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).