Pharmacological approach to wheezing in preschool children.

Review

Pharmacological approach to wheezing in preschool children

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Pittsburgh on 12/27/14 For personal use only.

Susanna Esposito† & Nicola Principi 1.

Introduction

2.

Wheezing phenotypes in preschool children

3.

Corticosteroids

4.

Bronchodilators

5.

Leucotriene receptor antagonists

6.

Antibiotics

7.

Conclusion

8.

Expert opinion

Universita` degli Studi di Milano, Department of Pathophysiology and Transplantation, Pediatric High Intensity Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy

Introduction: Wheezing disorders are very common during childhood (particularly among preschool children), and represent a significant burden for patients, their families, the healthcare system, and society as a whole. Identifying wheezing phenotypes, and recognizing the risk factors associated with each, may help to predict long-term outcomes, distinguish high-risk children who may benefit from secondary prevention measures, and ensure that the most effective therapy is prescribed for each case. Areas covered: The main aim of this review is to analyze the characteristics of the drugs currently used to treat wheezing in preschool children, and discuss the results obtained in children with different wheezing phenotypes. Expert opinion: The continuous or intermittent administration of various oral or inhaled drugs could theoretically be effective in preventing or controlling wheezing in preschool children. However, the optimal management of acute preschool wheezing episodes has not yet been determined mainly because of their phenotypical heterogeneity. Keywords: antibiotics, asthma, bronchodilators, children, corticosteroids, inhaled steroids, leukotriene receptor antagonists, respiratory tract infection, systemic steroids, wheezing Expert Opin. Pharmacother. (2014) 15(7):943-952

1.

Introduction

Wheezing is defined as the emission of a continuous high-pitched musical sound from the chest during expiration [1]. Wheezing disorders are very common during childhood (particularly among preschool children), and represent a significant burden for the patients, their families, the healthcare system, and society as a whole. It has been reported that about 30% of children suffer from at least one episode of wheezing in the first 3 years of life, and that the cumulative prevalence of wheezing is almost 50% by the age of 6 years [2,3]. Wheezing episodes are frequently recurrent and associated with a variety of clinical conditions that need specific diagnosis and treatment. Severe chronic diseases such as cystic fibrosis, primary ciliary dyskinesia and bronchomalacia, cardiac abnormalities, obliterative bronchiolitis, and gastroesophageal reflux can all be accompanied by wheezing [4]. Moreover, in the first years of life, wheezing is usually triggered by a respiratory tract infection (RTI). The most frequently isolated viruses in children with acute asthma exacerbations are rhinovirus, respiratory syncytial virus (RSV), coronavirus, human metapneumovirus, parainfluenza virus, and adenovirus [5]. Atypical pathogens such as Mycoplasma pneumoniae and, less frequently, Clamydophila pneumoniae may also play a role [6]. Finally, some cases of wheezing may be the expression of allergic asthma, and associated with early food and aeroallergen sensitization. Unfortunately, the characterization of wheezing is strictly age-dependent, and significantly more difficult in preschoolers than in older children. Diagnostically useful clinical features such as wheezing, reversible bronchial obstruction, bronchial 10.1517/14656566.2014.896340 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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S. Esposito & N. Principi

Article highlights. . .

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Wheezing is usually triggered by a respiratory tract infection in the first years of life. Preschool children experiencing an acute episode of wheezing of any phenotype should be treated with inhaled, short-acting b2-receptor agonists; ipratropium bromide may be added in the most severe cases. Oral or inhaled steroids should not be routinely used, but can be useful in patients with demonstrated rhinovirus infection or those with very severe wheezing and risk factors for persistent asthma. Montelukast may be considered as a means of preventing recurrent wheezing of any phenotype, and inhaled low-dose steroids may be given in more severe cases. In subjects with persistent symptoms, the combination of montelukast and inhaled low-dose steroids can be considered. In order to reduce the number of wheezing episodes, it is essential to decrease children’s environmental exposure to tobacco smoke, and provide educational programs aimed at improving their parents’ knowledge of asthma, and its prevention and treatment.

