Paediatric Respiratory Reviews 11 (2010) 185190

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review

Paediatric asthma: everything that seemed to be certain no longer is

Annemie L.M. Boehmer *
Maasstadziekenhuis, Groene Hilledijk 315, 3075 EA Rotterdam, The Netherlands

EDUCATIONAL AIMS The reader will become familiar with: 1. 2. 3. 4. Limitations in the characterisation of asthma phenotypes and the inuence of early viral infections on their development. The evidence regarding the utility of oral and high-dose inhaled corticosteroids for acute wheezing episodes in young children. The consequences of exposure to viral infections in the daycare setting and the development of asthma. Evidence regarding the lack of efcacy of FeNO in the routine monitoring of asthma.

A R T I C L E I N F O

S U M M A R Y

Keywords: Paediatric asthma Aetiology Risk factors Virus Day-care Preschool wheeze Acute viral wheeze Treatment Corticosteroids Asthma monitoring Exhaled NO

Paediatric asthma: everything that seemed to be certain no longer is, holds the promise of leaving you with more questions than answers at the end of this review of paediatric asthma 20082009. This has often been true for asthma research, in particular over the past few years. Research with direct consequences for a clinician managing children with wheezing or asthma is discussed such as limitations in the characterisation of asthma phenotypes and the inuence of early viral infections on asthma and the development of atopic sensitisation. It appears that wheezing in preschool children with specic viral pathogens confers differential rates of asthma risk. Viruses and day-care shift respiratory morbidity to an early age when it is more troublesome than at a later age but are not protective for sensitisation or asthma. What needs to be further explored is the relationship between viruses and recurrent wheeze or asthma in studies with stringently dened phenotypes including personal atopic status, timing of infection, and severity of infection. A modication of preschool wheeze phenotypes or replacement by other phenotypes that have been dened with the application of different methods is needed. Oral corticosteroids should not be prescribed in preschool children with acute mild to moderate viral wheeze, unless a severe outcome is anticipated or if the child has a classic atopic phenotype. Despite initial high expectations, FeNO was proven not to be benecial for routine monitoring of asthma treatment. 2010 Elsevier Ltd. All rights reserved.

INTRODUCTION Paediatric asthma: Everything that seemed to be certain no longer is. This outcry of many colleagues reading recent papers on paediatric asthma has left those in clinical practice searching for the most appropriate strategies in the management of wheezy children and searching for consistency in formulating the practical advice that they give to parents. For this Paediatric asthma: year in review, research that was published between September 2008 and September 2009 was reviewed, and articles

were chosen because they directly answered one of the following questions: 1. What is asthma? 2. Do early viral infections play a causal role in asthma and if so can we prevent asthma? 3. What is the best treatment of acute viral induced wheezing? 4. With monitoring of exhaled nitric oxide [FeNO], can we improve asthma control in clinical practice?

QUESTION 1: WHAT IS ASTHMA?

This review is based on the presentation at the annual meeting of the European Respiratory Society in Vienna, Sept 2009, Paediatric year in review. * Tel.: +31 10 2912414; fax: +31 291 3420. E-mail address: BoehmerA@Maasstadziekenhuis.nl.

Uncertain preschool wheeze phenotypes There is poor agreement on denitions of different phenotypes of preschool wheezing disorders was the conclusion of the ERS

