Received: 2 February 2022 | Accepted: 31 May 2022

DOI: 10.1002/ppul.26027

REVIEW

Enigma variations: The multi‐faceted problems of

pre‐school wheeze

Grigorios Chatziparasidis1 | Andrew Bush2

1
Department of Paediatrics, Metropolitan
Hospital, Athens, and Primary Cilia Dyskinesia
Unit, University of Thessaly, Volos, Greece
2
Departments of Paediatrics and Paediatric
Respiratory Medicine, Royal Brompton
Harefield NHS Foundation Trust and Imperial
College, London, UK
Correspondence
Grigorios Chatziparasidis, Department of
Paediatrics, Metropolitan Hospital, Athens,
and Primary Cilia Dyskinesia Unit, University
of Thessaly, Volos, Greece.
Email: gchatziparasidis@gmail.com
Abstract
Numerous publications on wheezing disorders in children younger than 6 years have
appeared in the medical literature over the last decades with the aim of shedding
light on the mechanistic pathways (endotypes) and treatment. Nevertheless, there is
yet no consensus as to the appropriate way to manage preschool wheeze mainly
because of the lack of a clear definition of “preschool asthma” and the paucity of
scientific evidence concerning its underlying endotypes. A symptom‐based approach
is inadequate since the human airway can respond to external stimuli with a limited
range of symptoms and signs, including cough and wheeze, and these manifestations
represent the final expression of many clinical entities with potentially different
pathophysiologies requiring different individualized treatments. Hence, new studies
challenge the symptom‐based approach and promote the importance of managing
the wheezy child based on the “airway phenotype.” This will enable the clinician to
identify not only the child with a serious underlying pathology (e.g., a structural
airway disorder or immunodeficiency) who is in need of prompt and specific
treatment but also increase the specificity of treatment for the child with symptoms
suggestive of an “asthma” syndrome. In the latter case, focus should be given to the
identification of treatable traits. This review summarizes the current understanding
in management of preschool wheezing and highlights the unmet need for further
research.

KEYWORDS
asthma, endotypes, management, preschool, wheezing

1 | INTRODUCTION Conventional treatment of recurrent preschool wheezers is based on

The prevalence of preschool wheezing (before age 6) varies worldwide
and seems to be increasing in countries where data are available1
Furthermore, recurrent wheezing defined as four or more episodes in
the previous year,2 affects one‐third of preschoolers with significant
impact on quality of life.3,4 Even mild preschool wheeze has quite a
disease burden.5 Despite being a common disease, the medical
community has been wandering for years, failing to provide the good
practice of medicine that all medical students are trained for, and so,
precision medicine has not yet entered routine clinical practice.6–10
two simple history‐based models (multiple trigger wheezers, MTWs,
and episodic viral wheezers, EVWs). Unsurprisingly, the phenotype‐
based management of preschool wheezing was proved to be rather
ineffectual in controlling both symptoms and disease burden since
these phenotypes may be difficult to distinguish and bear no
relationship to airway pathology.11,12
In paediatric pulmonology the term “chronic cough” has no
diagnostic value and is used solely as the starting point in the
evaluation and management of the chronically coughing child. The
same rule should apply to preschoolers with wheeze and the term

1990 | © 2022 Wiley Periodicals LLC. wileyonlinelibrary.com/journal/ppul Pediatric Pulmonology. 2022;57:1990–1997.