This box summarizes key points contained in the article.

hyper-reactivity, and spirometry variables can all be easily evaluated in school-age children, but there are no reliable biological parameters for younger patients, whose lung function cannot be easily tested in everyday clinical practice [4]. These are substantial limitations because identifying wheezing phenotypes, and recognizing the risk factors associated with each, may help to predict long-term outcomes, distinguish high-risk children who may benefit from secondary prevention measures, and ensure that the most effective therapy is prescribed for each case. Treating preschool wheezing can be challenging because there is no known treatment that is always effective in individual cases. The main aim of this review is to analyze the characteristics of the drugs currently used to treat wheezing in preschool children, and discuss the results obtained in children with different wheezing phenotypes.

widely accepted precisely because it was very easy to use [1]. It divided preschoolers with wheezing illness into children with episodic (viral) wheeze (EVW) and those with multiple-trigger wheeze (MTW). The former include children whose episodes of wheezing are systematically associated with an RTI and who remain asymptomatic between episodes: the wheezing tends to decrease over time and disappears by the age of 6 years although, in a minority of cases, it can be diagnosed in children of school age and can disappear later or change into MTW. The severity of the episodes and their long-term outcome seem to be related to the severity of the first episode and the type of infectious agent. Both RSV [13] and rhinovirus [14] have been associated with an increased risk of persistent wheezing over time although, in the case of rhinovirus, the association remains debatable. The children with MTW include those in whom the episodes are triggered not only by infectious agents, but also by other potential triggers such as tobacco smoke, allergen exposure, mist, crying, and laughter. These patients have symptoms such as nocturnal cough and exercise-induced dyspnea between their acute wheezing episodes, and MTW is more likely to persist in later life. Many experts believe that it reflects chronic allergic airway inflammation, particularly when the onset of wheezing occurs beyond 18 months of age, although there is little evidence to support this hypothesis [15]. This classification has not been validated and is strongly criticized, mainly because it does not take into account the severity and frequency of the wheezing, or the relevance of other respiratory symptoms that could permit the early identification of children who will have asthma in later life and need an immediately more aggressive diagnostic and therapeutic approach [4]. Moreover, longitudinal evaluations have clearly shown that some patients initially considered as having EVW can be subsequently classified as having MTW even in the same year [4]. The current therapeutic measures for preschool children with wheezing are mainly based on the response of EVW and MTW to potentially effective drugs.

3.

Wheezing phenotypes in preschool children

Corticosteroids

2.

Various attempts have been made to differentiate preschool wheezing phenotypes using lung function [2,7], exhaled nitric oxide (NO) [8,9], bronchoalveolar lavage [2,7], bronchial biopsy [10], and metabolomics [11]. Although these have been extremely useful in developing our understanding of the biological basis of preschool wheezing, they have failed in their primary purpose and classifications have had to rely on temporal patterns [2,12] that are not immediately useful in practical terms because they can only be assessed retrospectively. A classification based on a small number of simple clinical findings was considered the best solution, and was initially 944

Systemic steroids A number of studies have evaluated the effect of systemic steroids on preschool and school-age children suffering from an acute episode of wheezing, but the results are conflicting. It has been found that, as in adults, they can be beneficial in reducing the severity and duration of single wheezing episodes and the risk of recurrences in older children [16], and a systematic review of studies published before 2003 showed that their administration to children of any age hospitalized because of acute asthma led to a significantly earlier hospital discharge and a lower likelihood of relapse within 1 -- 3 months than observed in untreated controls [17]. Although the review included studies involving preschool children, these were not 3.1