1526-0542/$ see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2010.05.002

186

A.L.M. Boehmer / Paediatric Respiratory Reviews 11 (2010) 185190

Taskforce Report on preschool wheezing disorders 1. Their purpose was to produce guidelines for the treatment of wheezing in children aged < 6yrs based on the available evidence. They dened a phenotype as a cluster of associated features that is useful in some way, such as in managing the child or understanding the mechanisms of disease. They proposed to use the term episodic (viral) wheeze (EVW) to describe children who wheeze intermittently and are well between episodes, and multiple trigger wheeze (MTW) for children who wheeze in response to various triggers both during and outside discrete episodes. Much of our understanding of infant and preschool wheeze has come from epidemiologic birth cohort studies. Although these provided useful insights into the heterogeneity of the disease, the risk factors for the persistence and relapse of childhood asthma, and the outcome of pulmonary function, they can not be used prospectively, when diagnosing an infant or toddler. As the phenotypic classication of epidemiologic cohort studies is based on the duration of wheeze over the years, the labels transient, persistent and late-onset wheeze can only be assigned retrospectively once the child has become 6 years old. For use in clinical practice, to guide treatment, and for interventional studies, a prospective classication according to the temporal symptom patterns was proposed. Given the multifactorial nature of all wheezing disorders, it is highly likely that the described clinical phenotypes in the literature are the extremes of a broad spectrum of wheezing disorders 1. Many individual patients do not t neatly into the categories described. There may be overlap between phenotypes and they may change overtime 1. As EVW and MTW are not two separate distinct clinical phenotypes the design of valid studies is complicated by the use of phenotypes that change while we are studying risk factors, intervention, treatment and outcome in these phenotypes. Furthermore, although a classication dened by temporal pattern and by triggers is more useful in daily practice, this classication does not necessarily dene aetiology and prognosis. Systematic studies of triggers in MTW other than viruses are lacking, and the underlying pathology has not been claried 1. When making treatment decisions for the child, atopy and the severity of wheeze are usually taken into account, but these are not included in the classication system 2. Modications of these phenotypes, or replacement by different phenotypes that have been dened with the application of different methods, are therefore urgently needed. At present, the only logical approach for making decisions in individual patients is that we need to keep in mind that each published study has relevance for a dened group of patients for whom the ndings are valid and applicable (i.e. that is comparable to the patients in the study). Detailed description of the setting and of clinical characteristics is therefore needed.

The direction of causation between bronchiolitis and asthma The question of whether acute viral bronchiolitis or severe lower respiratory tract infections (LRTIs) in the rst months of life cause asthma, or whether they are only early markers of who will develop asthma in childhood, has been debated for decades 5. It has been established that infants hospitalised with bronchiolitis are at a signicantly increased risk for both recurrent wheezing 7 and childhood asthma. 8 Two recent studies have investigated the direction of causation in this relationship. In a population based sample of 8280 Danish twin pairs, genetic variance components models and direction of causation models were developed to consider this question (9). It was found that genetic determinants for bronchiolitis and asthma overlapped completely and the association between respiratory syncytial virus (RSV) and asthma was due to genetic defects shared between these traits. Modelling the direction of causation showed that a model in which asthma causes RSV hospitalisations tted the data signicantly better than the other way around. Furthermore, a model in which RSV hospitalisation causes asthma could be rejected by statistical tests, whereas one in which asthma causes RSV hospitalization could not. This favours the idea that severe RSV infection is an indicator of genetic predisposition to asthma and contradicts the hypothesis of a causal effect of RSV on asthma. The second study 10 in a Tennessee state based health-care program included data from 95000 infants and used the timing of birth in relation to the annual winter virus peak as a proxy for bronchiolitis. Infant age at the winter virus peak independently predicted asthma, with the highest risk for children seen at 4 months of age at the winter virus peak. When timing of virus peaks shifted over the years, asthma risk shifted too. It was concluded that this is evidence for a causal relationship of winter viruses with early childhood asthma. However, although the magnitude of this effect was much greater for those who developed bronchiolitis, this relationship was also found in infants that did not develop bronchiolitis but were just 4 months old during the winter virus peak. It is likely that this study shows a mere association that can also be explained by other seasonal varying exposures. As illness severity, viral aetiology and allergic sensitization may all contribute to the development of persistent wheezing and/or asthma 5,6,11,12, these entities need to be well described in studies searching for causation. Both studies had signicant shortcomings with regard to denitions. Asthma was poorly dened in both. This is especially important as cohort studies have shown bronchiolitis is frequently followed by recurrent wheeze, which will eventually disappear 7,13. In the Danish Twin study,9 hospital coding records and parent reported asthma at 39 years of age in questionnaires were used to diagnose asthma. The Tennessee study 10 included younger children aged 3.55.5 years. Both studies did not verify asthma objectively in terms of atopy, lung function or airway responsiveness (for obvious reasons in such large study populations). Due to variation in age, and because no further specication of clinical phenotype of the children under study was made, the term asthma in these studies probably encompasses a heterogeneous group of wheezing phenotypes. The severity of infections and the nature of the viruses studied also varied considerably in both studies. The twin study 9 included children with various diseases caused by RSV as dened by hospital discharge diagnoses. In the Tennesse study 10 some children were not even ill. RSV infection was veried by the nding that there was large overlap with another database of registered Danish RSV infections at the same time. The Tennessee study used the argument that the peak of bronchiolitis hospitalisations strongly correlated with the circulation of RSV as the basis of their inclusion criteria. This is probably