CHATZIPARASIDIS AND BUSH
should be regarded as an umbrella term for a number of different
diseases with diverse observable traits and measurable clinical
features (phenotypes).13 The human airway responds to adverse
stimuli with a shortage of signs and symptoms (such as wheeze,
cough, and chest tightness); thus, wheeze represents merely a
clinical sign which is the final “product” of different airway lumen
pathologies that lead to airflow limitation. The spectrum of
diseases that can present with wheezing in preschoolers is wide
and includes amongst others, chronic suppurative lung diseases,
chronic lung disease of prematurity, congenital structural airway
abnormalities, airway tumors, foreign bodies, viral‐wheezing and
“preschool asthma.”14–16
The real challenge is to identify the “asthmatic” preschoolers
from among children with other causes of wheeze (with viral
wheezing being the most common cause likely related in non‐
asthmatics to accumulation of secretions within the airways17
and not eosinophilic airway inflammation). The problem is the
lack of a clear definition of asthma and the lack of objective tests
18,19 20
in this age group. A systematic review examined all the
“preschool asthma/wheezing” guidelines published between
2007 and 2016. It concluded that “There is generalized although
not unanimous agreement that asthma can be diagnosed in
preschool children.” and commented that “The immense majority
accepted that asthma can be diagnosed from the first years of life,
without requiring pulmonary function tests or other complementary
techniques. The response to treatment and the exclusion of other
alternative diagnoses are key elements for establishing the diagnosis.
Only one of the guidelines denied the possibility of diagnosing
asthma in preschool children.” Recent papers propose the disrup-
tion of post‐natal homeostatic control of airways smooth muscle
as the defining feature of asthma of any age irrespective of the
presence of eosinophilic or neutrophilic inflammation. 17,18 More-
over, the Canadian Thoracic Society and Canadian Paediatric
Society position paper states that preschool asthma can be
diagnosed if there are recurrent episodes of reversible airflow
obstruction, and no clinical suspicion for an alternative diagnosis.
It also mentions that, although a personal or family history of
atopy heightens the suspicion for asthma in preschoolers, its
absence is not necessary for the diagnosis.21 These studies define
asthma as a constellation of symptoms that presents as an acute
exacerbation with or without in between symptoms and pay no
attention to underlying mechanistic pathways. Having a clear
definition of asthma is the first step forward to identify (based on
treatable traits) the underlying endotype that leads to symptoms
and customize treatment accordingly.
For progress to be made, precision medicine able to identify the
right child for the right treatment should become part of our medical
routine. The ability to identify treatable traits and based on them to
provide an effective management is the way forward. In this review
we summarize the current understanding on the management of
recurrent preschool wheeze in children 1–5 years. Treatment of
wheeze in the first year of life and management of acute wheeze
attacks is beyond the scope of this review.
| 1991
2 | PRESCHOOL WHEEZE I S N OT A
BEN I G N C O N D IT I O N
Large population‐based studies suggested that at least 60% of
wheezy preschoolers will become symptom‐free by age 6 years and
the majority before adolescence.2,22
However, disappearance of symptoms is not the same as a
benign prognosis. The Copenhagen Prospective Studies on Asthma in
Childhood23 and the Manchester Asthma and Allergy Study24
showed that a low lung function trajectory starting in infancy and
preschool years persisted at the age of 7 and 11, respectively. The
Tucson Children's Respiratory Study also suggested that low infant
lung function tests strongly predict adult lung function.25 Many
longitudinal cohort studies from different countries give a picture of
the natural course of childhood asthma into late middle age. Those
studies commencing in early life showed that adolescents and adults
with wheeze had a reduction in lung function before the age of
6 years compared to their peers who never wheeze.26,27
Moreover, objective mathematical methods have been used to
delineate trajectories of lung function, letting the data speak for itself
rather than impose investigator bias. The longitudinal studies suggest
that not only preschool children with wheeze have lung function
deficits at the age of 6 years, but also that lung function growth
patterns established at that age almost always extend to late middle
age. Hence some preschool wheezers never reach the normal plateau
level of lung function. Spirometry values normally rise to a plateau at
early to mid‐twenties and then gradually decline.28 Failure to reach
this normal spirometric plateau is associated with a 26% risk of later
development of chronic obstructive pulmonary disease.29
Furthermore, a low first second forced expired volume (FEV1) in
childhood correlates with both adverse respiratory outcomes and
increased all‐cause mortality beginning in early adult life.30–32 These
studies have recently been reviewed in detail.33
Although treating and preventing symptoms of preschool wheez-
ing (either continuous or intermittent) is important, there are no
treatments which alter the long‐term trajectories described above.34–36
3 | T H E CL I N I C A L AP P R O A C H : I S I T
TRU LY WHEEZ E, I S THERE AN
UNDER LYING OR A SSO CIATED
DIAGNOSIS?
Wheeze is a high pitched, continuous noise, usually associated with a
prolonged expiratory phase. It is mainly expiratory and because it lasts
at least 250 ms, it should be easily discriminated by the trained human
ear. It is generated by anything leading to narrowing of the airways and
depending on the level of obstruction, it can be polyphonic or
monophonic (peripheral and central obstruction, respectively).37
Auscultation of the chest when wheeze is present, usually during a
viral infection, is the best way to ascertain its presence since parental
report of wheeze is unreliable.38 If wheezing is heard, a short acting beta
agonist (SABA) should be administered to assess responsiveness (clinical
1992 | CHATZIPARASIDIS AND BUSH

TABLE 1 Five ways to determine whether wheeze is being described

1. Auscultate when wheeze is present Most reliable method

2. Imitate the sound for the parents Helpful if correctly performed

3. Ask parents to localize the origin of the sound Pointing to the child's chest makes wheeze more likely,
but crackling noises may arise from the chest

4. Ask parents to record the sound on a smart phone (in the future, the use of Useful but only in cases of audible wheeze
home e‐stethoscopes may be possible)

5. Demonstrate a prerecorded symptom video with different respiratory sounds Parental identification of wheeze among other recorded
respiratory sounds facilitates diagnosis

TABLE 2 Atypical causes of wheeze and suggested investigation T A B L E 3 Red flags in preschool wheezing suggesting further
investigation is required
Underlying causes of atypical wheeze Suggested investigation

