What are the goals of treatment?
General Measures Assuming that an underlying diagnosis has been excluded as far as possible, and the child is thought to have asthma, the next question is what treatment should be instituted. Before any pharmacotherapy is contemplated, attention should be turned to the environment. Smoking and vaping should be strictly avoided. Where possible, exposure to indoor and outdoor pollution should be minimised. If the child is sensitized to any aeroallergens, exposure should be minimised.
Pharmacotherapy: general principles Reasons for initiation of pharmacotherapy therapy could be treatment of present symptoms, or prevention of progression to school age, atopic asthma. It was initially thought that since ICS are excellent in treating the symptoms of school age asthma, starting them very early would prevent atopic, allergic asthma developing at school age. However, three excellent randomised controlled trials (two of early initiation of continuous ICS [19, 20], one of intermittent ICS just at the time of viral wheeze [21]) have shown that there is no effect on long-term asthma outcomes. So unlike in school age asthma, where failure to institute ICS therapy in children having multiple asthma attacks is associated with a less favourable pattern of growth in spirometry [22], there is no need to institute preventive therapy unless it is needed to control present symptoms. Indeed, inappropriate use of ICS may actually worsen airflow obstruction [20].
Pharmacotherapy: bronchodilators In clinical practice, lung function tests are infrequently used to guide treatment response, and the paediatrician has to rely on auscultation or changes in oxygen saturation. First line therapy is with either or both of short-acting β-2 agonists or anticholinergics (Ipratropium) administered via a large volume spacer and mask (or a mouthpiece in those age three years and over). Experience is that response is variable to both these agents, and empirical trials are the best that can be offered. However, before prescribing any inhaled medications it is important to be sure that treatment is actually indicated – administering inhaled medications to a fractious and vigorous toddler is not easy, and if the child is only making a noise when breathing, with no respiratory distress or increased work of breathing, then the question arises, are we trying to treat the child or the parents?
A recent small study explored the use of the anti-muscarinic agent tiotropium in preschool wheeze [23]. This was a 48 week, open-label parallel-group randomised controlled trial in children aged between six and 35 months, who had suffered at least two episodes of doctor-confirmed wheeze with or without dyspnoea. Children were randomised during a respiratory tract infection to either tiotropium 5 µg once daily for seven-14 days (n=27), or as needed short-acting β-2 agonists (n=28) or twice daily fluticasone propionate 125 µg and as needed short-acting β-2 agonists (n=25) for the same time period. The primary outcome was the proportion of episode-free days. The tiotropium regime was significantly better than either of the others, with more symptom free days, and patients less likely to discontinue treatment. However, it is a relatively small study, requires confirmation and tiotropium needs to be licensed before it can be widely recommended for this indication.
Clearly if a spacer is to be used, correct technique and education is essential; and most children aged three years and older can use a mouthpiece. Medication must be administered during quiet breathing – a crying infant guarantees that no medication will be deposited in the lower airway. Unsurprisingly, adherence is often poor [24].
Pharmacotherapy: leukotriene receptor antagonists Montelukast is popular and widely prescribed, but the evidence base is weak and the side-effect profile unfavourable. The theoretical basis is sound, cysteinyl leukotrienes are released during viral infections and are pro-inflammatory; but they just do not work for the majority. Respiratory viral infections cause elevations in cysteinyl leukotrienes [25], and treatment with intermittent or continuous montelukast has been suggested. However, recent trials [ 26-29] are discouraging (Table 4). The two largest recent trials [28, 29], recruiting over 3000 children, have failed to show benefit for either intermittent or continuous montelukast. Anecdotally a few pre-school wheezers respond to montelukast, but most do not. A therapeutic trial may be considered, but unless there is clear benefit it should be discontinued. Parents should be warned about the behavioural side-effects of montelukast which have a prevalence of around 20% and can be very distressing [30]. Hence, for most pre-school wheezers, montelukast is not useful.
