Efficacy of Systemic Glucocorticoid in the Treatment of Wheezing in Children
Efficacy of Systemic Glucocorticoid in the Treatment of Wheezing in Children
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

 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 expiratory 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?

 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

 -  age 3 months to 16 years

 -  hospitalization for expiratory wheezing

 -  written informed consent from the parents

 Exclusion criteria

 -  Any chronic disease (other than allergy or asthma), e.g. heart disease, immune
 deficiency, or diabetes

 -  varicella and exposure to varicella if not previously have had it

 -  Systemic glucocorticoid 4 weeks prios to the study

 -  Severe disease that needs treatment in the intensive care unit or oxygen saturation
 below 92% despite of additional oxygen and frequent salbutamol inhalations

 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

 1. Ruuskanen O, Ogra PL. Respiratory syncytial virus. Curr Probl Pediatr 1993;23:50-79.

 2. Martinez FD, Wright AL, Taussig LM, Holmberg CJ, Halonen M, Morgan WJ. Asthma and
 wheezing in the first six years of life. The Group Health Medical Associates. N Engl J
 Med 1995;332:133-8.

 3. Habbick BF, Pizzichini MM, Taylor B, Rennie D, Senthilselvan A, Sears MR. Prevalence of
 asthma, rhinitis and eczema among children in 2 Canadian cities: the International Study
 of Asthma and Allergies in Childhood. CMAJ 1999;160:1824-8.

 4. Hesselmar B, Aberg B, Eriksson B, Aberg N. Asthma in children: prevalence, treatment,
 and sensitization. Pediatr Allergy Immunol 2000;11:74-9.

 5. McIntosh K. Bronchiolitis and asthma: possible common pathogenetic pathways. J Allergy
 Clin Immunol 1976;57:595-604.

 6. Mertsola J, Ziegler T, Ruuskanen O, Vanto T, Koivikko A, Halonen P. Recurrent wheezy
 bronchitis and viral respiratory infections. Arch Dis Child 1991;66:124-9.

 7. Rakes GP, Arruda E, Ingram JM, et al. Rhinovirus and respiratory syncytial virus in
 wheezing children requiring emergency care. IgE and eosinophil analyses. Am J Respir
 Crit Care Med 1999;159:785-90.

 8. Glezen PW, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory virus
 infections on persons with chronic underlying conditions. JAMA 2000;283:499-505.

 9. Johnston SL, Pattemore PK, Sanderson G, et al. Community study of the role of viral
 infections in exacerbations of asthma in 9-11 year old children. BMJ 1995;310:1225-9.

 10. Storr J, Barrell E, Barry W, Lenney W, Hatcher G. Effect of a single oral dose of
 prednisolonee in acute childhood asthma. Lancet 1987;1:879-82.

 11. Roosevelt G, Sheehan K, Grupp Phelan J, Tanz RR, Listernick R. Dexamethasone in
 bronchiolitis: a randomised controlled trial. Lancet 1996;348:292-5.

 12. Wang EEL, Law BJ, Boucher FD, et al. Pediatric investigators collaborative network on
 infections in Canada (PICNIC) study of admission and management variation in patients
 hospitalized with respiratory syncytial viral lower respiratory tract infection. J
 Pediatr 1996;129:390-5.

 13. Ruohola A, Heikkinen T, Waris M, Puhakka T, Ruuskanen O. Intranasal fluticasone
 propionate does not prevent acute otitis media during viral upper respiratory infection
 in children. J Allergy Clin Immunol 2000;106:467-71.

 14. Gustafson LM, Proud D, Hendley JO, Hayden FG, Gwaltney JM Jr. Oral prednisone therapy in
 experimental rhinovirus infections. J Allergy Clin Immunol 1996;97:1009-14.

 15. Puhakka T, Mäkelä MJ, Malmström K, et al. The common cold: effects of intranasal
 fluticasone propionate treatment. J Allergy Clin Immunol 1998;101:726-31.

 16. De Boeck K, Van der Aa N, Van Lierde S, Corbeel L, Eeckels R. Respiratory syncytial
 virus bronchiolitis: a double-blind dexamethasone efficacy study. J Pediatr
 1997;131:919-21.

 17. Mäkelä MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, Kimpimäki M, et al. Viruses and
 bacteria in the etiology of the common cold. J Clin Microbiol 1998; 36: 539 42.

 18. Halonen P, Rocha E, Hierholzer J, Holloway B, Hyypiä T, Hurskainen P, Pallansch M.
 Detection of enteroviruses and rhinoviruses in clinical specimens by PCR and
 liquid-phase hybridization. J Clin Microbiology 1995;33:648-53.

 19. van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, Osterhaus AD.
 A newly discovered human pneumovirus isolated from young children with respiratory tract
 disease. Nat Med 2001;7:719-24.

 20. American Thoracic Society. Recommendations for standardized procedures for the online
 and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide
 in adults and children - 1999. Am J Respir Crit Care Med 1999; 160: 2104-17.
Inclusion Criteria:

 -  age 3 months to 16 years

 -  hospitalization for expiratory wheezing

 -  written informed consent from the parents

 Exclusion Criteria:

 -  Any chronic disease (other than allergy or asthma), e.g. heart disease, immune
 deficiency, or diabetes

 -  varicella and exposure to varicella if not previously have had it

 -  Systemic glucocorticoid 4 weeks prios to the study

 -  Severe disease that needs treatment in the intensive care unit or oxygen saturation
 below 92% despite of additional oxygen and frequent salbutamol inhalations