Expert Opin. Pharmacother. (2014) 15(7)



separately analyzed and no definite conclusions could be drawn. The results of trials exclusively involving preschool subjects have not shown any favorable effect of orally or intravenously administered systemic steroids. Panickar et al. conducted a randomized, double-blind, placebo-controlled trial comparing a 5-day course of oral prednisolone (10 mg once a day for children aged 10 -- 24 months, and 20 mg once a day for older children) with placebo in 700 children aged 10 -- 60 months with mild-to-moderate viral-induced wheezing [18], and found no significant between-group difference in the duration of hospitalization, symptom scores, the time to returning to normal activities, bronchodilator use at home, or hospital re-admission because of wheezing. Interestingly, the lack of benefit of prednisolone was also noted in a subgroup of 124 children at high risk for atopic asthma because of their history of previous wheezing episodes and the fact that they had a parent with asthma or clinician-diagnosed eczema, thus suggesting that oral steroids do not have a positive effect on either EVW or MTW. Similar conclusions have been drawn from studies evaluating the effect of home-administered oral steroids. Children who suffer from repeated episodes of wheezing are frequently treated by their parents as soon as the symptoms appear in order to truncate the attack and avoid hospitalization [19]. Oommen et al. allocated hospitalized children with viral wheeze aged 1 -- 5 years to a high- or low-primed stratum depending on their serum levels of eosinophil cationic protein and eosinophil protein X, and then randomized them to parent-initiated prednisolone (20 mg once daily for 5 days) or placebo for the next episode [20]. The primary outcomes were the 7-day mean daytime and night-time respiratory symptom scores. A total of 120 children experienced a subsequent episode (51 treated with prednisolone and 69 with placebo), and there was no difference between the treatment groups in terms of mean daytime respiratory symptom scores or the need for hospitalization. There was also no difference in primary outcome within the high- (n = 59) and low-primed strata (n = 61), thus confirming the poor effect of oral steroids regardless of the wheezing phenotype [20]. On the basis of these findings, a number of experts have concluded that systemic steroids should not be prescribed to preschool children with episodes of mild-to-moderate wheezing of any phenotype [21]. However, it is not clear whether systemic steroids may be beneficial in some subgroups of preschool children, and it cannot be excluded that the etiology of the infection triggering the wheezing may play a role. Jartti et al. studied the response to steroids of preschool children hospitalized because of viral wheezing, and found that prednisolone administration was associated with a significant reduction in the length of hospital stay and the duration of cough and dyspnea only in the patients infected by rhinovirus [22], whereas no effect has been found in those infected by RSV [23] or bocavirus [24]. The importance of rhinovirus seems to be further supported by the findings that

prednisolone reduces recurrent wheezing after a first rhinovirus-induced wheeze until the age of 7 years [25] and that allergic sensitization is associated with wheezing induced by rhinovirus but not by other viruses [26]. This could explain why the importance of atopy in conditioning the response to systemic steroids is quite different from study to study [27]. Maintained inhaled steroids The effect of maintained inhaled steroids on preventing or attenuating wheezing in preschool children has been evaluated in a number of controlled trials. Although the studies are difficult to compare because of differences in the type and dose of the drug used, the timing of its administration in relation to symptom onset, and the methods of evaluating the primary outcome, the available data indicate that the effect of maintained inhaled steroids can vary depending on their dose and administration route, and the child’s wheezing phenotype. In particular, they seem to be effective in children with MTW (at least during the period of administration) but ineffective in those with EVW. Bisgaard et al. found that that the 52-week administration of fluticasone propionate 100 µg twice daily to a group of children aged 1 -- 3 years, most of whom had MTW, led to significant benefits in terms of reductions in symptoms and wheezing exacerbations, as well as the need for oral steroids and rescue treatment [28]. Similar findings have been described by Blake et al. [29] and Chavasse et al. [30] in groups of infants and toddlers with the same clinical characteristics treated with the same steroid at the same dose. Finally, in the Prevention of Early Asthma in Kids (PEAK) study, Guilbert et al. randomly assigned 285 children aged 2 -- 3 years with a positive asthma predictive index (API) to treatment with fluticasone propionate (at a dose of 88 µg twice daily) or placebo for 2 years [31]. During the treatment period, the use of the inhaled steroid was associated with a greater proportion of episode-free days (p = 0.006), a lower rate of exacerbations (p < 0.001), and a reduction in the supplementary use of controller medication (p < 0.001). A meta-analysis of these and other similar studies involving a total 3592 children by Castro-Rodriguez and Rodrigo [32] confirmed the positive effect of maintenance therapy with inhaled steroids, and showed that it was independent of the type of inhaled drug, and greater in the patients with a diagnosis of asthma. All of the respiratory symptoms were greatly improved, there were fewer withdrawals due to wheezing exacerbations, and the use of short-acting b2-receptor agonists was reduced. However, maintenance treatment is only effective while it is being used but not after its discontinuation. The PEAK study monitored the respiratory condition of the enrolled children for 1 year after the discontinuation of fluticasone propionate [31], and found no significant difference between the controls and previously treated patients in terms of the proportion of episode-free days, the number of exacerbations, or lung function. These findings are quite similar to those 3.2


