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\begin{document}

\title{Basic Clinical Management of Preschool Wheeze}



\author[1]{Andrew Bush}%
\affil[1]{Imperial College Business School}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Pre-school wheeze is very common and often difficult to treat. Most
children do not require any investigations, only a detailed history and
physical examination to ensure an alternative diagnosis is not being
missed; the differential diagnosis, and hence investigation protocols
for the child in whom a major illness is suspected, shows geographical
variation. The pattern of symptoms may be divided into episodic viral
and multiple trigger to guide treatment, but the pattern of symptoms
must be re-assessed regularly. However, symptom patterns are a poor
guide to underlying pathology. Attention to the proper use of spacers,
and adverse environmental exposures such as tobacco smoke exposure, is
essential. There are no disease-modifying therapies, so therapy is
symptomatic. This paper reviews recent advances in treatment, including
new data on the place of leukotriene receptor antagonists, prednisolone
for acute attacks of wheeze and antibiotics, based on new attempts to
understand the underlying pathology in a way that is clinically
practical.%
\end{abstract}%



\sloppy


\textbf{Basic Clinical Management of Preschool Wheeze}

\textbf{Andrew Bush MB BS (Hons) MA MD FRCP FRCPCH FERS FAPSR}

\textbf{Professor of Paediatrics and Head of Section (Paediatrics),
Imperial College}

\textbf{Professor of Paediatric Respirology, National Heart and Lung
Institute}

\textbf{Consultant Paediatric Chest Physician, Royal Brompton Harefield
NHS Foundation Trust.}

\textbf{Correspondence: Department of Paediatric Respiratory Medicine,
Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.}

AB was supported by the NIHR Respiratory Disease Biomedical Research
Unit at the Royal Brompton and Harefield NHS Foundation Trust and
Imperial College London

I have no financial or other conflict of interest with regard to this
manuscript

\begin{itemize}
\tightlist
\item
  \textbf{Tel: -207-351-8232}
\item
  \textbf{Fax: -207-351-8763}
\item
  \textbf{e mail:- a.bush@imperial.ac.uk}
\item
  \textbf{ORCID -}0000-0001-6756-9822
\end{itemize}

\textbf{Abstract} Pre-school wheeze is very common and often difficult
to treat. Most children do not require any investigations, only a
detailed history and physical examination to ensure an alternative
diagnosis is not being missed; the differential diagnosis, and hence
investigation protocols for the child in whom a major illness is
suspected, shows geographical variation. The pattern of symptoms may be
divided into episodic viral and multiple trigger to guide treatment, but
the pattern of symptoms must be re-assessed regularly. However, symptom
patterns are a poor guide to underlying pathology. Attention to the
proper use of spacers, and adverse environmental exposures such as
tobacco smoke exposure, is essential. There are no disease-modifying
therapies, so therapy is symptomatic. This paper reviews recent advances
in treatment, including new data on the place of leukotriene receptor
antagonists, prednisolone for acute attacks of wheeze and antibiotics,
based on new attempts to understand the underlying pathology in a way
that is clinically practical.

\textbf{Keywords:} Atopy, prednisolone, leukotriene receptor antagonist,
azithromycin, tiotropium

\textbf{Introduction}

The epidemiology of pre-school wheeze is covered in detail elsewhere in
this series. In brief, this is a common problem with few solutions. In
the UK, the greatest burden of hospitalisations for wheeze is on
children age less than 5 years old {[}1,2{]}.~Most suffer from recurrent
episodic, commonly viral induced attacks (EVW). Most remit over time
{[}3{]}.~Worldwide, preschool wheeze is a problem in all environments
{[}4{]}, which makes it all the more disappointing that we have so few
evidence based, personalised treatments

