Community-acquired sepsis-like syndrome and paediatric acute respiratory tract infection in childhood study

• Register: ISRCTN
• Last refreshed on: 24 October 2016
• Main ID: ISRCTN66872125
• Date of registration: 30/08/2016
• Prospective Registration: No
• Primary sponsor: Fondazione PENTA Onlus
• Public title: Community-acquired sepsis-like syndrome and paediatric acute respiratory tract infection in childhood study
• Scientific title: Multi-centre EuRopean study of MAjor Infectious Disease Syndromes (MERMAIDS): community-acquired sepsis-like syndrome and paediatric acute respiratory tract infection in childhood
• Date of first enrolment: 15/08/2016
• Target sample size: 1000
• Recruitment status: Completed
• URL: http://isrctn.com/ISRCTN66872125
• Study type: Observational
• Study design: Observational prospective case-control study (Other)

Countries of recruitment

Estonia, France, Germany, Greece, Italy, Lithuania, Romania, Spain, Switzerland, United Kingdom

Contacts

• Name: Jessica Jarvis

Key inclusion & exclusion criteria

Inclusion criteria: The study will recruit into three groups (SLS, ARI and controls), each with different inclusion criteria.

SLS Group Cases:
1. Age <6 months old on the day of admission (day 0) into the study
2. Onset of symptoms within 7 days
3. The attending physician has decided that the infant requires hospitalisation
4. Temperature =38°C or <36°C measured by any method
5. Informed consent collected on admission or within 48 hours available from guardian/carer

AND at least TWO of the below (with at least ONE of either 1 or 2):
1. Signs of cardiovascular dysfunction: age-related tachycardia or bradychardia or hypotension or need for =40 ml/kg fluid resuscitation in first hour after presentation to hospital on day of recruitment
2. Signs of respiratory dysfunction: age-related tachypnoea or brady/apnoea or decreased oxygen saturation (<92% in room air)
3. Skin signs: mottled skin appearance or non-blanching rash or central CRT >2 seconds
4. Neurological signs: irritability, hypotonia, lethargy or an AVPU score V or below

ARI Group Cases:
1. Age <6 years old on the day of admission (day 0) into the study
2. Clinical suspicion of a new episode of acute respiratory tract illness within the last 7 days
3. The attending physician has decided that the child requires hospitalisation
4. Primary reason for hospital admission is clinical suspicion of a new episode of ARI
5. Temperature =38°C measured by any method
6. Informed consent collected on admission or within 48 hours available from guardian/carer

AND at least TWO of the below (with at least ONE of 1 or 2):
1. Signs of lower respiratory tract infection: cough, abnormal sounds on chest auscultation (crackles, reduced breath sounds, bronchial breathing, wheezing), dyspnoea (chest indrawing, nasal flaring, grunting)
2. Signs of upper respiratory tract infection: coryza, nasal congestion, sore throat, pharyngitis, myringitis, acute otitis media
3. Signs of respiratory dysfunction: age-related tachypnoea or brady/apnoea or decreased oxygen saturation (<92% in room air)
4. Signs of reduced general state: poor feeding, vomiting, lethargy/drowsiness

CONTROLS:
1. Age < 6 years old on the day of enrolment into the study
2. Afebrile on the day of enrolment
3. No evidence of severe infection as judged by attending physician
4. Informed consent available from guardian/carer

Controls aged < 6 months old will be shared between both groups. Controls should be matched to cases stratified by five age groups (0-3 months, 4-6 months, 7-11 months, 12 months-2 years and 3-5 years) and season (three-monthly intervals starting with January-March). They may be selected from the following patient groups:
1. Attending for an elective or semi-elective procedure requiring general anaesthesia or moderate-deep sedation
(including e.g. surgery, radiological examinations etc)
2. Well and otherwise healthy children attending outpatient clinic for a non-emergency clinical assessment for which a blood test is indicated as part of routine clinical care
Exclusion criteria: The study will recruit into three groups (SLS, ARI and case-controls), each with different exclusion criteria.

SLS Group Cases:
1. In-patient care for 24 hours or more for any condition within the previous 30 days, except for routine postnatal care
2. Aetiology other than infection (such as trauma, autoimmune disorder, malignancy) is suspected to be the primary cause of the current illness episode
3. Any signs and symptoms suggesting a clear primary focus of infection, such as pneumonia, urinary/kidney infection, open wounds, indwelling catheters, re-activation of previously diagnosed infectious or inflammatory condition
4. Dehydration due to previous illness episode such as diarrhoea and vomiting
5. Immunocompromised infant (stem cell transplant, solid organ transplant, HIV, AIDS, immunosuppressive therapy, inherited or congenital immunodeficiency, haemodialysis)
6. Presence of complex chronic comorbidities
7. Body weight <3kg on day of assessment and/or corrected gestational age <37 weeks

ARI Group Cases:
1. In-patient care for 24 hours or more for any condition within the previous 30 days, except for routine postnatal care
2. Aetiology other than infection (such as trauma, autoimmune disorder, malignancy) is suspected to be the primary cause of the current illness episode
3. Any signs and symptoms suggesting a clear primary focus of infection, such as urinary/kidney infection, open
wounds, indwelling catheters, re-activation of previously diagnosed infectious or inflammatory condition
4. Dehydration due to previous illness episode such as diarrhoea and vomiting
5. Immunocompromised infant (stem cell transplant, solid organ transplant, HIV, AIDS, immunosuppressive therapy, inherited or congenital immunodeficiency, haemodialysis)
6. Presence of complex chronic comorbidities
7. Body weight <3 kg on day of assessment and/or corrected gestational age <37 weeks

