THE USE OF STEROIDS TO TREAT VIRAL INDUCED WHEEZE. GILLIAN HAGGERTY ADVANCED PAEDIATRIC & NEONATAL HEALTH ASSESSMENT SEPTEMBER 2009

INTRODUCTION Viral induced wheeze is common in preschool children (up to 6yrs old), nearly 1/3 of childrenin the UK have the condition, however, the majority of them will grow out of it with only a minority going on to develop interval symptoms & atopic asthma (BTS/SIGN 2009, Bush 2009). Often parents use the term wheeze to describe any abnormal respiratory noise but it is important to distinguish it from other noises such as rattly breathing or stridor. BTS/SIGN describe wheeze as - “ a continuous, high pitched musical sound coming from the chest”.

VIRAL INDUCED-WHEEZE OR ASTHMA? Not all wheezing is asthma. Children with asthma will wheeze at other times (interval symptoms) not just when they have a respiratory virus. Intermittent wheezing in association with a respiratory virus and no interval symptoms, caused by irritability of the airways rather than inflammation. Separate entity to asthma and as such use of steroids is questionable. A small, clinically indistinguishable amount of children will have atopic asthma, therein lies the problem, it is not possible to tell which child will have asthma. (Bush 2009, Frey & Von Mutius 2009, Panickar & Grigg 2006).

CURRENT PRACTISE Currently there are no guidelines for the treatment of preschool viral-induced wheeze, treatment is based on that of asthma and the use of oral steroids is commonplace. The suggestion that steroids may change the course of viral induced wheeze is causing much debate in the medical literature (Bush 2009, Frey & Von Mutius 2009, Panickar & Grigg 2006). As APNPs we will be responsible for assessing & treating the large volumes of children who attend hospitals with this condition and as such it is important to look at the evidence for this practise.

THE QUESTION P I C O Preschool children with viral-induced wheeze Steroid C Placebo O Length of hospital stay & duration of symptoms Do preschool children with viral induced wheeze benefit from treatment with steroids?

SEARCH STRATEGY Via Scottish eLibrary www.elib.scot.nhs.uk/ (accessed 06/09/09) Search terms Child* or paediatric or pediatric or infant Corticosteroid or prednisolone or steroid Respiratory Wheez* Virus or viral Cochrane Library – 22 reviews (none oral steroids & PVW), 17 clinical trials Ovid medline – 194 results Embase – 116 results

INCLUSION/EXCLUSION CRITERIA INCLUDED Must be available on line or locally Pre-school children ( 0 – 6yrs) with viral induced wheeze Hospital initiated Year 2000 – present EXCLUDED Inhaled steroids Diagnosis of asthma, bronchiolitis or specific virus ie. RSV, rhinovirus. Of the search results only two fitted the criteria.

THE ARTICLES Panickar J., Lakhanpaul M., Lambert P., Kenia P., Stephenson T.,Smyth A., Grigg J. (2009) Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheeze. The New England Journal of Medicine 360 (4) 329-338. A double blind randomised controlled trial was conducted in 3 hospitals in the Uk in children aged from 10 months to 6 years with viral-induced wheeze. To determine if a short course of oral prednisolone would improve the outcomes of length of hospital stay and secondary outcomes of score on the Preschool Respiratory assessment Measure, use of salbutamol and a 7 day symptom score.

THE ARTICLES Csonka P., Kaila M., Laippala P., Iso-Mustajarvi M., Vesikari T., Ashorn P. (2003) Oral Prednisolone in the Acute Management of Children Age 6 to 35 Months With Viral Respiratory Infection-Induced Lower Airway Disease: A Randomized, Placebo-Controlled Trial The Journal of Pediatrics 143 725-730. A double blind randomised controlled trial was conducted in a hospital in Finland in children aged between 6 & 35 months, presenting with viral induced respiratory distress (tachypnoea, wheeze or use of accessory muscles), patients with asthma or 2 or more wheezing episodes were not eligible. To investigate the efficacy of a 3 day course of oral prednisolone on exacerbation of symptoms, length of hospital stay and duration of symptoms.