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previously reported by Pao and McKenzie, who studied children with MTW aged 2 -- 5 years who completed a 6-week randomized and controlled crossover trial of fluticasone propionate (100 µg twice daily) followed by a 10-week parallel extension [33], and found that lung function significantly improved in the sensitized children during treatment but deteriorated after it was stopped. Moreover, Murray et al. found that maintenance treatment cannot prevent lung function decline or reduce airway reactivity at the age of 5 years in children with a high API [34]. The safety of maintained inhaled steroids strictly depends on the dose of the administered drug. Daily doses of about 100 µg using a spacer device (which are usually effective in children with MTW) are not associated with any serious adverse events, and are considered safe and well tolerated [35], but higher doses can cause problems [36,37]. A study of fluticasone dipropionate given at a dose of 200 µg per day found that in the inhaled-corticosteroid group as compared with the placebo group the mean increase in height was 1.1 cm less at 24 months (p < 0.001), but by the end of the trial, the height increase was 0.7 cm less (p = 0.008) [31]. During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively, and it has also been reported that the administration of 400 µg of budesonide or fluticasone dipropionate reduces lower limb growth rate [38]. Maintained inhaled steroids seem to have no effect on children with EVW. Wilson et al. assessed the effect of budesonide 400 µg per day in a 4-month, double-blind, parallelgroup trial involving 41 children (aged 0.7 -- 6.0 years) with predominantly EVW [39]. Analysis of the last 3 months showed no difference between the budesonide and placebo groups in terms of the mean daily total symptom score, the number of episodes, or the severity of each episode. However, it should be noted that there are very few studies looking at the effect of maintained inhaled steroids in children with EVW. The study by Wilson et al. analyzed only 41 children over only a 4-month period [39]. In addition, the majority of these children had a family history of atopy, suggesting a mixed population. Thus, more studies are needed before a definite conclusion can be made. Intermittent inhaled steroids It has been demonstrated that the administration of inhaled steroids for a short period at the time of onset of an RTI is only effective in preschool children affected by recurrent wheezing when given at doses that are significantly higher than those effective as maintenance therapy [40]. Moreover, it is not known whether the wheezing phenotype conditions this clinical response because various studies in which the majority of the enrolled children satisfied the criteria for EVW also included a substantial number of children with eczema or a positive family history of asthma, thus suggesting mixed populations [40-45]. The most recent of these studies [41] involved 129 children aged 1 -- 6 years who received inhaled 3.3

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fluticasone propionate 750 µg twice per day for a maximum of 10 days over a period of 6 -- 12 months. In comparison with placebo, the treatment led to a 50% reduction in the need for rescue oral steroids, and a 20% reduction in other markers of the severity and duration of exacerbations. However, the children who were treated with fluticasone showed smaller mean gains from baseline in height (6.23 ± 2.62 cm) and weight (1.53 ± 1.17 kg), although there was no significant between-group difference in baseline cortisol levels, bone mineral density, or adverse events. This was considered a substantial problem, and so this strategy of managing preschool wheezing was not recommended. Furthermore, the intermittent administration of inhaled steroids is not more effective than maintained administration (a method that has been demonstrated to be safe and tolerable at appropriate doses). Zeiger et al. studied 278 children aged 12 -- 53 months with positive modified API scores, recurrent wheezing episodes, and at least one exacerbation in the previous year [46], who were randomly assigned to receive a budesonide inhalation suspension for 1 year as an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a respiratory infection) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebo. Both treatment regimens were more effective than placebo alone, and there was no significant difference in the frequency of exacerbations or other measures of asthma severity, including the time to the first exacerbation. 4.

