challenge will be recorded but not considered an exclusion criteria to be able to exclude these patients in a sub-analysis
Control definition
Children 1-59 months at Sachs Children and Youth Hospital treated for a minor orthopedic or minor surgical disease The parents to the controls will be contacted via emailtelephone 1-2 weeks after enrollment and be asked whether the child has developed respiratory symptoms or not No matching will be performed but adjustments for age and season will be performed in the analyses
Sampling
A capillary blood sample and nasopharyngeal swabsaspirates will be collected from all study subjects
Microbiological and Biochemistry Analyses
MariPOC Respi as well as real-time PCR analysis detecting 16 respiratory viruses as well as Streptococcus pneumoniae Bordetella pertussis B parapertussis and Mycoplasma pneumoniae will be performed
Biochemistry Analyses
Serum MxA procalcitonin and CRP levels will be analysed
Study Variables
Information regarding the study subject number of siblings days of illness current symptoms vaccinations antibiotic treatment medication underlying diseases heredity for asthma previous hospitalization recent stay abroad allergies smoking recent travel abroad recent contact with unwell individual breastfeeding preschool origin of parents and socio-economic status will be collected through a standardized questionnaire based on previous studies
Clinical parameters will be registered by the study doctor responsible for patient screeningenrolment in line with the study protocol of PERCH Some of the clinical parameters included in the PERCH protocol are very rare in a Swedish context and to avoid overloading of the case report form these will not be systematically registered at inclusion However information about these symptoms will be retrospectively collected from the medical records Some clinical parameters are routinely recorded multiple times at the emergency unit In these cases the most extreme value highest pulserespiratory ratebody temperatureetc and lowest peripheral oxygen saturation during the visit at the emergency unit until enrolment will be recorded Information regarding admission length of stay radiological routine clinical examination microbiological and chemistry analyses treatment discharge diagnosis and complications will be retrospectively collected from the medical records
All study subjects will be linked to the National Vaccination register to collect information regarding previous immunizations To allow assessment of long-term complication study subjects will also be linked to the National Patient Register the National Death Register and the National Prescribed Drug Register for collection of discharge diagnoses according to ICD-10 as well as prescribed drugs
Classification of Disease
Etiology will be classified as probable or definitive based on clinical significance of the different microbiological test in the studies above In TREND the combination of probable and definitive etiology will be used in the main analysis whereas children with definitive etiology will be assessed separately in a sub-analysis
Definitive Viral Infection
PCR positive for influenza RS virus metapneumovirus or parainfluenza virus
Probable Viral Infection
PCR positive for adenovirus
PCR positive for coronavirus rhinovirus bocavirus or enterovirus AND CRP 20 AND reported fever 24h
Definitive Bacterial Infection
positive bacterial blood culture in blood or pleura fluid
positive pneumococcal antigen test in pleura fluid
Probable Bacterial Infection
CRP 80 children 2 years 120 children 2-5 years ANDOR
Radiographic evidence of empyema on X-ray or ultrasound ANDOR
Large dense infiltrate or lobar consolidation on chest x-ray
Definitive Atypical Bacterial Infection
Positive PCR B pertussis or B parapertussis
Probable Atypical Bacterial Infection
Positive PCR M pneumoniae
Undetermined
Cases not fulfilling any criteria above
Mixed Viral-bacterial Infection
Children fulfilling criteria for both viral and bacterial infection
Classification of Long-term Complications
Long-term complications asthma and number of hospital-requiring respiratory infections will be assessed after 3 7 and 10 years following study completion by linking to the National Patient Register Asthma will be classified as ICD-10 diagnosis of J45 or 3 prescriptions of inhalation steroids beta-2-agonists or leukotriene antagonists according to the Prescribed Drug Register
Power Calculation
For the sample size calculation the investigators focused on the assessment of MxA-levels in cases with viral CAP as compared to cases with bacterial CAPcontrols study I Two power calculations were made one for viral CAP versus bacterial CAP and one for viral CAP versus controls The following assumptions were made
A difference in MxA-level of 500µgl between the groups was considered clinically relevant A standard deviation of 1000 and 300 was assumed in cases with viral CAP and bacterial CAPcontrols respectively based on previous studies on MxA
Using an alpha-level of 005 two-sided at an 80 power with an additional 20 addition to account for non-parametric testing and multivariate analyses 42 children in each group viral CAP bacterial CAP and controls would be needed
To ensure that enough of the included cases would fulfill the TREND definition of viral and bacterial CAP the proportion of viral respectively bacterial CAP TREND definition was calculated in our previous study that assessed Swedish children with x-ray verified CAP By doing this the prevalence of viral and bacterial CAP was estimated to 45 and 14 respectively Hence 300 cases and 42 controls would be needed to ensure sufficient collection of cases with viral and bacterial CAP respectively The investigators also would like to compare cases with viral CAP with controls testing positive for one or more virus by PCR In our previous study 354 of asymptomatic children tested positive for one or more virus To include a sufficient number of virus-positive controls the investigators hence aim at including 300 cases and 119 controls 420354119 in the TREND-study