The treatment of preschool wheeze, especially the role of inhaled
corticosteroids (ICS), has been be-devilled by the mindless ``at what
age can asthma be diagnosed?''. Clearly the answer depends on the
definition of asthma {[}5{]}. The \emph{Lancet} Asthma Commission cut
through this by defining asthma purely clinically, wheeze, chest
tightness, breathlessness and sometimes excessive cough {[}6{]}. This is
because asthma is considered an umbrella term like anaemia (low
haemoglobin) and arthritis (hot, painful joints). As with anaemia and
arthritis, so with asthma, the next question is, ``what sort of asthma
has this child got?'' with a specific focus on treatable traits {[}7{]}
(Table 1). Notably, the treatable trait approach should be extended
beyond pulmonary disease; description of the detailed management of
extrapulmonary and social/environmental treatable traits is outwith the
scope of this review. However consideration of these traits is necessary
for the holistic management of the child Thus, asthma can be diagnosed
at any age if a good history is taken, but the underlying endotype will
vary across the life course. In preschool wheeze, the key treatable
traits are the presence or otherwise of eosinophilic airway
inflammation, bronchodilator responsiveness, and bacterial airway
infection. Thus the management approach set out in this review draws on
this paradigm to determine treatment options. Preschool is defined as
age 2-5 years inclusive. Very little is known about the pathophysiology
and management of wheeze in the first year of life {[}8{]}. We do know
that there is no evidence of airway inflammation in these very young
children, even if they are really severely affected, atopic and with
documented acute bronchodilator reversibility {[}9{]}; it is thus very
difficult to justify any prescription of ICS in wheezing babies.

\textbf{Clinical approach to the pre-school child referred with wheeze
and cough}

The first step is to determine what respiratory noises are being
described by the parents. The word ``wheeze'' is used by parents in the
UK at least to describe many different sounds, including the true
musical polyphonic noise of diffuse airway narrowing, upper and lower
airway crackling noises, and even stridor. The use of a
video-questionnaire may help determine this {[}10, 11{]}. Asking the
parent to record what they hear on their mobile phone may be useful.
Many medical professionals cannot be relied on to diagnose wheeze
{[}12{]}, and a healthy scepticism is indicated until the noise has been
assessed by a really experienced professional. In the future, hand-held
detectors with the data downloaded to a smartphone given to the family
may be helpful in resolving this conundrum. If in fact the child has a
chronic wet cough, then investigations need to be directed to confirming
or otherwise persistent bacterial bronchitis {[}13{]} and bronchiectasis
{[}14, 15{]}, both themselves umbrella terms {[}16{]}, and the
underlying cause thereof, which is beyond the scope of this review.

There are five main groups of causes of chronic respiratory symptoms in
preschool children (Table 2) {[}17{]}. It is important to appreciate the
extent of respiratory symptomatology in normal children {[}18{]}.
Isolated dry cough in an otherwise well child rarely betokens a
significant diagnosis. Asthma should not be diagnosed if cough is the
sole symptom, with no breathlessness, chest tightness or wheeze; neglect
of this rule has led to over-diagnosis and over-treatment of ``cough
variant asthma''. All normal children cough; intermittent wet cough in
association with viral colds, with complete recovery between colds, is
normal; and a normal preschool child may have more than ten colds/year
with symptoms lasting 2-3 weeks each time {[}18{]}. In my practice, this
``Nursery School syndrome'' is very common; the child is placed early
into a childcare facility, by often first-time parents. As a result, the
child (and the parents!) gets a succession of viral colds with very few
healthy days in between each cold. These do not respond to inhalers or
antibiotics; reassurance is what is needed. A prolonged but gradually
clearing post-bronchiolitic syndrome of cough and wheeze is also
commonly seen in an otherwise normal child. Red flags are progressive
symptoms with no symptom free intervals, and a chronic wet cough with no
periods of remission.

Although most pre-school children with cough and wheeze are normal or
have pre-school asthma, in a few these symptoms betoken a serious
disease. The differential diagnosis shows geographical differences, for
example compression of the large airways by tuberculous lymph nodes is
common in endemic areas. Clues on history and physical examination are
shown in Table 3. Most pre-school children with wheeze are managed just
on the basis of history and physical examination. If investigations are
performed, they should be focussed and address two questions, ``can I
confirm or exclude an underlying diagnosis?'' and ``what sort of asthma
does this child have?'' (This last is addressed later in the review)
There is no place for doing many investigations in the hope that
something will turn up.

\textbf{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
\selectlanguage{greek}β-\selectlanguage{english}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
\selectlanguage{greek}µ\selectlanguage{english}g once daily for seven-14 days (n=27), or as needed short-acting \selectlanguage{greek}β-\selectlanguage{english}2
agonists (n=28) or twice daily fluticasone propionate 125 \selectlanguage{greek}µ\selectlanguage{english}g and as
needed short-acting \selectlanguage{greek}β-\selectlanguage{english}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).