Bronchodilators

b2-receptor agonists Inhaled short-acting b2-receptor agonists such as salbutamol and albuterol are widely used to treat acute wheezing in preschool children; the use of an oral preparation is significantly less frequent because of the fear of adverse events [47]. The administration of b2-receptor agonists to younger children should have the same significant bronchodilatory effect that has been repeatedly demonstrated in older children and adults because infants possess albeit immature functional b2-receptors from birth which, when adequately stimulated, can induce the relaxation of bronchial wall smooth muscle. Moreover, the use of inhalation is supported by the evidence that it is well tolerated and the most frequent adverse events following the systemic use of b2-receptor agonists (headache, agitation, palpitation, and hypokalemia) only appear after very high and repeated doses. A number of double-blind, placebo-controlled studies have shown that the administration of b2-receptor agonists has a significant bronchodilatory effect in preschool children with acute wheezing by restoring lung function and normalizing clinical parameters, regardless of the wheezing phenotype [48-50]. Unfortunately, differences in doses and the duration and method of administration prevent any conclusions concerning optimal treatment, and some studies have reported negative results, including evidence of a paradoxical 4.1




response [51-58]. Furthermore, in a Cochrane review of all of the studies involving children aged < 2 years published before 2002, Chavasse et al. pointed out that the use of short-acting b2-receptor agonists does not influence the rate or duration of hospitalization [59]. There are relatively few clinical evaluations that have been made of the use of long-acting b2-receptor agonists such as formoterol and salmeterol in preschool children with wheezing, although the results are apparently positive [60,61]. Primhak et al. demonstrated that in recurrently wheezy children aged < 4 years a single dose of salmeterol between 25 and 100 µg has a dose-dependent effect on methacholine-induced wheeze, and this is significantly different from placebo at 50 and 100 µg [60]. However, no definite conclusion can be drawn concerning their possible use in such patients. Anticholinergic agents These are the other group of bronchodilators widely used in preschool children with wheezing. They block the acetylcholine neurotransmitter in both the central and peripheral nervous systems and, as they inhibit parasympathetic nerve impulses by selectively blocking acetylcholine binding to its receptor in nerve cells, this relaxes the bronchial wall smooth muscles that are innervated by the parasympathetic system. Ipratropium bromide is the most widely used, but its efficacy remains controversial. A Cochrane review first published in 2000 [62], and updated in 2013 [63], found no clear benefit in terms of outcomes, but it seems that parents prefer ipratropium bromide over nebulized water with placebo as a means of relieving their children’s symptoms. There are some data indicating that the drug may be beneficial when combined with a b2-receptor agonist in recurrently wheezy infants treated at home. In comparison with a b2-receptor agonist alone, the combination is associated with a reduced need for additional treatment, although there was no difference in terms of treatment response, respiratory rate, or oxygen saturation improvement in an emergency department [64]. There is no significant difference in the duration of hospitalization between patients treated with ipratropium bromide or placebo, or between those treated with ipratropium bromide plus a b2-receptor agonist and those treated with a b2-receptor agonist alone. However, in comparison with placebo, the combination leads to a significant improvement in clinical scores after 24 h, which is why some experts consider ipratropium bromide as possible adjunctive therapy in the acute phase [64]. 4.2

5.

Leucotriene receptor antagonists

The knowledge that cysteinyl-leucotrienes (CysLTs) play a central role in the pathophysiology of asthma when they activate leucotriene (LT) receptors [65] has led to the development of LT receptor antagonists, a drug class that acts by binding to CysLT1 and CysLT2, thus blocking their activation and the subsequent inflammatory cascade.