QUESTION 2: DO EARLY VIRAL INFECTIONS PLAY A CAUSAL ROLE IN ASTHMA AND IF SO CAN WE PREVENT ASTHMA? As 30%50% of children with recurrent virus-induced wheezing in infancy go on to develop asthma 3 it has been suggested that viral respiratory infections might damage the airways and initiate asthma 4. It is, however, also possible that the relationship is not causal, and that virus-induced wheezing episodes reveal a pre-existing tendency for asthma, secondary to impaired lung physiology or antiviral responses 5. A third possibility is a two hit hypothesis in which viral infections promote asthma mainly in predisposed children when exposed at a critical age 6.

A.L.M. Boehmer / Paediatric Respiratory Reviews 11 (2010) 185190

187

correct for the majority of their patients as rhinovirus (RV) bronchiolitis is less frequent in young infants than RSV bronchiolitis and RV and RSV infections peak in different months 5. Nonetheless, some children with RV bronchiolitis and with bronchiolitis caused by other viruses were probably included. So what does this new data add to our understanding of the relationship between asthma and early severe viral LRTIs? Possibly, the data suggest that the association between RSV and asthma is due to a shared predisposition, but RSV does not appear to cause asthma. However, without homogeneous and tight denitions of both early childhood viral disease and subsequent wheezing disorders this type of epidemiological or genetic research will remain inconclusive 14. The development of persistent viral wheezing or asthma; Specic viruses (RV versus RSV) and the severity of respiratory infections Many studies linking bronchiolitis with asthma in later childhood have involved hospitalised patients, but recent reports 6,12 have indicated that outpatient respiratory tract illnesses during infancy may also contribute to the development of persistent wheezing. The relationship between virus specicity (RV versus RSV) and severity of viral respiratory infections on the development of persistent viral wheezing at 6 years of age was analysed in the COAST study 12. This was a prospective birth cohort study in children at high-risk for developing asthma and allergy as suggested by parental allergy or/and asthma 12. In the follow-up of their previous ndings,4 the COAST group demonstrated that outpatient wheezing illnesses with RV during infancy confer the greatest risk of persistent wheezing at 6 years of age. Odds ratios quadrupled in children that wheezed with RV only (OR 9.8) or both RSV and RV (OR 10) as compared with wheezing with RSV only (OR 2.6). Only lower respiratory illnesses that where accompanied by wheezing were signicant determinants of asthma risk at age 6 years. Thus, wheezing with specic viral pathogens (RV versus other viruses) conferred differential rates of asthma risk. Probably the most important nding of the COAST study 12 was that children who still wheeze with RV at age 3 years have an OR of 25.6 to continue to wheeze at the age of 6 years. This risk was much higher than that of aeroallergen sensitisation (OR 3.6) or other known risk factors, such as sensitisation to food allergens (OR 2.8), passive smoke exposure (OR1.1) or atopic dermatitis (OR 1.7). Nearly 90% of children who wheezed with RV in year 3 had persistent wheezing at 6 years of age regardless of the presence or absence of early allergen sensitisation, also in the rst year of life. Both RV wheezing and aeroallergen sensitisation independently conferred increased risk of asthma at age 6. This differed from ndings in a high-risk birth cohort from Perth (6), in which an increased risk for persistent wheezing with RV or RSV at age 5 was restricted to children with early allergic sensitization. Whether this difference is caused by differences in virus detection rates or variations in the denition of severity of respiratory tract infections and wheezing episodes or genetic or environmental background, needs to be resolved by additional studies. The question of whether genetic predisposition to atopy per se creates susceptibility to the wheezing-promoting effects of viruses or whether active expression of the atopic phenotype during infancy via sensitization to environmental allergen(s) is required 6,15 remains unanswered. Additional prospective birth cohort studies both in similar patients and in non high-risk patients are needed. Daycare attendance neither protects against nor increases the risk of developing asthma Uncertainty in the causation of asthma by viruses, or selection by viruses of patients already predisposed to asthma, raises the

