We can not predict which wheezing child younger than 3 years of age benefits from systemic glucocorticoid and which one does not. It is not known whether the differences in the efficacy are related to the differences in viral etiology, atopy, immunogical maturity or age of the patient. The study aims to answer the following questions: 1. What is the viral etiology of acute childhood expiratory wheezing? 2. What is the efficacy of prednisolone in relation to age, atopy and viral etiology in acute childhood wheezing? 3. Does prednisolone treatment increase risk for secundary bacterial infection in acute childhood expiratory wheezing? 4. What is the significance of inflammatory markers in predicting the efficacy of systemic steroid or patient outcome in acute childhood expiratory wheezing? Study will follow randomized, double blind, placebo-controlled parallel design. Study will start in Septemper 2000 and will be performed at the Department of Pediatrics, Turku University Hospital, Turku Finland. The study population will be 300 hospitalized wheezing children aged 3 months - 15 years. Investigational drug will be prednisolone, first dose 2 mg/kg, then 2 mg/kg/d/3 (max. 60 mg/vrk) p.o. for 3 d and comparative drug will be placebo tablet similar to investigational drug with the equal dosage. The primary outcome will be the time until ready for discharge. The study will provide new and important information for the diagnostics, treatment, disease outcome and prevention of acute childhood expiratory wheezing.
Introduction
Extensive surveys have shown that 6-20 % of children have acute expiratory wheezing (1, 2). The lifetime prevalence of wheezing among 12-14-year-old children in the Western countries is 8-19 % (3, 4). The clinical illness is called bronchiolitis when occuring for the first time in infants younger than 12 months (5). When occuring later or recurring, beside bronchiolitis a diagnosis of wheezy bronchitis has been used (6). In older children wheezy bronchitis cannot be distinguished from virus-induced-asthma. In many countries the first expiratory wheezing attack at the age of > 3 years is diagnosed as asthma. To some extent, bronchiolitis, wheezy bronchitis, and asthma are expressions of the same pathologic process and at present there are no rigid criteria to separate these three illnessess.
Acute bronchiolitis is most commonly caused by respiratory syncytial virus (RSV) and wheezy bronchitis by rhinovirus infections (6 - 8). Exacerbations of asthma are induced in 80-85% of the cases by viral respiratory infections in children, mostly rhinovirus infections (7, 9).
It is well established that systemic glucocorticoids are the cornerstone in the management of acute asthma (10). However, systemic glucocorticoids do not appear to be effective in bronchiolitis in young children (11). Despite the lack of evidence for efficacy, glucocorticoids are used up to 60 % of patients with RSV bronchiolitis (12).
The unfavourable effects of glucocorticoids during viral infections have received increasing attention. For example, steroids have been found to increase the risk of acute otitis media during rhinovirus infections in children (13). In adults glucocorticoids have increased the titers of rhinovirus and the shedding of the virus from the pharynx (14, 15). It may be possible that glucocorticoids increase the severity of some viral respiratory tract infections.
Today, we can not predict which wheezing child younger than 3 years of age benefits from systemic glucocorticoid and which one does not. It is not known whether the differences in the efficacy are related to the differences in viral etiology, atopy, immunogical maturity or age of the patient.
Main Questions
Rationale
The study provides new and important information for the diagnostics, treatment, disease outcome and prevention of acute childhood expiratory wheezing.
Design and setting
Study follows randomized, double blind, placebo-controlled parallel design. Study will start in Septemper 2000 and continue until June 2002 (except June and July 2001). The study will be performed at the department of pediatrics, Turku University Central Hospital, Turku Finland.