Zafirlukast, panlukast, and montelukast have all been approved for the treatment of asthma in adults and older children, but only montelukast is approved for use in preschool children in most industrialized countries. It is available in formulations that are suitable for young patients (i.e., granules or chewable tablets) and, although the summary of product characteristics lists sleep disturbances, headache, abdominal pain, and diarrhea as adverse effects, it is generally well tolerated. Bisgaard et al. evaluated the safety and tolerability data collected up to 2009 in published and unpublished placebo-controlled, double-blind, pediatric trials, and their active-controlled, open-label extension or extended studies [66], which involved a total of 2751 patients aged between 6 months to 14 years. Only a minority of the enrolled children experienced mild and transient adverse events such as upper respiratory infections, worsening asthma, and pharyngitis, and their incidence and severity was no different in the patients treated with montelukast, placebo or active control drugs. Moreover, as the safety profile of montelukast did not change with long-term use, it was confirmed that this drug could be used in children of any age without any substantial risk. However, despite these positive assumptions and the clinical demonstration that the drug can be as beneficial as inhaled steroids, the available data do not indicate whether its effects may be different depending on the wheezing phenotype. Only some of the studies observed a slightly greater benefit in children with a positive API. In comparison with placebo, the continuous administration of montelukast 4 -- 5 mg/kg once a day for 12 months to children aged 2 -- 5 years with a history of repeated attacks of EVW reduced the rate of asthma exacerbations by 31.9% [67]. The average rate of new wheezing episodes per patient in the montelukast and placebo group was, respectively, 1.60 and 2.34 per year (p < 0.001). The drug also delayed the median time to the first exacerbation by approximately 2 months (p = 0.024), and reduced the rate of inhaled corticosteroid courses (p = 0.027). However, about 30% of the children enrolled in this study had a history of atopic dermatitis, allergic rhinitis, or evidence for specific IgE against an inhalant allergen, which suggests that a proportion of the study population probably had persistent asthma rather than EVW, and should have been considered as having MTW. The intermittent use of monteleukast has led to only partially positive results. Robertson et al. studied 220 children with EVW aged 2 -- 14 years (107 treated with montelukast 4 mg/kg once a day, and 113 treated with placebo) in a 12-month, multicentre, randomized, double-blind, and placebo-controlled clinical trial [68]. The patients were treated by their parents at the onset of each RTI or asthma symptoms, and the treatment was continued for a minimum of 7 days or until the symptoms had disappeared for 48 h. During the study period, there were 681 treated wheezing episodes: 345 in the montelukast group and 336 in the placebo group. The patients in the montelukast group made unscheduled use


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of healthcare resources because of asthma on 163 occasions, as against 228 in the placebo group. Symptoms were reduced by 14%, nights with awakenings by 8.6% (p = 0.043), days off from school or childcare by 37%, and parent time off from work by 33% (p < 0.0001 for both). On the contrary, there was a nonsignificant reduction in specialist attendances and hospitalizations, episode duration, and the use of a b-agonist and prednisolone. Similarly, Bacharier et al. obtained only partially positive results in children aged 12 -- 59 months with supposed EVW (but in some cases a positive API) who, together with albuterol, received montelukast 4 mg/kg once a day, highdose inhaled budesonide (1 mg) or placebo for 7 days at the first sign of RTI [69]. During the 12-month trial, there was no between-group difference in the proportion of episodefree days, oral corticosteroid use, healthcare use, or the quality of life. However, montelukast slightly reduced troubled breathing and interference with activity scores during RTI, particularly in the patients with a positive API. The possible efficacy of montelukast in preschool children with atopic wheezing is suggested by data collected by Straub et al., who administered the drug to 30 children aged 2 -- 5 years with newly diagnosed asthma, a positive firstdegree family history of asthma, and a positive allergy test result [70]. All of the patients underwent exhaled NO and airway resistance measurements (using the interrupted technique) before and after the run-in period, and after 4 weeks’ treatment with montelukast 4 mg once daily. There were no significant differences in any of the parameters before and after the run-in period, but treatment led to significantly lower mean exhaled NO (p < 0.001) and airway resistance (p = 0.01). Finally, Kooi et al. found that 3 months’ treatment with montelukast reduced circulating eosinophil levels in a small group of children (the majority of whom seem to have been atopic), thus confirming the drug’s anti-inflammatory properties although there was no effect on lung function [71]. 6.