issue whether there is enough evidence for advising parents against daycare, especially in high risk, or very young children. Many studies have investigated the effects of daycare and the risk of asthma. Daycare has been consistently associated with more respiratory infections and wheezing in early childhood. Thereafter, at an older age, results of studies vary between no effect and a protective effect at certain ages. A prospective study in a Dutch birth cohort of nearly 4000 children found no effect of early daycare (0-2 years old) on the development of asthma symptoms, airway hyperresponsiveness and allergic sensitisation at age 8 years 16. The ndings were the same in children at high-risk for the development of asthma by virtue of their mothers history of allergy. Day-care starting before 6 months old also did not inuence the ndings. As these factors were analysed separately, the ndings are not valid in the combined group: high-risk children with early day-care. The results can not be compared with those studies discussed above (from the COAST study and Perth) as early sensitisation and the severity of LRTIs were not studied. The authors argue that studying daycare as a proxy for infections has two major advantages compared with reported infections. First, the relation between daycare and asthma is unlikely to be inuenced by reversed causation. Second, daycare is a feasible target for prevention. Children with early day-care and older siblings had a more than fourfold greater risk of frequent respiratory infections and a more than twofold higher risk of wheezing in the rst year compared to children without older siblings and day-care. Early day-care was associated with more airway symptoms until the age of 4 years, and, only in children without older siblings, with a transient decrease in symptoms between 4 and 8 years. Children with early day-care and older siblings had the highest prevalence of respiratory symptoms in early childhood, but no increased or decreased prevalence of asthma symptoms at any time point. This pattern of early increase in airway symptoms followed by a later reduction has been described previously 17,18. This may be due to maturation of the immune system by recurrent viral infections. Therefore, daycare causes a lot of asthma symptoms/ recurrent wheeze in the rst years of life but does not appear to cause asthma at the age of 8 years. What does this mean for the current management of our patients? At present, there is insufcient evidence to advise against high viral exposure for reasons that it could cause asthma. For the whole population: viruses and daycare shift respiratory morbidity to an early age when it is more troublesome than at a later age but does not protect against sensitisation or asthma. In infants that are young at the beginning of the virus season and at high-risk of developing asthma, such as those with an atopic background, it is undecided. Parents should be given this information when considering day care arrangements for their children. QUESTION 3: WHAT IS THE BEST TREATMENT OF ACUTE VIRAL INDUCED WHEEZING? Oral corticosteroids for acute preschool wheeze Guidelines 1921 recommend the use of oral corticosteroids (OCS) for preschool children with virus-induced wheezing presenting to a hospital, and indeed, the vast majority of such patients are being treated with oral corticosteroids 22. However, this recommendation is based on limited data, expert opinion and extrapolations from studies in older children and adults 1. Former small studies on the efcacy of oral steroids in acute preschool wheeze that comprised heterogeneous study groups showed contradictory results. Some studies found a benecial effect of prednisolone on severity and duration of symptoms,23 whereas others did not nd any effect, even when initiated by parents at the