Controls:
1. In-patient care for 24 hours or more for any condition within the previous 30 days except for routine postnatal care or current planned hospitalisation/procedure
2. Temperature =38.5°C or <36°C
3. Immunocompromised infant (stem cell transplant, solid organ transplant, HIV, AIDS, immunosuppressive therapy, inherited or congenital immunodeficiency, haemodialysis)
4. Presence of complex chronic comorbidities
5. Body weight <3kg on day of assessment and/or corrected gestational age <37 weeks

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Sepsis-like syndrome (SLS) and acute respiratory infections (ARI) in children
Infections and Infestations

Intervention(s)

ELIGIBILITY
Participants will be assessed against pre-determined eligibility criteria (inclusion and exclusion criteria). Cases will be assessed at the time of presentation or within 24 hours of admission.

This study will recruit children into three groups:
1. Infants (<6 months old) admitted to a participating hospital with a new episode of community-acquired sepsis-like syndrome
2. Children (< 6 years old) admitted to a participating hospital with a new episode of community-acquired acute
respiratory infection
3. Age-matched afebrile controls (< 6 years old)

STUDY PROCEDURES FOR PARTICIPANTS WITH SLS OR ARI

Informed consent (Day 0) with the option of deferred consent will be sought. All participants for whom legal guardians/carers have provided informed consent will have a baseline assessment that will be recorded on a designated CRF. This will include:
1. Demographics, medical history, physical examination findings and vital signs
2. Basic information on clinical management
3. Results of routine investigations

Sampling (Day 0-1)
For SLS and ARI cases, research-specific samples (blood, urine, nasopharyngeal, stool, and if available CSF) will be obtained with the first set of routine samples within 24 hours of admission (day 0) and processed once eligibility has been confirmed and written informed consent has been obtained.

Clinical data
Clinical observations, medications and clinical management will be recorded in the CRF on admission/baseline
assessment (Day 0), and weekly (every 7 days) for cases until discharge, death or day 30 of hospitalisation (whichever comes first)

Weekly clinical data will include:
1. Documentation of survival status, total days of supplemental oxygen, total days of invasive or non-invasive ventilator support and total days of pharmacological inotropic support
2. Admission to Paediatric Intensive Care Unit or Paediatric High Dependency Unit, and total length of stay, receipt of immunomodulators and duration of antibiotic and/or ant

Primary Outcome(s)

SLS
1. The proportions of infants with SLS in whom EV or HPeV is detected in blood (day 0) and the strength of association between EV or HPeV detection in blood in SLS cases compared to controls (odds ratio and 95% CI)
2. The proportions of infants with SLS in whom EV or HPeV is detected in nasopharyngeal and/or stool samples (day 0) and the strength of association between EV or HPeV detection in nasopharyngeal and/or stool samples in SLS cases compared to controls (odds ratio and 95% CI)

ARI
The proportions of infants with ARI in whom RSV, FLU, HRV or S. pneumoniae is detected in nasopharyngeal samples (day 0) and the strength of association between their detection in nasopharyngeal samples in ARI cases compared to controls (odds ratio and 95% CI)

Secondary Outcome(s)

SLS
1. Association between viral load in blood on day 0 and disease severity
2. Association between pathogen co-detection on day 0 and disease severity
3. Subtypes of EV or HPeV identified in blood collected on day 0
4. Characterisation of key parameters describing clinical management of SLS including:
4.1. Proportion admitted to intensive care (and duration) during hospitalisation
4.2. Proportion treated with antimicrobials, antivirals and/or immunomodulators during admission (and average duration of treatment)
4.3. Proportion of cases requiring during admission: supplemental oxygen, non-invasive or invasive mechanical ventilation, extra-corporeal life support
4.4. Duration of invasive mechanical ventilation and extra-corporeal life support, if applicable
4.5. Average length of hospitalisation (in days)
4.6. In-hospital mortality
5. Bayley scales of infant development and Denver II developmental screening test at discharge and at 12 months of age in a subset of 40 SLS cases
Severe disease will be defined as cases with requirement for supplementary oxygen, ventilatory and/or inotropic support (pharmacological or mechanical) and/or cases who die in hospital (all-cause mortality)

ARI
1. Association between viral load in nasopharyngeal swabs on day 0 and disease severity
2. Association between bacterial load in nasopharyngeal swabs on day 0 and disease severity
3. Association between pathogen co-detection in nasopharyngeal swabs on day 0 and disease severity
4. Characterisation of key parameters describing clinical management of ARI including:
4.1. Proportion admitted to intensive care during hospitalisation and average length of stay
4.2. Proportion treated with antimicrobials, antivirals and/or immunomodulators during admission (and average duration of treatment)
4.3. Proportion of cases requiring during admission: supplemental oxygen, non-invasive or invasive mechanical ventilation, extra-corporeal life support
4.4. Duration of invasive mechanical ventilation and extra-corporeal life support, if applicable
4.5. Average length of hospitalisation (in days)
4.6. In-hospital mortality
5. Comparison of gene expression profiles (microarray) associated with SARI in adult patients to gene expression profiles in children with severe disease ARI
Severe disease will be defined as cases with requirement for supplemental oxygen and/or ventilatory and/or inotropic support (pharmacological or mechanical) and/or cases who die in hospital (all-cause mortality)

Secondary ID(s)

Protocol version 1.0 (18/09/2015)

Source(s) of Monetary Support

Seventh Framework Programme