Antibiotics

Mycoplasma pneumoniae and C. pneumoniae infections are frequent in older children and adults with chronic asthma, and in subjects with asthma exacerbation [72]. The recently identified CARDS toxin of M. pneumoniae seems to provide a convincing mechanism for its pathogenic effect on the airways [73], but the role of these atypical bacteria in initiating wheezing episodes is not clear and there is insufficient evidence concerning their role in preschool children with recurrent EVW or MTW. A number of studies have found that macrolide and tetracycline antibiotic treatment has a beneficial effect on lung function and exacerbations in patients with chronic pulmonary infections due to atypical bacteria [74], and it has been reported that the administration of clarithromycin to school-age children with recurrent wheezing and atypical bacterial infection can limit the number of new 948

recurrences [74] and reduce cytokine and chemokine concentrations in respiratory secretions [75]. However, it has not been established whether the favorable effect of these drugs depends on their antibacterial activity or their well-defined anti-inflammatory and immunomodulatory properties [76]. Macrolide administration in preschool children with wheezing is only reasonable in the case of documented infection due to such pathogens.

7.

Conclusion

Various continuously or intermittently administered oral or inhaled drugs could theoretically be effective in preventing or controlling wheezing in preschool children. However, the optimal management of acute wheezing episodes has yet to be determined, mainly because of the heterogeneity of the wheezing phenotypes. It has been shown that asthma is a very complex disease in older children, adolescents, and adults, and that similar clinical pictures can arise from the interplay of genetic, environmental, and other factors; it is, therefore, highly likely that the same is true of wheezing in preschool children. The problem is that identifying the factors conditioning the development of wheezing is significantly more difficult in younger children, and it is often impossible to identify the patients that might obtain a real benefit from treatment because they are potentially at higher risk of recurrences and persistent disease with progressive lung damage in later life. Distinguishing whether individual preschool children have EVW or MTW does not seem to assure the best pharmacological approach to wheezing because it does not take into account the heterogeneity of the wheezing disorders, as is demonstrated by the fact that most of the clinical trials evaluating drug efficacy in wheezing patients have switched a number of children from one group to another between enrolment and the final analysis. However, it is possible that attempts at phenotyping could be strengthened by describing the symptoms in more detail and acquiring more information concerning atopy [77]. On the basis of the available data, it can be suggested that preschool children with an acute episode of wheezing should be treated with inhaled short-acting b2-receptor agonists, regardless of the wheezing phenotype. The use of other routes of administration or long-acting preparations cannot be recommended because their efficacy, safety, and tolerability have not been adequately evaluated in the youngest patients, although ipratropium bromide may be added in the most severe cases. Whatever the phenotype, oral or inhaled steroids should not be routinely used, although exceptions may be made in the case of patients with documented rhinovirus infection, and those with very severe wheezing and risk factors for persistent asthma as assessed by a positive API, particularly if they have previously responded to oral steroids or are already on daily inhaled steroids for recurrent MTW.




In order to prevent recurrent wheezing, montelukast may be considered regardless of the phenotype. In the more severe cases of MTW, inhaled low-dose steroids may be given provided that linear growth is regularly monitored and the drug is discontinued after some months in order to evaluate whether it is really effective and required. In subjects with persistent symptoms, the addition of montelukast can be considered. Chromones are not indicated. Whatever treatment strategy is chosen, good multidisciplinary support and education are essential. It is necessary to reduce environmental exposure to tobacco smoke, and provide parents with educational programs aimed at improving their knowledge of asthma, and its prevention and treatment in order to reduce the incidence of RTIs and subsequent wheezing episodes [78]. Finally, in families with a history of atopy, allergen avoidance may be useful and can even be started prenatally [4]. 8.