188

A.L.M. Boehmer / Paediatric Respiratory Reviews 11 (2010) 185190

onset of symptoms 24,25. These studies were dissimilar in terms of age range, inclusion criteria, severity of wheeze, and timing of initiation of corticosteroid therapy. A large double blind placebo-controlled trial in 700 children 1-5 years old, with acute mild to moderate virus- induced wheezing, published this year, showed that OCS are not benecial 26. Oral prednisolone did not shorten the duration of hospitalization or reduced symptom scores like the Preschool Respiratory Assessment Measure (PRAM) score, nor did it affect readmission rates after discharge. The children studied were a heterogeneous population with mild to moderate wheezing, including 35% of children with a rst wheezing attack, 15% MTW with wheezing without a cold in the previous year and 10% with food allergy. The response to OCS was also similar to that to placebo in the subgroup of children with a positive modied asthma predictive index 27. We know that not all preschool children with a positive asthma predictive index will develop asthma 27 and that these indices have a poor positive predictive value and a modest negative predictive value28. As personal atopic history in early life seems to be one of the key factors to identify an individuals risk of persistent asthma 16, and the children in this study were not tested for the presence of specic IgE, the results of this study can not be applied to children with a classic atopic phenotype (food allergy, early sensitisation to (multiple) inhalant allergens, allergic rhinitis and atopic dermatitis) 15. The problem with early identication of this phenotype is that the majority of wheezing preschoolers with an atopic phenotype develop symptoms over time or have a more subtle presentation. In addition, the results of this study can not be applied to severe acute preschool wheezing. It seems that OCS have been overprescribed in the past to preschool children with episodic (viral) wheeze, and that OCS should no longer be prescribed in preschool children with acute mild to moderate viral wheeze. As the authors state: many clinicians justify the routine treatment of all preschool children who present with virus induced wheezing in order to preclude overlooking potentially responsive subgroups 26. Nevertheless, the effect of OCS in the classic atopic preschool child, in multipletrigger wheeze with a severe viral exacerbation, or in severe exacerbations of episodic wheeze necessitating high-intensity hospital care, has not been studied. A benecial effect in these subgroups cannot be excluded. Future studies should be carried out with stringently dened phenotypes, and should include atopic features, early- and multiple sensitisations to allergens and prespecied subgroups of children wheezing with RV. Pre-emptive high-dose inhaled ICS for viral induced wheeze A smaller randomized controlled trial in 129 children with moderate to severe virus induced wheezing, aged 16 years, found that pre-emptive use of high dose inhaled steroids at the rst signs of an upper respiratory tract infection reduced the need for oral steroids 29. The numbers needed to treat to prevent systemic corticosteroid use were 4 children (95% CI, 3 to 13) and 13 upper respiratory tract infections (95% CI, 9 to 39). Since the children had an average of 9 upper respiratory tract infection during the year of the study and duration of treatment with twice daily 750 micrograms of uticasone propionate [FP] could last for ten days, applying this protocol could cause exposure of these patients to a high cumulative dose of inhaled steroids. In the FP treated group, a smaller height and weight gain was observed.The authors stress that this and other potential adverse effects are cause for concern, and highlight that this management strategy should not be recommended for use in clinical practice. As the uticasone trial 29 studied severe recurrent viral wheezers with no allergies, and the prednisolone trial 26 studied mild to moderate wheezers and included a more heterogeneous

population, the difference in benecial effects in the two studies could be due to dissimilar patient characteristics. Taken together, these two studies suggest that steroids may be effective in severe recurrent wheezing. QUESTION 4: WITH MONITORING OF EXHALED NITRIC OXIDE [FENO], CAN WE IMPROVE ASTHMA CONTROL IN CLINICAL PRACTICE? In recent years, inammometry with exhaled nitric oxide (FeNO) raised great expectations as a potential useful monitoring tool in asthma management. Despite the fact that asthma is an inammatory disease, which is treated with anti inammatory agents, current asthma guidelines do not recommend monitoring of inammation directly, but only recommend monitoring indirect features such as symptoms and lung function21. Adding FeNO measurements, asthma monitoring would comprise all three main asthma characteristics: variable symptoms, airow obstruction and inammation. A proof of concept study on the potential usefulness of inammometry showed a decrease of exacerbations when titrating inhaled steroid dose based on sputum eosinophil counts in adults 30. Last year, two studies using FeNO for ICS titration in children were published 31,32. If we bring together all evidence on titrating ICS on FeNO in children,3034 it is clear that despite high expectations, titrating steroids on FeNO, in addition to symptoms and lung function, has shown little if any benet. Monitoring FeNO did not make a difference for markers of asthma control, such as symptom free days, unscheduled hospital visits, quality of life, and FEV1. Although airway hyperresponsiveness was lower in the FeNO group in the two studies in which it was measured, 33,34 and a decrease in the use of OCS was observed in one study,31 this was at the cost of higher cumulative doses of ICS 31,34. Economic costs of adding FeNO monitoring were not studied in any of of the FeNO guided asthma management studies in children. Based on earlier studies, it had been postulated that both the limited benets of FeNO and the differences in outcomes between different studies may have been due to dissimilar patient selection, ICS dosing algorithms, inexible dose adjustments and infrequent FeNO measurements 32. This led to the design of a new study in which daily measurements of FeNO were performed in atopic children with stable mild-to-moderate asthma, with concomitant frequent adjustments in ICS dose 32. In this open label study, FeNO guided frequent adjustments of ICS dose had no effect on the percentage of symptom free days. At the same time, both the FeNO and the symptom group were able to lower the dose of their ICS signicantly. There were also no signicant differences in secondary endpoints: cumulative symptoms scores, ICS dose, lung function, FeNO, prednisone courses, emergency visits, hospitalisation for asthma or quality of life scores. All patients showed a gradual increase in symptom free days, allowing a mean reduction of ICS dose of 50%, and 20% of patients successfully stopping their ICS. Therefore, frequent monitoring of FeNO was of no additional benet to frequent monitoring of patients with mild to moderate atopic asthma. Both this study and another, large American, study 31 conrm earlier observations that provision of current best practice care and strict supervision improves asthma control and allows treatment doses to be reduced 35,36. Possible mechanisms are: improved adherence to medication and avoidance of environmental triggers, reduction of recall bias when reporting symptoms to the doctor, and improved interpretation of symptoms (disregarding nonspecic symptoms unrelated to asthma). Although this was not the intended purpose of these studies, it is an important message with direct applicability in clinical practice: Extensive symptom monitoring and adjustment to asthma therapy is so successful