\textbf{Treatment approaches: symptom-based treatment}

The 2008 European Respiratory Society Task Force proposed dividing
pre-school wheezers into EVW and ``multiple trigger (MTW)'' wheeze
{[}3{]}. Both EVW and MTW were characterised by symptoms present only
with a (usually clinically) diagnosed viral respiratory tract infection,
but in MTW there were also symptoms between viral infections, triggered
by, for example, exposure to allergens to which the child was
sensitised, and excitement. It was made clear that EVW was not the same
as transient wheeze, and could persist beyond school age, and MTW was
not the same as persistent wheeze, and could be transient. Furthermore,
it was clear that the pattern of wheeze could change spontaneously over
time, and with treatment (MTW treated with ICS could present as EVW).
MTW was often but not exclusively associated with atopic disease and
allergen sensitisation, whereas EVW was usually not. Intermittent
therapy was the recommendation for EVW, whereas children with MTW were
considered for continuous ICS therapy. However, the obvious weaknesses
of this approach are that there is heavy reliance on parental reporting
of symptoms, and the underlying endotype was not even considered, let
alone measured. The 2012 update {[}41{]} recognised the reliance on
parental reporting and recommended that an N-of-1 trial of ICS was
reasonable in EVW if symptoms were very severe or parental
under-reporting of symptoms was suspected but discontinuing if there was
no benefit. However, there was still no attempt to tailor treatment to
underlying pathology, and it should also be said that just because
symptoms are severe is not a reason to try a treatment which does not
work! Proposed treatment algo rhythms have been published, but these
remain symptom based {[}47{]}.

However, when symptom pattern is compared to pathology, it was very
clear that both EVW and MTW could have BAL eosinophilia or a normal BAL,
and atopy was also not predictive of BAL findings {[}48{]}. This may
reflect the difficulties of symptom perception and recall by parents.
Whatever the reason, it became increasingly clear that history taking is
an inadequate guide to treatment.

\textbf{Treatment approaches: personalising therapy using biomarkers}

The first serious attempt to personalise therapy was the INFANT study,
using peripheral blood eosinophil count and aeroallergen sensitization,
both readily available in the clinic {[}49{]}. 300 children age between
12 and 59 months prescribed step two treatment were recruited from 18
sites in the USA. They received in a blinded, three-way crossover trial
in random order either daily ICS, daily montelukast or as needed ICS and
short acting \selectlanguage{greek}β-\selectlanguage{english}2 agonist. Each treatment period was 4 months, with the
first two weeks of data in each treatment arm being discarded in lieu of
a washout period which was thought to be unethical. The primary endpoint
was a composite outcome of asthma control days and time to attack
requiring oral corticosteroids. They prespecified that aeroallergen
sensitization, gender and wheeze attacks would predict a differential
treatment response; the use of blood eosinophil count was
a\emph{post-hoc} analysis. Sixty of 300 improved spontaneously, and
unsurprisingly there was no differential response to treatment; whatever
they received they did well. 170 children showed a differential
response, and in this group as a whole, regular ICS was the best option,
and montelukast the least good. When they divided the group by
aeroallergen sensitization, the non-sensitized patients (n=130) did
equally well (or badly) irrespective of treatment, whereas those
allergen sensitized (n=100) did best in the regular ICS arm. They then
carried out a post-hoc analysis, dividing the groups at the
semi-arbitrary cut point of a blood eosinophil count of 300 cells/\selectlanguage{greek}μλ.
\selectlanguage{english}Below this level, the treatment results were the same in all three arms
(n=82). Those with a count of 300 and above (n=71) were the group that
did best on regular ICS. Those who were both aeroallergen sensitized and
with a blood eosinophil count of at least 300 (n=64) were the group who
did best when prescribed regular ICS; in all others, treatment effects
were the same.