Subjects
The study population will be 300 patients. To allow detection of a 18-h difference (half of the average duration of stay in our hospital) in the time until ready for discharge between the prednisolone-treated group and the placebo groups (with an estimated standard deviation of 24 h) and to maintain an alpha error of 0.05 and a beta error of 0.20, the required size of the sample is 27 children for each treatment group in RSV bronchiolitis (16). No estimate is available for rhinovirus group. If patients are separated to different groups according to e.g. age or viral infection, 108 patients are needed. On the other hand to get 31 patients with a viral infection (viral infection in 80 % of patients with expiratory wheezing, and sensitivity of methods 69 %), 49 children are needed in each treatment group (to assess different subgroups, 196 children) (9, 17). To take account the variations of epidemics, a total of 300 children will be recruited. The estimated time to get enough patients, which need hospitalization for expiratory wheezing, will be 2 years at the department of pediatrics, Turku University Central Hospital, Turku, Finland.
Inclusion criteria
Exclusion criteria
Study drugs
Investigational drug
Prednisolone, first dose 2 mg/kg, then 2 mg/kg/d/3 (max. 60 mg/vrk) p.o. for 3 d (5 mg tabletti, Prednisolon ®, Leiras, Finland).
Comparative drug
Placebo tablet similar to investigational drug (tablet, Leiras) will be given with the equal dosage.
Addministration of the drug
Tablets will be cut in four pieces, which mixt into jelly ot yogurt. If the child vomits, the drug will be given again after 30 min. If the child still vomits, he or she will be given equal dose of methylprednisolone or physiologic saline i.v. or i.m. (62,5 mg/ml inject, Solomet®, Orion, Finland).
Randomization
The randomization will be performed by an independent person not participating in the study. According to the randomization, each volunteer will be allocated to one treatment. Individual number 01 onwards will be assigned.
Protocol
The study physician will inform the subject and his or her guardian about the study and gives the subject information (Appendix 1). Guardian's written informed concent (Appendix 2) will be obtained after he or she has got acquainted with the test procedure. The subject can withdraw the consent to the study at any time. Guardian will be asked to fill the modified ISAAC questionaire (Appendix 3). New patients will enter the study at 8-10 a.m. and p.m.
The study is outlined in the study flow sheet (Appendix 4). The study physician will examine the patients twice daily at 8-10 a.m. and p.m. during the hospitalization (Appendix 5). The patients will be hospitalized until he or she does not wheeze or have breathing difficulties. After the hospitalization the patients will fill symptom diary for 2 weeks (Appendix 6). Follow-up visit will be 2 weeks after the hospitalization and follow-up telephone contact will be 2 months after the hospitalization. If the patient had a first wheezing episode, he or she will be re-examined 12 months after the study and oscillometric examination will be performed (if older than 24 months).
Nasal swap virological studies will also be performed to 60 healthy control children at outpatient clinic or surgical department in the Turku University Central Hospital during the study period.
Methods
Nasopharyngeal swap samples for virologic studies will be collected with 3 sterile cotton swaps which are dipped through the nostrils against nasal mucosa. These samples will be placed in a separate viral transport medium tubes for antigen, culture and PCR analysis.
Virus culture (influenza A and B , adeno-, RS-, parainfluenza type 1, 2 and 3 virus) was done by using the Ohio strain of HeLa cells and human foreskin fibroplasts according to routine procedure. Viral antigens (influenza A and B , adeno-, RS-, parainfluenza type 1, 2 and 3 virus) were detected by time-resolved fluoroimmunoassay with monoclonal antibodies (17). Reverse transcription-PCR assays were used for detection of corona-, rhino-, entero-, RS-, influenza A and B as well as human metapneumovirus (hMPV). The details of methods have been discribed earlier (18, 19). Virus-specific serum antibody titers (Influenza A and B virus, adenovirus, parainfluenza type 1/3 and 2 virus, RSV, HHV-6 and enterovirus IgG as well as for enterovirus also IgM) were determined by enzyme immunoassay (EIA) using antigen-coated solid phase and horsedish peroxidase conjugated rabbit antihuman IgG (Dako, Glostrup, Denmark). Three fold increase in IgG antibody titers was considered positive except four fold increase in RSV IgG antibody titers. Enterovirus was also considered positive if virus specific IgM was positive.