Pharmacotherapy: macrolide antibiotics Azithromycin has been most studied in this context; it has a complex portfolio of antibiotic and anti-inflammatory properties [31]. Although it was once thought that exacerbations of wheeze were driven solely by respiratory viruses, the role of bacteria has attracted increasing attention. Adults with viral colds and a positive upper airway bacterial culture treated with co-amoxyclav had a significantly shorter duration of symptoms [32]. In a study of acute wheeze in children and adults, bacteria and viruses were equally likely to be cultured from the upper airway [33]. However, because bacteria are present does not mean they are of pathophysiological significance; it might merely be that viral infection causes a transient local immune paresis leading to secondary bacterial colonization. In this setting, three studies attempted to determine whether azithromycin was a useful treatment in pre-school wheeze. A Danish study [34] recruited 72 children age 1-3 years who had a total of 158 of what were termed “asthma-like episodes” lasting at least 3 days. They were randomised to a three-day course of either azithromycin or placebo. Symptom duration was less in the azithromycin group, especially if treatment was started less than 6 days after the onset of symptoms. No bacterial cultures results were reported in most children. In a larger study, 607 children (12-71 months) who had been acutely ill enough to have previously been prescribed at least one prednisolone burst and had no interval symptoms were randomised to azithromycin or placebo, and fewer further prednisolone bursts were given in the azithromycin group [35]. A third large study was completely negative; 300 children aged 1-5 years were randomised to azithromycin or placebo in the emergency room, and there was no effect of active treatment [36].
Is there then a role for azithromycin in pre-school wheeze? If azithromycin is prescribed indiscriminately to children with trivial symptoms, macrolide resistance in the community will rise dramatically [37]. Perhaps a trial of azithromycin is warranted in pre-school children with wheeze so severe that they require at least intravenous treatment and oxygen, and only continued if it prevents hospital admission. It is unclear whether any effects of azithromycin are immunomodulatory or antibacterial [31].
Pharmacotherapy: ICS The major relevant studies are summarised in Table 5 [27, 38-40]. ICS may be prescribed either as intermittent or continuous therapy. A very high dose intermittent strategy reduced the use of prednisolone, but at a cost of growth suppression [39]; the efficacy of lower doses (e.g. beclomethasone equivalent 400 mcg/day) is less clear. Neither continuous inhaled or nebulized steroids prevent EVW. If attacks are really so severe that it is felt that something must be done then a of trial ICS for a defined and well monitored period (Dutch regime) may be indicated [41], especially if parental under-reporting of interval symptoms is suspected. However they should be discontinued if as is likely, there is no benefit. The indications for targeted ICS therapy are discussed in more detail below.
Pharmacotherapy: oral corticosteroids The use of oral corticosteroids for acute wheeze in school age children is not controversial. A large study randomised pre-school children who had been admitted to hospital to placebo or prednisolone to be given by the parents at the next wheeze attack; no benefit was seen [42]. From this study, it is clear that pre-school children with acute wheeze which is insufficiently severe to merit admission to hospital do not need to be prescribed oral corticosteroids. A subsequent study in children with acute pre-school wheeze who were admitted to hospital showed that the duration of admission was not significantly shortened by administering oral prednisolone [43]. A subsequent meta-analysis of 1773 children in 11 studies confirmed that in most contexts oral prednisolone was not useful in acute preschool wheeze [44]. Surprisingly, a subsequent study of 624 patients randomised to placebo or prednisolone in the emergency department, [45] the prednisolone group had a shorter admission time (170 minutes, p=0.0227 – exactly the same time shortening as in the previous study, which was not statistically significant!). The design of this latter study was severely criticised [46]. In terms of parental preference, I suspect most families would think an extra time period of less than three hours in hospital a small price to pay for the avoidance of a course of prednisolone.
Which pre-school child with acute wheeze who is admitted to hospital should be prescribed oral prednisolone? I suggest that most do not, but systemic steroids are only indicated in really severe pre-school wheeze requiring treatment in a High Dependency Unit. There is no dolubt they have been over-prescribed in the past (and this still continues).