This study has opened the door to personalising treatment using two
simple biomarkers, but a note of caution must be sounded. The blood
eosinophil analyses were \emph{post-hoc} , and thus hypothesis
generating and requiring confirmation in a second study. The stability
of blood eosinophil count was not measured; at least in school age
children with asthma, sputum inflammatory biomarkers are not stable
{[}50{]}. The cut-off level of blood eosinophils needs thought; 300
cells/\selectlanguage{greek}μλ \selectlanguage{english}is the upper limit of normal for adults and used as an
indicator for Type 2 biologics, {[}51{]} but the upper limit of normal
in children is much higher {[}52{]}. Furthermore, elevated blood
eosinophil count may be caused by eczema or other atopic disease, or
parasitic infections. There are limited paediatric data showing
bronchoalveolar lavage and peripheral blood eosinophil counts correlate
{[}48{]} but probably the safest interpretation is that if blood
eosinophil count is normal, airway eosinophilia is unlikely; if high,
then one possible explanation is that the treatable trait of airway
eosinophilia may be present.

The use of biomarkers was further explored in a meta-analysis {[}53{]}
of three previously reported randomised controlled trials in 1074
children age 12-71 months (Table 6) {[}27. 35, 40{]}. Blood eosinophil
count and aeroallergen sensitisation were determined at the start of the
trial. The investigators determined the predictive value of different
blood eosinophil counts from \emph{\textgreater{}} 150 to 350 cells/\selectlanguage{greek}μλ.
\selectlanguage{english}Unsurprisingly, patients with eczema had higher blood eosinophil counts.
The risk of an exacerbation increased with increasing blood eosinophil
count, but the predictive value of a blood eosinophil count was low.
Prediction was improved if allergen sensitization was added to the
model, such that at any level of eosinophil count, allergen
sensitization was present. In children prescribed ICS, the predictive
effect of the two biomarkers was not clinically significant. Perhaps it
is unsurprising that these three studies did not give clearcut answers;
the treatments were randomised, not clinically prescribed, and this may
well have affected the findings.

Future work, in addition to validating the original INFANT observations,
will include optimising the eosinophil cut-off, including in areas of
high parasite burden, and exploring whether the addition of exhaled
nitric oxide (FeNO), as in adults {[}54{]}, will improve risk assessment
and personalising medicine. At the present time, it seems reasonable at
least in secondary care to measure both biomarkers and use them to guide
whether ICS are indicated -- specifically, if neither blood eosinophilia
nor aeroallergen sensitisation is present, it is probably right to
withhold ICS.

Whatever the biomarker status, if an N-of-1 trial of ICS is
contemplated, a three step protocol is advocated, to prevent transient
symptoms being interpreted as chronic. The steps are:

\begin{enumerate}
\tightlist
\item
  Commence ICS through an age-appropriate spacer; dose is arbitrary, but
  I would use a relatively high dose, beclomethasone 200 mcg twice daily
  on the basis that if the child does not respond, then a steroid
  sensitive airway disease is unlikely. The family is told that the
  treatment will be reviewed and discontinued after six weeks (again, an
  arbitrary time period). Ideally adherence should be monitored
  electronically
\item
  Review the child at six weeks. If there has been no response, then the
  treatable trait of airway eosinophilia is not present, and alternative
  diagnoses and management strategies should be sought. If the child is
  symptomatically improved, it is not clear whether this was
  spontaneous, or treatment related. This is resolved by a period off
  treatment.
\item
  Review again after 6-8 weeks. If the child is asymptomatic, no further
  action is needed. If symptoms have recurred, then ICS are re-started
  and titrated down to the lowest dose needed to control symptoms
\end{enumerate}

\textbf{Futuristic treatment approaches: beyond allergy and the
eosinophil}

Increasingly, attention is turning to the role of chronic bacterial and
viral infection in preschool wheeze. In a study of 35 severe preschool
wheezers who underwent bronchoscopy and bronchoapveolar lavage (BAL) at
a time of clinical stability {[}55{]}, 60\% had a positive bacterial
culture or viral detection, and 26\% had both. Unsupervised analysis
revealed two subgroups. One was positive for \emph{Moraxella
catarrhalis} with marked BAL neutrophilia, the second was a mixed
microbiota picture. Although there was a tendency for EVW patients to be
in the \emph{Moraxella} group, in general there was very poor agreement
between symptom patterns and BAL findings.