CRITICAL APPRAISAL TOOL Critical Appraisal Skills Programme (Casp) - 10 questions to help you make sense of randomised controlled trials from the Public Health Resource Unit (2006).

WAS A CLEARLY FOCUSED QUESTION ASKED? Panickar et al (2009) To determine the efficacy of a short course (5 days) of oral steroids to treat children aged between 10months & 6yrs with viral-induced wheeze – children randomised to receive either prednisolone or a placebo, primary outcome was length of hospital stay, secondary outcomes were PRAM score, salbutamol use & 7 day symptom score. Csonka et al (2003) To investigate the effect of a 3 day course of oral prednisolone in children aged 6-35 months with viral induced respiratory distress – primary outcome measures were development of severe respiratory symptoms requiring additional treatment, secondary outcomes hospitalisation rate from the emergency dept., length of hospital stay, duration of symptoms and hospital revisits.

WAS THIS A RANDOMISED CONTROL TRIAL? Double blind randomised controlled trial, the most appropriate approach for the question. Double blind randomised controlled trial.

WERE THE PARTICIPANTS APPROPRIATELY ALLOCATED TO THE GROUPS? Randomisation was achieved by generating numerical codes in random permuted blocks of 10. Baseline characteristics of each group presented in table, well balanced. Inclusion & exclusion criteria clearly stated, also reason for lower age limit of 10months stated to reduce risk of recruiting infants with bronchiolitis. Children were allocated using a computer to generate a random list in blocks of four. Baseline characteristics of each group well balanced, presented in a table. Inclusion & exclusion criteria clearly stated, reason for specific age group was to concentrate on a homogeneous group of children with viral induced respiratory symptoms.

WERE PARTICIPANTS, STAFF & STUDY PERSONNEL BLIND? Yes. Prednisolone & placebo in identical packaging – capsules containing identical amounts of lactose in container labelled with patients’ number. Staff unaware of group assignments. Randomisation codes locked in hospital pharmacy until all data entry was complete. Yes. Doses prepared by hospital pharmacy, delivered in identical, numbered containers. Doctors, nurses & parents all remained blinded throughout the study. Randomisation list was concealed in opaque envelopes until the data analysis was performed.

WERE ALL THE PARTICIPANTS WHO ENTERED THE TRIAL ACCOUNTED FOR AT ITS CONCLUSION? 1180 patients assessed, 480 not enrolled (162 not eligible & 318 parents declined to participate). Total of 700 children randomised – 3 bottle number not recorded & group could not be determined, 10 children enrolled a second time in error – the remaining 687 were included in the intention to treat analysis. Primary outcome was not recorded in 3 patients ( 2 in prednisolone group 1 in placebo). Of 467 children eligible during the trial period, 327 were approached (140 were not approached, no reason given), 71 declined to participate & 8 were unstable, therefore 248 children were randomised. 18 were excluded due to false inclusion, leaving 230 analysed on an intention to treat basis. 6 missing data in revisits of hospitalised children, 7 missing in non-hospitalised children.

WERE THE PARTICIPANTS IN ALL GROUPS FOLLOWED UP & DATA COLLECTED IN THE SAME WAY? The treatment & observation policy was identical in all 3 hospitals, medical history was obtained by the treating clinician with a standardised data collection form, PRAM score recorded after inhaled salbutamol at 4, 12 & 24hrs. Parents were provided with a diary to complete on discharge, instructions on the use of scale from 0-3 given, were all called at 1 & 4 weeks after discharge. At the 4 wk call information was obtained on hospital readmission & when the child was ‘back to normal’. Treatment was standardised both in the emergency dept. and following admission. No scoring system as above, patients were treated at discretion of attending doctor. No mention of time intervals patients reviewed at. Diary cards were given to parents at discharge, recordings were made twice daily for 14 days. Children were examined and cards reviewed 14-21 days after initial presentation, non-attenders were contacted by phone. No explanation of scoring system used, diary seems to be at discretion of parent.