Expert opinion

The phenotype-directed treatment of wheezing in preschool children is limited by our inability to differentiate the phenotypes accurately, as shown by the substantial failure of attempts to characterize them on the basis of wheezing triggers and persistence of respiratory symptoms between wheezing episodes, and to use the results for purposes of prevention and therapy. It is currently not possible to draw any definite conclusions concerning the best approach to wheezing children. When faced with a preschool wheezing child, it is worth remembering that most children experiencing recurrent wheezing in the first years of life have mild episodes that disappear by the time they are 6 years old and are not followed by any deterioration in lung function. An aggressive pharmacological approach should be limited to the most severe and recurrent cases, particularly when reliable factors clearly indicate a positive API. Moreover, clinicians need to assess the risk--benefit ratio of specific treatment for individual patients, knowing that more symptomatic patients are more likely to receive a benefit. The knowledge that classifying wheezing as EVW or MTW is only partially useful in deciding whether and how drugs

should be administered to preschool children has promoted the search for new variables that might allow the more accurate distinction of wheezing phenotypes. One good example of this is the study by Just et al., who made a cluster analysis of a number of the most usual variables in 551 children with recurrent wheezing aged < 36 months [79] and, on the basis of gender, body mass index, maternal and paternal history of asthma, a history of allergic rhinitis, eczema or food allergy, wheezing severity, the efficacy of high doses of inhaled steroids, hospitalizations due to exacerbations, and the EVW and MTW classification, they identified three phenotypes with different outcomes for which different therapeutic approaches could be proposed. There was a cluster of children with mild episodic wheezing related only to respiratory infections; a cluster with asthmatic parents who experienced non-atopic, moderate-to-severe wheezing that remained uncontrolled despite high doses of inhaled steroids; and a third cluster of cases of atopic MTW that included a large number of children with MTW (including patients with eczema) who had positive IgE tests for inhaled and/or food allergens and abnormal chest X-ray findings. These phenotypes will need to be confirmed by means of long follow-up studies aimed at verifying the most appropriate prophylactic and therapeutic approach to each. Moreover, as the identification of preschool wheezers who will develop asthma in later life is essential for providing parents with a prognosis of respiratory symptoms, and can help in guiding research into more guided treatment or prevention strategies, it will be necessary to improve the rules of prediction. This can be done by developing more precise definitions and measures and, ultimately, by learning more about the pathophysiological mechanism(s) of bronchial obstruction. The use of biomarkers and genomic risk profiles in order to develop personalized medicine might further improve asthma prediction, prevention, and treatment [80].

Declaration of interest The authors declare that they have no conflict of interest and have received no payment for preparing this manuscript. This review was supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009).


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Affiliation

Susanna Esposito† & Nicola Principi † Author for correspondence Universita` degli Studi di Milano, Department of Pathophysiology and Transplantation, Pediatric High Intensity Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milano, Italy Tel: +39 02 55032498; Fax: +39 02 50320206; E-mail: [email protected]

Classification and pharmacological treatment of preschool wheezing: changes since 2008.

Macrolides for Acute Wheezing Episodes in Preschool Children.

Recurrent wheezing in the preschool child.

Parental psychological distress during pregnancy and wheezing in preschool children: the generation R study.

Management of preschool recurrent wheezing and asthma: a phenotype-based approach.

Recurrent wheezing in children.

Methacholine challenge test by wheezing and oxygen saturation in preschool children with asthma.

Wheezing children.

Functional constipation in children: non-pharmacological approach.

Management of Preschool Children with Recurrent Wheezing: Lessons from the NHLBI's Asthma Research Networks.

The association between vitamin D status and the rate of exacerbations requiring oral corticosteroids in preschool children with recurrent wheezing.

Low-Cost, Scalable Classroom-Based Approach to Promoting Physical Activity in Preschool Children.

A novel approach to characterize physical activity patterns in preschool-aged children.

Wheezing in children with sickle cell disease.

Infection-induced wheezing in young children.

Wheezing in young children: WAITing for pharmacogenomics?

Vision screening in preschool children.

Vision screening in preschool children.

Managing wheeze in preschool children.

Vision screening in preschool children.

Pharmacological approach to diabetic macular edema.

The recurrently wheezing preschool child-benign or asthma in the making?

Contributors to Intelligibility in Preschool- Aged Children with Cerebral Palsy.

Advancing a multidimensional, developmental spectrum approach to preschool disruptive behavior.