A.L.M. Boehmer / Paediatric Respiratory Reviews 11 (2010) 185190

189

that further expensive monitoring tools are unlikely to confer further benet. With these large studies showing no benet of FeNO monitoring, the expectation for further use in routine asthma monitoring has vanished. One could argue that specic patient selection and different ICS dosing algorithms need to be tested. However, studies so far were done in several dissimilar patient groups that, taken together, are representative of the asthmatic children treated by paediatricians in secondary and tertiary centres. Therefore, it is clear that FeNO measurement is not benecial for routine monitoring of asthma control. However, selected small groups of patients may still benet from FeNO monitoring. For example, asthma phenotypes may exist that are either concordant or discordant with respect to eosinophilic inammation and symptoms 37. Studies on titrating steroids with the use of FeNO in severe asthmatic patients with symptom concordant eosinophilic severe asthma are still pending. In this group, benets could be gained as the intensity of necessary treatment is high enough to cause side effects and a decrease in the magnitude and severity of their symptoms is most desirable. Furthermore, in complex models of asthma phenotyping, FeNO may serve as one of the many markers that denes a personalised phenotype.

PRACTICE POINTS  Wheezing in preschool children with specic viral pathogens confers differential rates of asthma risk.  Viruses and day-care shift respiratory morbidity to an early age when it is more troublesome than at a later age but are not protective for sensitisation or asthma.  OCS should not be prescribed in preschool children with acute mild to moderate viral wheeze, unless a severe outcome is anticipated or if the child has a classic atopic phenotype.  FeNO is not benecial for routine monitoring of asthma treatment.

RESEARCH DIRECTIONS  Modications of preschool wheeze phenotypes or replacement by other phenotypes that have been dened with application of different methods.  The relationship between viruses and recurrent wheeze or asthma in studies with stringently dened phenotypes including personal atopy, timing of infection, and severity of infection needs to be further explored.  The efcacy of OCS in pre specied groups of acute preschool wheezing.  The role of FeNO as one of the many markers that denes a personalized phenotype.

DISCLOSURE OF POTENTIAL CONFLICT OF INTEREST None. References

1. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al. Denition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008;32(4):1096110.