The influenssa A ja B , adeno , parainfluenssa type 1 , 2 and 3 as well as respiratory synsytial virus (RSV) antigen and culture, and rhino-, entero- and coronavirus PCR will be performed in the Department of Virology, Turku university, Finland. Human metapneumovirus PCR will be performed in the Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands. RSV A and B as well as Influenza virus A and B PCR will be performed in the National Health Institute, Helsinki, Finland. Viral and bacteral (C. pneumoniae, M. pneumoniae , S. pneumoniae, H. influenzae ja M. catarrhalis) will be performed in the National Health Institute, Oulu, Finland (17).
Expiratory nitric oxide will collected bed side with a bag collection system (Siemens) and analysed within 72 h at the Department of Clinical Physiology, Turku University Central Hospital, Turku, Finland (20). Oscillometric studies will be performed at the Department of Paediatric Turku University Central Hospital, Turku, Finland. Nasal cytokine (IL-8 and RANTES) measurements will be performed in the Children's Hospital, University of Texas Medical Branch, Galveston, Texas, USA. Other laboratory tests will be performed in the Central Laboratory, Turku University Central Hospital, Turku, Finland.
Primary endpoint: Our primary endpoint will be the time until ready for discharge, which will be defined as a duration of respiratory symptoms score >3 during hospital stay. The respiratory symptoms score, which will be assessed every 12 h during hospitalization, will consist of the degree of dyspnea (0=none, 1=mild, 2=moderate, 3=severe), type of breathing (0=normal, 1=use of stomach muscles, 2=use of intercostal muscles, 3=nasal flaring), severity of auscultatory findings on wheezing (0=none, 1=expiratory, 2=inspiratory and expiratory, 3=audible without stethoscope), and assessment of expiratory:inspiratory time (0=1:2, 1=1:1, 2=2:1, 3=3:1). An estimation of 6 h will be used for the last 12 h period between hospital assessments, i.e. the period during which the patient became ready for discharge.
Secondary endpoints: Oxygen saturation during hospital stay, wheeze and cough during two weeks after discharge from the hospital (assessed each day as none, mild, moderate or severe), readmission to the out-patient clinic or hospital for recurrent wheezing during a two-month period after discharge and blood eosinophil counts at discharge and two weeks later.
Adverse events
All adverse events encountered during the study period will be reported on the case record forms. The subjects will be urged to report any adverse events immetiately after appearance. All adverse events will be grated on a scale form 1 to 3, where 1 = mild, 2 = moderate and 3 = severe. The investigator will also be requested to judge the causality of each adverse event to the treatment (1 = not related, 2 = possibly related and 3 = probably related). If serious adverse effects occurs the sponsor shall be notified within 24 h by telephone and subsequently in writing by the investigator. All serious adverse events must be reported to national regulatory authorities within 24 hours of occurence.
Amendment of protocol
A new approval by the ethics committee has to be obtained before execution of any prospective deviation from the signed protocol.
Subject recruitment and information
Before recruitement, the guardian will be informed about the aims, character and risks of the study using the information text in the Subject Information (Appendix 1). After the subject has had sufficient time to acquaint himself with the information text, the investigator seeks for his written consent (Appendix 2). The original signed consent form will be retained by investigator. The investigator is responsible for informing all study team members of sufficient details of the study and the methods to be applied.
Ethical aspects
This study follows the recommendations for biomedical research involving human subjects (current revision of the Declaration of Helsinki of the World Medical Assembly). Prior to initiation of the study, the protocol, the subject information and the informed consent form will be submitted to and approved by the ethics committee of Turku University Central Hospital.
Data management and statistical analysis
The data will be collected in statistical software and the results will be analysed using statistical tests appropriate for parallel design. All study correspondence, records and documents related to the conduct of the study and the distribution of the investigational drug (e.g. diskettes, case record forms, concent forms and other pertinent information) must be retained by the investigator for a period of at least 15 years.
References
Inclusion Criteria:
Exclusion Criteria:
tuomas.jartti@utu.fi+358 2 313 0000
olli.ruuskanen@tyks.fi+358 2 313 0000