We also performed a larger analysis of 136 children aged 1-5 years, of
whom 105 had recurrent severe wheeze-RSW and 31 had non-wheeze
respiratory disorders (the best control group we could find, since
normal children cannot ethically undergo bronchoscopy {[}56{]}. We
measured peripheral blood leukocyte counts, and specific IgE to common
inhalant and food allergens. We defined allergic sensitization as
allergen-specific IgE [?]0.35 kUA/L to at least one allergen tested. All
children underwent a clinically indicated bronchoscopy, BAL, and
endobronchial biopsy. Bacterial culture, multiplex PCR to 20 viruses
and\emph{Mycoplasma} were performed on BAL. Data were analysed by the
Partition Around Medoids algorithm coupled with Gower's distance for
mixed data. Clinically, 30/105 of the severe wheeze patients had EVW,
and 44/105 as MTW; 28 patients could not be classified as either, again
underscoring the weakness of clinical phenotyping. Eight variables were
used to determine the clusters, namely blood and BAL neutrophil and
eosinophil counts, atopy, whether viral PCR and bacterial culture were
positive, and whether ICS had been prescribed (it was considered
unethical to stop treatment in these very fragile patients). We
identified four clusters on 134/136 children, which ore no relationship
to symptom pattern. All patients in cluster 1 were sensitized; they had
the highest blood eosinophils (mean=5.54\%, SD=2.86\%), the highest rate
of ICS use (91.7\%), and moderate rates of bacterial culture positivity
(69.5\%, especially \emph{Moraxella} ) and viral detection (56.5\%).
Cluster 2 was characterised by low BAL neutrophils (mean=9.44\%,
SD=13.89\%), and a low rate of positive bacteriology (17.1\%) ad viral
detection (15.0\%). All were prescribed ICS. In cluster 3 there was the
highest rate of positive bacterial cultures (\emph{H. Influenzae, Staph
Aureus, Strep. pneumoniae} ) ad viral infection (96.8\% \& 86.7\%,
respectively), and the highest level of bAL neutrophils (mean=31.7\%,
SD=25.11\%); 67.7\% were prescribed ICS. Finally, no-one in cluster 4
was prescribed ICS, and most were non-atopic with persistent cough not
wheeze.

A number of things need to be considered when interpreting this first
preschool wheeze cluster analysis. This is a highly selected group of
children with really severe wheeze who have failed to respond to
therapy. There needs to be another validation cohort. We could not
ethically stop treatment. We do not know how well the families were
adherent to treatment or how much of the prescribed dose was actually
deposited in the lower airway. Hence the effect of any prior ICS
prescription on pathology, especially airway eosinophilia, cannot be
determined. We also do not know stability of phenotypes over time.
However, what this study does do is to turn the spotlight firmly on
infection, in at least some children. The relationship between disease
and infection is unclear. One hypothesis is that chronic infection
causes wheeze; another that infection is merely a marker of underlying
topical immunosuppression which is the underlying cause of wheeze. It is
also possible to hypothesise that ICS may be causing topical
immunosuppression and thus allowing infection to become chronic.

This study points to possible cluster-based treatments (Table 7). It
must be stressed that this is speculative, and the approach needs to be
subjected to testing with randomised controlled trials before it can be
recommended. However it is hoped that considering this will broaden the
reader's perspective on the aetiology of preschool wheeze.

\textbf{Is phenotype-based treatment practical?}

This was studied in a proof-of-concept, randomized trial {[}24{]}. Sixty
children aged 1-5 years with at least two wheeze attacks in the previous
year were categorized on history as EVW or MTW. The intervention group
was prescribed ICS if blood eosinophils [?]3\%, or targeted antibiotics if
there was a positive culture on induced sputum or cough swab, compared
with a control group receiving standard care. The primary outcome was
unscheduled health care visits over 4 months. There was no relationship
between EVW, MTW and either blood eosinophils, atopic status or
infection. Median blood eosinophils were 5.2 (range 0-21)\%, 27 of 60
(45\%) children were atopic, and 8 (13\%) had airway bacterial
infection. 67\% in each group were prescribed ICS. There was no
difference in the primary end point between groups. Median ICS adherence
was 67\% in the 50\% of patients who returned adherence monitors. Also,
parents were reluctant to change treatment during the winter viral
season, when these patients were recruited; reluctance to change is also
a feature of adult studies {[}57{]} and is a factor that needs to be
overcome. In summary, clinical phenotype was unrelated to allergen
sensitization or blood eosinophils. ICS treatment determined by blood
eosinophils did not impact outcomes, but ICS adherence was poor.