Ethical Considerations
The study will be conducted in accordance with the latest version of The Declaration of Helsinki and the fundamental principles of respect for the individual Article 8 their right to self-determination and the right to make informed decisions Articles 20 21 and 22 regarding participation in research both initially and during the course of the research
Significance
The findings from the TREND project can be an important step to improve the care of children with clinical CAP Improved near-patient differential diagnosis is a prerequisite for rational antibiotic use and decreasing unnecessary antibiotic treatment Further better diagnosis of the pathogens causing acute respiratory infections makes it easier to give advice to parents on how their children should be cared for and better surveillance in the society
Myxovirus resistance protein A MxA is a promising biomarker for viral infection but no studies have investigated MxA in children with CAP Procalcitonin PCT is used as a biomarker for severe bacterial infection as the protein rapidly increases in plasma levels in response to stress and systemic infection PCT has been reported to be more specific for bacterial infection as compared to CRP but there are conflicting data on the clinical utility of PCT in children with CAP
The role of viruses and atypical bacteria in childhood CAP Is increasingly recognized Recent studies have reported an increasing incidence of B pertussis and there have been several deaths in previously healthy infants associated with whooping cough in Sweden over the last ten years Consequently there is a need for new etiologic studies in childhood CAP
Real-time PCR is currently considered gold-standard for detection of respiratory viruses in children with respiratory tract infection Nevertheless the turn-around time is usually long and the test results can rarely be used for decision making regarding treatment There are currently several new antigen-based point-of-care tests of respiratory infections on the market one is Multianalyte Point-of-care Antigen Detection Test System MariPOC Respi The sensitivity for respiratory syncytial virus RSV and influenza virus is as high as 90 as compared to PCR the current gold-standard PCR but the sensitivity for less common respiratory viruses such as metapneumovirus hMPV parainfluenza virus PIV coronavirus and bocavirus have been insufficiently investigated
Recombinase polymerase amplification RPA is a nucleic acid amplification method that doesnt require thermal cycling As the test reaction can be carried out at room temperature it is a particularly interesting method for resource-limited settings where the need for new diagnostic tests is high
Studies on long-term outcomes of radiologically confirmed bacterial CAP have indicated that the disease is associated with later development of asthma and decreased lung-function Given the ongoing change in etiology of pediatric CAP there is a need for new studies of long-term complications in pediatric CAP
Overall Aim
The overall aim of the TREND study is to improve the differential diagnosis of bacterial and viral etiology in children below 5 years of age with clinical CAP
Specific objectives
To assess the diagnostic accuracy of MxA for viral CAP sub-study I
To study etiologies in children with CAP sub-study II
To evaluate sensitivity and specificity for MariPOC Respi test versus PCR for detection of respiratory viruses sub-study III
To assess sensitivity and specificity for a novel RPA-based point-of-care test versus PCR for detection of respiratory viruses sub-study IV
To assess long-term complications in children with CAP sub-study V
Study Design
The TREND study is a hospital-based prospective observational study of children with clinical CAP with asymptomatic controls at the emergency department at Sachs Children and Youth hospital Stockholm
Case definition Children 1-59 months with clinical CAP according to WHO-criteria
Bronchodilator challenge
Inhalation with a rapid acting bronchodilator will be administered to children with wheezing and in-drawings to improve the specificity of the WHO clinical CAP criteria as suggested by the PERCH study team Resolved in-drawings after bronchodilator challenge will be recorded but not considered an exclusion criteria to be able to exclude these patients in a sub-analysis
Control definition
Children 1-59 months at Sachs Children and Youth Hospital treated for a minor orthopedic or minor surgical disease The parents to the controls will be contacted via emailtelephone 1-2 weeks after enrollment and be asked whether the child has developed respiratory symptoms or not No matching will be performed but adjustments for age and season will be performed in the analyses
Sampling
A capillary blood sample and nasopharyngeal swabsaspirates will be collected from all study subjects
Microbiological and Biochemistry Analyses
MariPOC Respi as well as real-time PCR analysis detecting 16 respiratory viruses as well as Streptococcus pneumoniae Bordetella pertussis B parapertussis and Mycoplasma pneumoniae will be performed
Biochemistry Analyses
Serum MxA procalcitonin and CRP levels will be analysed
Study Variables
Information regarding the study subject number of siblings days of illness current symptoms vaccinations antibiotic treatment medication underlying diseases heredity for asthma previous hospitalization recent stay abroad allergies smoking recent travel abroad recent contact with unwell individual breastfeeding preschool origin of parents and socio-economic status will be collected through a standardized questionnaire based on previous studies
