Bronchiolitis All-study, SE-Norway

• No of hours before deemed fit for discharge from hospital [ Time Frame: Throughout the hospital stay ] [ Designated as safety issue: No ]
  

• Clinical status (by parents as well as nurses) every 12 hrs [ Time Frame: prior to inhalation every morning and evening ] [ Designated as safety issue: No ]
  
• Need for feeding support (no. of hours) [ Time Frame: Throughout the hospital stay. ] [ Designated as safety issue: No ]
  
• Need for supplementary oxygen. [ Time Frame: Throughout the hospital stay. ] [ Designated as safety issue: Yes ]
  
• Clinical score measured by doctor [ Time Frame: Throughout the hospital stay. Daily before and 30min after inhalation in daytime. ] [ Designated as safety issue: No ]
  

OVERALL AIMS OF THE STUDY:

1. To compare the efficacy of two common treatments by determining whether inhalation treatment with racemic adrenaline is more effective than saline inhalations in acute bronchiolitis in children younger than 12 months throughout an hospital admission, as well as to define the optimal inhalation treatment intervals.
2. To identify clinical and virological risk factors for development of persisting obstructive airways disease after an initial bronchiolitis, and to assess if specific vira or subsequent asthma development influences the efficacy of bronchiolitis management.
3. To assess whether hospital admissions for bronchiolitis has increased in parallel with the increase in childhood asthma seen in the last 10-15 years.

METHODS AND STUDY PROGRESSION

Design:

This multicenter study will be performed after initial appropriate common training by all participating.

1. Treatment study: The study will follow the standard operating procedure of Good Clinical Practice, including a clinical monitor from Oslo University Hospital, Ullevål who will provide study quality assurance in all centers. Two main groups randomised into RA vs saline, each divided into two arms of the active drug/NaCl groups: fixed or on demand inhalations. The trial will be double blinded by the pharmacy. One glass with sufficient medication for the entire hospital stay will be designated per patient throughout. No cross-over. Outcomes will be analysed by intention to treat, with treatment given and recorded throughout the hospital admission. No interim analyses are planned since the study compares two established treatment modalities used for the last decades.

   Inclusion into the treatment study provides the basis for the follow-up (prognosis) part of the study.

2. Prognosis: 18 months follow-up study (clinical assessment) of all subjects in the treatment study.The prognosis study will also retrospectively answer whether treatment efficacy depend upon later allergic disease development.
3. Epidemiology: a retrospective chart study for hospital admissions for bronchiolitis within populations referred to the collaborating centres in HSØ from 1995-2009

Methods:

a. Treatment: Randomisation: block randomisation. Randomization will be performed by computer programs by the ORAACLE statistician, and provided to the Pharmacy preparing and labeling the vials for each patient.

Treatment: Nebulised racemic adrenaline vs saline throughout the hospital stay. Inhalations given on demand (parents/nurse) vs fixed x 4--12. Open saline inhalations may be given at any time, other inhalations is not allowed. Neither is systemic corticosteroids (which is not a proper treatment for acute bronchiolitis, according to Norwegian guidelines). All other treatment will be given according to usual local practice.

Study end-points:

1. Treatment study: Completion of the study at discharge + possible re-admission according to protocol. Need for intensive care management or assisted ventilation (continuous CPAP-Ventilator) in which conventional management will be given. Treatment failure when the child is assessed severely ill and in need of open label treatment. These data will be recorded and analysed to see if there is a difference between the two treatment groups. We expect a small number of drop-outs, which should not make it necessary to expand the study above our goal of 500 patients.
2. Prognosis study: Number of children with recurrent bronchial obstruction (wheeze), secondary: asthma diagnosis, the "Oslo severity score".
3. Hospital admissions first time, secondary: re-admissions or multiple admissions

Methods:

Clinical scores will be assessed before and 30 minutes after inhalation the first time, and subsequently once a day during ordinary doctor visit.

Global clinical assessment completed by nurses and parents will be done every morning and evening until discharge. Time at start, end and hours with naso-gastric tube feeding as well need for supplementary oxygen will be recorded daily and complications and adverse event will be recorded as they appear.