\textbf{How do we measure success of treatment?}

Patient reported outcomes (PROMs) highlight what is important to the
patient (``can I get upstairs?'') rather than what is conventionally
measured by physicians, e.g. changes in spirometry, and are increasingly
used in clinical practice and research {[}58{]} . They need to be
co-designed with families. Unfortunately, currently none such exist for
preschool wheeze. Disease control can be assessed by the Test for
Respiratory and Asthma control {[}59{]}~and the Paediatric Asthma
Quality of life questionnaire in children age over 2 years. There are
versions designed for parentsto answer {[}60, 61{]},~and instruments
assessing the severity of attacks and parental feelings during the
episode{[}62, 63{]}.~Developing PROMs for pre-school wheeze is an
important research priority.

\textbf{Summary and Conclusions}

Basic management requires the paediatrician to determine that wheeze is
really present, and that an underlying diagnosis is not being missed.
Symptom based assessments bear little relationship to the presence or
otherwise of the treatable trait of airway eosinophilia. We are
beginning to appreciate that chronic bacterial infection may also be
important, and perhaps some patients will benefit from targeted
antibiotics. A proposed treatment algorithm is shown in the Figure
{[}47{]}. The future must be phenotype not history-based treatment, but
it will be essential to convince parents of the merits of this approach.

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\item
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\end{enumerate}

\textbf{Table1} Examples of treatable traits in pre-school wheeze
{[}based on reference 7{]}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Treatable trait}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Treatment}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{What treatment success looks like}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Airway}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Eosinophilic airway inflammation Reversible airflow obstruction due to
smooth muscle constriction Airway bacterial infection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
ICS Salbutamol Ipratropium ?Tiotropium Antibiotics\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Fewer and less severe wheeze attacks Improved quality of life Less
severe wheeze attacks Improved quality of life Eradication of infection
Fewer and less severe wheeze attacks Improved quality of life\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Extra-pulmonary}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Obesity Gastro-oesophageal reflux Unsafe swallow Rhinitis Eczema Food
allergy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Weight reduction May be coincidental PPI Thicken feeds Antihistamine
Nasal steroids Emollients Topical steroids Avoidance\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Restore normal BMI Fewer wheeze attacks and better quality of life Fewer
wheeze attacks and better quality of life Improved symptoms Rash and
itching resolved No allergic reactions\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Social/} \textbf{Environmental}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Nicotine exposure (tobacco or vapes) Exposure to allergens to which
child sensitised\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Refer to smoking cessation clinic Allergen avoidance, including pet
removal\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Exposure ceases, fewer attacks and better quality of life Exposure
ceases, fewer attacks and better quality of life\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BMI, body mass index; ICS, inhaled corticosteroids; PPI,
proton pump inhibitors