Clinical parameters will be registered by the study doctor responsible for patient screeningenrolment in line with the study protocol of PERCH Some of the clinical parameters included in the PERCH protocol are very rare in a Swedish context and to avoid overloading of the case report form these will not be systematically registered at inclusion However information about these symptoms will be retrospectively collected from the medical records Some clinical parameters are routinely recorded multiple times at the emergency unit In these cases the most extreme value highest pulserespiratory ratebody temperatureetc and lowest peripheral oxygen saturation during the visit at the emergency unit until enrolment will be recorded Information regarding admission length of stay radiological routine clinical examination microbiological and chemistry analyses treatment discharge diagnosis and complications will be retrospectively collected from the medical records
All study subjects will be linked to the National Vaccination register to collect information regarding previous immunizations To allow assessment of long-term complication study subjects will also be linked to the National Patient Register the National Death Register and the National Prescribed Drug Register for collection of discharge diagnoses according to ICD-10 as well as prescribed drugs
Classification of Disease
Etiology will be classified as probable or definitive based on clinical significance of the different microbiological test in the studies above In TREND the combination of probable and definitive etiology will be used in the main analysis whereas children with definitive etiology will be assessed separately in a sub-analysis
Definitive Viral Infection
PCR positive for influenza RS virus metapneumovirus or parainfluenza virus
Probable Viral Infection
PCR positive for adenovirus
PCR positive for coronavirus rhinovirus bocavirus or enterovirus AND CRP 20 AND reported fever 24h
Definitive Bacterial Infection
positive bacterial blood culture in blood or pleura fluid
positive pneumococcal antigen test in pleura fluid
Probable Bacterial Infection
CRP 80 children 2 years 120 children 2-5 years ANDOR
Radiographic evidence of empyema on X-ray or ultrasound ANDOR
Large dense infiltrate or lobar consolidation on chest x-ray
Definitive Atypical Bacterial Infection
Positive PCR B pertussis or B parapertussis
Probable Atypical Bacterial Infection
Positive PCR M pneumoniae
Undetermined
Cases not fulfilling any criteria above
Mixed Viral-bacterial Infection
Children fulfilling criteria for both viral and bacterial infection
Classification of Long-term Complications
Long-term complications asthma and number of hospital-requiring respiratory infections will be assessed after 3 7 and 10 years following study completion by linking to the National Patient Register Asthma will be classified as ICD-10 diagnosis of J45 or 3 prescriptions of inhalation steroids beta-2-agonists or leukotriene antagonists according to the Prescribed Drug Register
Power Calculation
For the sample size calculation the investigators focused on the assessment of MxA-levels in cases with viral CAP as compared to cases with bacterial CAPcontrols study I Two power calculations were made one for viral CAP versus bacterial CAP and one for viral CAP versus controls The following assumptions were made
A difference in MxA-level of 500µgl between the groups was considered clinically relevant A standard deviation of 1000 and 300 was assumed in cases with viral CAP and bacterial CAPcontrols respectively based on previous studies on MxA
Using an alpha-level of 005 two-sided at an 80 power with an additional 20 addition to account for non-parametric testing and multivariate analyses 42 children in each group viral CAP bacterial CAP and controls would be needed
To ensure that enough of the included cases would fulfill the TREND definition of viral and bacterial CAP the proportion of viral respectively bacterial CAP TREND definition was calculated in our previous study that assessed Swedish children with x-ray verified CAP By doing this the prevalence of viral and bacterial CAP was estimated to 45 and 14 respectively Hence 300 cases and 42 controls would be needed to ensure sufficient collection of cases with viral and bacterial CAP respectively The investigators also would like to compare cases with viral CAP with controls testing positive for one or more virus by PCR In our previous study 354 of asymptomatic children tested positive for one or more virus To include a sufficient number of virus-positive controls the investigators hence aim at including 300 cases and 119 controls 420354119 in the TREND-study
Ethical Considerations
The study will be conducted in accordance with the latest version of The Declaration of Helsinki and the fundamental principles of respect for the individual Article 8 their right to self-determination and the right to make informed decisions Articles 20 21 and 22 regarding participation in research both initially and during the course of the research
Significance
The findings from the TREND project can be an important step to improve the care of children with clinical CAP Improved near-patient differential diagnosis is a prerequisite for rational antibiotic use and decreasing unnecessary antibiotic treatment Further better diagnosis of the pathogens causing acute respiratory infections makes it easier to give advice to parents on how their children should be cared for and better surveillance in the society
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None