Nasopharynx aspiration is done at inclusion and is analysed by local routine, usually within 24 hours (except Sundays). Half of the aspirate will be frozen for batch PCR analyses at the virological laboratory (Oslo University Hospital) after all patients are enrolled.

Blood tests are sampled at inclusion. General analyses (see table 6) and sample to biobank for epigenetic analyses.

Saliva are sampled at inclusion and the following morning. Deemed fit for discharge will be decided by the attending physician. Minimum requirement is clinical score 3 or less at least 2 hours after last inhalation.

Urine tests are sampled at inclusion. Will be analysed at leukotrienes and arachidonic acid metabolites (eoxines) and other relevant inflammatory and infection markers.

Outcomes measured upon inclusion, after first inhalation (clinical score) as well as throughout the hospital stay according to flow-chart.

Main outcome: No of hours before deemed fit for discharge from hospital

Secondary:

Need for feeding support (no. of hours) Need for supplementary oxygen. Clinical score throughout admission Complications (presence of and time to confirmed) such as atelectasis Global assessments (parents and nurses) Need for ICU treatment Data from each hospital will in addition to collated data analysis be assessed independently.

Illness caused by different vira will be compared in regard to treatment efficacy.

b. Prognosis: This follow-up-study will be performed in collaboration between the principal investigator and the collaborating physicians at the local paediatric departments. The clinical follow-up visit includes a structured parental interview, application of the "Oslo severity score"20 for obstructive airways disease, assessment of atopic eczema and rhinitis, skin prick test as well as blood sampling for analyses including IgE and DNA for epigenetic studies (see table 4) .

c. Epidemiology: Retrospective study of all children 0-18 months admitted to hospital with the diagnosis of bronchiolitis. The study will mainly be a hospital registry study, but with 20% random chart scrutiny to ensure appropriateness of diagnosis.

Ammendment: Two further substudies were included;

a) Quality of life after bronchiolitis b) A population-based control group of 241 children from Oslo and Fredrikstad were included.

1. Description Quality of Life:

   ITQOL was sent to all children included in the RCT cohort, as well as the control group (see below) 6-9 months after enrollement in the study, as well as prior to the 18-month follow-up study.

   Main objective: To assess if quality of life after acute bronchiolitis in infancy is associated with development of persisting obstructive airways disease or allergic disease in early childhood.

   Specific aim 1: What is the quality of life in infants and parents 6 and 18 months after hospital admission for acute bronchiolitis? Specific aim 2: Is quality of life in infants and their parents 6 and 18 months after hospital admission for acute bronchiolitis related to recurrent or persisting obstructive airways symptoms? Specific aim 3: Is a possible association between quality of life and persistent obstructive airways disease modified by allergic sensitisation, gender or type of virus infection during the bronciolitis

2. Description Control group:

Since we established the "Bronchiolitis" cohort of children admitted to hospital for acute bronchiolitis, the prognostic perspective of this three-phase study has gained increasing focus. This relates in particular to immunological influence of different viral agents during the acute disease, as well as Quality of Life and the role of early "stress" in relation to development of allergic diseases in children with as well as without acute bronchiolitis in early life.

The aims are to assess physiological, immunological, environmental and "stress" (including psychosocial) factors in the development of allergic diseases, including asthma, atopic eczema, allergic rhinitis and allergies in children who have been hospital admitted due to acute bronchiolitis in infancy as well as children of the same age who have not been admitted for bronchiolitis.

Control children will be consecutively included at 2 Well-baby clinics in Fredrikstad and Oslo, respectively, total number 150 (100 + 150, respectively) ensuring similar variability of demographic data (age and ethnic background) as the enrolled bronchiolitis children. Inclusion will be assessed mid-way for adequate demographic variability.

Inclusion criteria: children 1- 11 months (inclusive) of age presenting to the Well-Baby Clinics, Exclusion criteria: Significant cardiac, previous severe respiratory disease, neurologic, immunologic, oncologic or other disease that may significantly influence the outcomes, including Down's syndrome.