\textbf{Table 2} A pre-school child with cough or wheeze will fall into
one of these five categories {[}17{]}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{Diagnostic category}\strut
\end{minipage} & \begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{Examples}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Normal child (the hardest diagnosis!)\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Recurrent viral colds Pertussis ``Nursery School Syndrome'' (see
text)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Serious illness\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Will show regional variation; includes cystic fibrosis, bronchiectasis,
interstitial lung disease, tuberculosis\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
An `asthma syndrome'\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Episodic viral wheeze Multiple trigger wheeze\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Minor mimics or exacerbators of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Allergic or infective rhinitis Gastro-oesophageal reflux\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Over-anxious parents\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Often first-time parents who do not appreciate the range of normality
Find out if they have some concealed fear, e.g. a friend's child died of
leukaemia having had a non-specific presentation\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3} Red flags on history and physical examination which
should prompt consideration of more detailed investigations {[}17{]}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Red Flags on the History} & \textbf{Red Flags on the Physical
examination}\tabularnewline
\midrule
\endhead
\vtop{\hbox{\strut Prominent upper airway symptoms Symptoms from first
day of life}\hbox{\strut Sudden onset symptoms, which always suggests a
foreign body}\hbox{\strut Chronic moist cough/sputum \textgreater{}8
weeks duration every day}\hbox{\strut Worse after meals, irritable
feeder, arches back, vomits, suggests gastro-oesophageal
reflux}\hbox{\strut Systemic illness or
immunodeficiency}\hbox{\strut Continuous, unremitting symptoms}} &
\vtop{\hbox{\strut Clubbing, weight loss, failure to
thrive}\hbox{\strut Upper airway disease -- tonsillar hypertrophy,
rhinitis, nasal polyps which last mandates consideration of cystic
fibrosis}\hbox{\strut Unusually severe chest
deformity}\hbox{\strut Fixed monophonic wheeze, stridor, asymmetrical
signs}\hbox{\strut Signs of cardiac or systemic disease}}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4} Recent large trials of montelukast in episodic wheeze\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Author}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Numbers}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Result}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Robertson et al {[}26{]}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Intermittent ML vs. placebo\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
220\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Intermittent ML superior to placebo\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Bacharier et al {[}27{]}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Intermittent ML vs. intermittent nebulised BUD vs. placebo\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
238\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Intermittent ML and nebulized BUD equivalent and better than
placebo\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Valovirta et al {[}28{]}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Intermittent ML vs. continuous ML vs. placebo\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1771\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
No benefit of either ML regime\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Nwokoro et al {[}29{]}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Intermittent ML vs. placebo Sub analysis by \emph{ALOX5} promoter
polymorphisms\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1346\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
No benefit of ML Possible benefit of ALOX5 promoter genotyping\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: ALOX, Arachidonate 5-Lipoxygenase; BUD =budesonide;
ML=montelukast\textbf{Table 5} Relevant studies of ICS in episodic
wheeze in preschool children\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Author} & \textbf{Intervention} & \textbf{Numbers} &
\textbf{Result}\tabularnewline
\midrule
\endhead
Wilson et al {[}38{]} & Regular inhaled BUD 200 mcg bd vs. placebo & 40
& No effect of BUD on episodes of wheeze\tabularnewline
Bacharier et al {[}27{]} & Intermittent ML vs. intermittent nebulised
BUD vs. placebo & 238 & Intermittent ML and nebulized BUD equivalent and
better than placebo\tabularnewline
Ducharme et al {[}39{]} & Intermittent FP 1.5 mg/day vs. placebo & 129 &
Less use of prednisolone in FP group\tabularnewline
Zeiger et al {[}40{]} & Intermittent nebulized BUD vs. continuous
nebulized BUD (no placebo) & 278 & No difference between the
regimes\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BUD=budesonide; FP=fluticasone propionate; ICS=inhaled
corticosteroids\textbf{Table 6} Trials re-analysed to study the effect
of biomarker driven treatments in preschool wheeze\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Bacharier et al.} {[}27{]}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Zieger et al.} {[}40{]}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Bacharier et al.} {[}35{]}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Number enrolled}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
238\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
278\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
607\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Age (months)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12-59\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12-53\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12-71\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Entry criteria}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\emph{\textgreater{}}2 clinically significant wheeze attacks\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\emph{\textgreater{}1} clinically significant wheeze attacks Positive
API\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\emph{\textgreater{}}2 clinically significant wheeze attacks\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Duration (weeks)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
52-78\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Intermittent ICS, or intermittent LTRA, vs. placebo during respiratory
illnesses\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Daily ICS versus ICS only during respiratory illnesses\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Azithromycin vs. placebo during respiratory illnesses\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: API, asthma predictive index; ICS, inhaled
corticosteroid; LTRA, leukotriene receptor antagonist

\textbf{Table 7} Hypothetical cluster-based treatments for preschool
wheeze. Note that this is a speculative analysis, and needs testing in
prospective randomised controlled trials {[}56{]}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Nature of cluster}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Possible treatment}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textbf{Cluster 1}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Highly atopic and eosinophilic\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
ICS ?Type 2 biologics or omalizumab\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Cluster 2}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Low BAL neutrophils, no infection\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
LAMA\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Cluster 3}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
No atopy, infection common\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Targeted antibiotics\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Cluster 4}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
No sensitization, infection or inflammation\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
LAMA\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BAL, bronchoalveolar lavage; ICS, inhaled
corticosteroids; LAMA, long-acting muscarinic agents

\textbf{Legend for figure} . Proposed treatment algorithm for the
treatment of pre-school wheeze. Adapted from Bush A, Saglani S. Medical
Algorithm: Diagnosis and Treatment of Pre-school Asthma {[}47{]}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/ALLERGY-algorithm-PSW-2019-Final-SS/ALLERGY-algorithm-PSW-2019-Final-SS}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