DID THE STUDY HAVE ENOUGH PARTICIPANTS TO MINIMISE THE PLAY OF CHANCE? Power for the study was determined from data prospectively collected from 208 preschool children presenting with viral-induced wheeze. Calculated that total of 350 in each group would give a power of 80%, 343 in prednisolone group & 344 in placebo group. Calculated 230 participants were required to provide a power of 80%, 117 in placebo group & 113 in prednisolone group.

HOW ARE THE RESULTS PRESENTED & WHAT IS THE MAIN RESULT? Primary & secondary outcomes clearly presented in tables. The time to discharge from hospital 13.9hrs in placebo & 11.0 hrs in prednisolone groups. There was no significant difference in the secondary outcomes. In children presenting with mild to moderate wheeze induced by a viral infection no significant benefit was noted in the children treated with prednisolone when compared to a placebo. Results presented in tables. Number of children hospitalised 53% placebo, 54% prednisolone. Number requiring additional medication placebo 37.1%, prednisolone 18%. Median length of hospital stay (of 123 children admitted) 3 days placebo, 2 days prednisolone. Systemic steroids may influence the outcome.

HOW PRECISE ARE THE RESULTS? P values & confidence intervals clearly reported. Well designed study, clear and concise results reported, acknowledged limitations. P values and confidence intervals reported for all outcomes. Well designed study. A lot of statistics to plough through. Limitations acknowledged

WERE ALL IMPORTANT OUTCOMES CONSIDERED SO THE RESULTS CAN BE APPLIED? Acknowledged that substantial amount of children whose parents declined to participate meaning that possibly children who were selected were at low risk of atopic asthma. PCR analysis and viral cultures not performed. On the whole the study population is similar to my own. Young age group and decision not to test for viruses may have included infants with RSV bronchiolitis. Acknowledged: that first time wheezers are less likely to require additional medication, children with milder symptoms may have diluted results; diary cards were subjective, nature of symptoms were double –checked at follow-up; duration of hospital stay could be influenced by reasons other than the intervention.

IMPLICATIONS FOR PRACTICE The current approach to treating viral induced wheeze is based on the treatment of asthma – inhaled salbutamol & steroids, with oral steroids for acute exacerbations. However, more & more medical staff are prescribing steroids for wheezing episodes other than acute exacerbations. Managing preschool wheeze is a challenge which is causing much debate in the medical literature (Bush 2009, Frey & Von Mutius 2009, Panickar & Grigg 2006), as it is seen as a separate entity to the classic atopic asthma and should thus be treated differently. From the 2 articles analysed there is little evidence to support the use of steroids in the treatment of viral-induced wheeze in preschool children. The lack of research available & the current debate would suggest that further research is clearly required. Steroids should be prescribed on a case by case basis, particularly in severe attacks and the practise of prescribing them unnecessarily should be stopped. As APNPs we have the opportunity here to directly influence the treatment our patients receive.

REFERENCES BTS, SIGN (2009) British Guideline on the Management of Asthma. Edinburgh Bush A (2009) Practice Imperfect – Treatment for Wheezing in Preschoolers The New England Journal of Medicine 360 (4) 409 Csonka P., Kaila M., Laippala P., Iso-Mustajarvi M., Vesikari T., Ashorn P. (2003) Oral Prednisolone in the Acute Management of Children Age 6 to 35 Months With Viral Respiratory Infection-Induced Lower Airway Disease: A Randomized, Placebo-Controlled Trial The Journal of Pediatrics 143 725-730. Frey U., & Von Mutius E (2009) The Challenge of Managing Wheezing in Infants The New England Journal of Medicine 360 (20) 2130-2133 Panickar J. & Grigg J (2006) Controversies in the management of preschool viral wheeze. Paediatric Respiratory Reviews. 7 293-298 Panickar J., Lakhanpaul m., Lambert P., Kenia P., Stephenson T., Smyth A., Grigg J. (2009) Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheezing. The New England Journal of Medicine. 360 (4) 329-338 Public Health Research Unit (2006). CASP 10 questions to help you make Sense of randomised control trials. www.phru.nhs.uk/Pages/PHD/resources.htm