2. Bacharier LB, Guilbert TW, Zeiger RS, Strunk RC, Morgan WJ, Lemanske Jr RF, et al. Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma. J Allergy Clin Immunol 2009;123(5):107782. 82 e1-5. 3. Martinez FD. What have we learned from the Tucson Childrens Respiratory Study? Paediatr Respir Rev 2002;3(3):1937. 4. Lemanske Jr RF, Jackson DJ, Gangnon RE, Evans MD, Li Z, Shult PA, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol 2005;116(3):5717. 5. Singh AM, Moore PE, Gern JE, Lemanske Jr RF, Hartert TV. Bronchiolitis to asthma: a review and call for studies of gene-virus interactions in asthma causation. Am J Respir Crit Care Med 2007;175(2):10819. 6. Kusel MM, de Klerk NH, Kebadze T, Vohma V, Holt PG, Johnston SL, et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 2007;119(5):110510. 7. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999;354(9178):5415. 8. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000;161(5):15017. 9. Thomsen SF, van der Sluis S, Stensballe LG, Posthuma D, Skytthe A, Kyvik KO, et al. Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study. Am J Respir Crit Care Med 2009;179(12):10917. 10. Wu P, Dupont WD, Grifn MR, Carroll KN, Mitchel EF, Gebretsadik T, et al. Evidence of a causal role of winter virus infection during infancy in early childhood asthma. Am J Respir Crit Care Med 2008;178(11):11239. 11. Devulapalli CS, Carlsen KC, Haland G, Munthe-Kaas MC, Pettersen M, Mowinckel P, et al. Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of age. Thorax 2008;63(1):813. 12. Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, et al. Wheezing rhinovirus illnesses in early life predict asthma development in highrisk children. Am J Respir Crit Care Med 2008;178(7):66772. 13. Henderson J, Hilliard TN, Sherriff A, Stalker D, Al Shammari N, Thomas HM. Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: a longitudinal birth cohort study. Pediatr Allergy Immunol 2005;16(5):38692. 14. Kuehni CE, Spycher BD, Silverman M. Causal links between RSV infection and asthma: no clear answers to an old question. Am J Respir Crit Care Med 2009;179(12):107980. 15. Sly PD, Boner AL, Bjorksten B, Bush A, Custovic A, Eigenmann PA, et al. Early identication of atopy in the prediction of persistent asthma in children. Lancet 2008;372(9643):11006. 16. Caudri D, Wijga A, Scholtens S, Kerkhof M, Gerritsen J, Ruskamp JM, et al. Early daycare is associated with an increase in airway symptoms in early childhood but is no protection against asthma or atopy at 8 years. Am J Respir Crit Care Med 2009;180(6):4918. 17. Ball TM, Castro-Rodriguez JA, Grifth KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000;343(8):53843. 18. Celedon JC, Wright RJ, Litonjua AA, Sredl D, Ryan L, Weiss ST, et al. Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years. Am J Respir Crit Care Med 2003;167(9):123943. 19. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007; 120(5 Suppl): S94138. 20. British Guideline on the Management of Asthma. Thorax. 2008; 63 Suppl 4:iv1121. 21. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008 accessed online March 2010; 31(1):143178. 22. Davies G, Paton JY, Beaton SJ, Young D, Lenney W. Children admitted with acute wheeze/asthma during November 1998-2005: a national UK audit. Arch Dis Child 2008;93(11):9528. 23. Csonka P, Kaila M, Laippala P, Iso-Mustajarvi M, Vesikari T, Ashorn P. 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. J Pediatr 2003;143(6):72530. 24. Oommen A, Lambert PC, Grigg J. Efcacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Lancet 2003;362(9394):14338. 25. Jartti T, Lehtinen P, Vanto T, Vuorinen T, Hartiala J, Hiekkanen H, et al. Efcacy of prednisolone in children hospitalized for recurrent wheezing. Pediatr Allergy Immunol 2007;18(4):32634. 26. Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med 2009;360(4):32938. 27. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to dene risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162(4 Pt 1):14036. 28. Matricardi PM, Illi S, Gruber C, Keil T, Nickel R, Wahn U, et al. Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence. Eur Respir J 2008;32(3):58592. 29. Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, et al. Preemptive use of high-dose uticasone for virus-induced wheezing in young children. N Engl J Med 2009;360(4):33953.

190

A.L.M. Boehmer / Paediatric Respiratory Reviews 11 (2010) 185190 34. Fritsch M, Uxa S, Horak Jr F, Putschoegl B, Dehlink E, Szepfalusi Z, et al. Exhaled nitric oxide in the management of childhood asthma: a prospective 6-months study. Pediatr Pulmonol 2006;41(9):85562. 35. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a trial effect J Clin Epidemiol 2001;54(3): 21724. 36. Strunk RC, Bacharier LB, Phillips BR, Szeer SJ, Zeiger RS, Chinchilli VM, et al. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study. J Allergy Clin Immunol 2008;122(6). 11381144 e4. 37. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178(3): 21824.

30. Petsky HL, Cates CJ, Li AM, Kynaston JA, Turner C, Chang AB. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev 2008;2:CD006340. 31. Szeer SJ, Mitchell H, Sorkness CA, Gergen PJ, OConnor GT, Morgan WJ, et al. Management of asthma based on exhaled nitric oxide in addition to guidelinebased treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet 2008;372(9643):106572. 32. de Jongste JC, Carraro S, Hop WC, Baraldi E. Daily telemonitoring of exhaled nitric oxide and symptoms in the treatment of childhood asthma. Am J Respir Crit Care Med 2009;179(2):937. 33. Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med 2005;172(7):8316.