Gastro‐esophageal reflux pH study, multiple intraluminal • Abnormality detected in antenatal ultrasound scans
impedance testing • Stormy perinatal period in a term baby with neonatal intensive care
Cystic fibrosis (CF) Sweat test, genetics unit admission

Primary ciliary dyskinesia (PCD) Nasal nitric oxide, electron • Neonatal/infantile onset of symptoms
microscopy, genetics • Chronic wet cough with no periods of remission
Congenital airway anomaly Bronchoscopy • Abnormal signs e.g., digital clubbing, focal wheezing, persistent
Immunodeficiency Immune studies tachypnoea, hypoxaemia, failure to thrive

Bronchopulmonary dysplasia (BPD)
Foreign body aspiration
Endobronchial mass
Cardiac disease
Postinfectious bronchiolitis
obliterans
Bronchiectasis
Interstitial lung disease
Neonatal history
Bronchoscopy
Bronchoscopy and biopsy
Echocardiography
History, high resolution chest
computed tomography, CT
High resolution chest CT
High resolution chest CT,
genetic studies, lung biopsy
• Failure to respond to short acting beta agonist, and/or inhaled
corticosteroids
• Wheezing associated with feeding or vomiting
• The toddler with a history of choking and/or very sudden onset of
symptoms suggestive of foreign body inhalation
• Wheezing with little cough and varying with changes in position
• History of pulmonary or systemic infections suggestive of
immunodeficiency (severe, persistent, unusual organisms, recurrent
infection)

or more blind therapeutic trials with combinations of inhaled

improvement, reduction/disappearance of wheezing, rise of oxygen
saturation, SpO2). A diagnosis of reversible airflow obstruction can be
made if there is reduction in wheeze, especially if the child has previously
experienced similar attacks.21,39 In case of diagnostic doubt there are
other ways to determine if wheeze is truly the problem (Table 1).
Correct identification that wheezing is the problem is important,
but only denotes the presence of airway narrowing or obstruction
which has many potential causes. The wheezy preschooler may in
fact have a more serious underling disease that needs to be further
investigated, see Table 2.
A detailed history combined with a thorough clinical examination
may reveal red flags suggestive of an underlying specific condition
and the need for further investigation. Table 3 displays some
important red flags; more comprehensive lists may be found
elsewhere in literature.40–44
Conclusively, the identification of wheeze is followed by excluding
other pathologies manifesting with wheeze and needing specific
treatment (Table 2). With the absence of red flags, the probable
diagnosis is preschool asthma. The current practice is to carry out one
corticosteroids (ICS), leukotriene receptor antagonist (LTRA) and SABA.
We need to move from a management pathway of blind N‐of‐1 trials to
personalized medicine and attempt to phenotype the airway.
Therefore, the use of simple tests that help determine whether
our wheezy preschooler has a reversible airflow obstruction likely
associated with an airway infection and/or inflammation (either
eosinophilic or neutrophilic),17 would delineate treatable traits to
allow targeted and personalized treatment to be deployed.
4 | O B J E C T I V E TE S T S T O P H E N O TY P E
T H E AI R W A Y AN D D E L I N E A T E T R E A T A BL E
TRAITS
4.1 | Verifying the presence of reversible airflow
obstruction
Personalized management of preschool wheezing is hampered by
the lack of objective tests at this age.18,19 In contrast with school
CHATZIPARASIDIS AND BUSH
age and adult asthma where increasingly objective tests are used
in management, the same does not apply for preschoolers. As an
example, although measurement of bronchodilator reversibility
(BDR) using spirometry in older asthmatic children is well
standardized,45 objective lung function is rarely performed in a
clinical setting in preschool children. Howbeit, where local
expertize exists, spirometry with BDR measurement is feasible
in children 3–5 years and the presence of a negative BDR makes a
46
diagnosis of asthma less likely although does not exclude it.
Hopefully, the advent of impulse oscillometry in preschoolers will
facilitate diagnosis since it is easy to perform, needs minimal
patient cooperation and does not require effort. However,
for the time being, its clinical use is hindered by the lack of
established adequate range of normal values, particularly in
young patients. 47–49
4.2 | Is eosinophilic inflammation (with or without
an infection) present?
It has been well established that corticosteroids work well in patients
with eosinophilic airway inflammation.50 There is also evidence that an
eosinophil ‐predominant endotype is present in a subgroup of severe,
recurrent preschool wheezers with tissue and airway eosinophi-
lia14,51,52 and noticeably, tissue eosinophilia is not always associated
with an atopic phenotype.52 Recently, Robinson et al.11 performed
bronchoscopy and bronchoalveolar lavage (BAL) in preschool children
with a history of recurrent severe wheeze. The patients were initially
assigned as MTWs or EVWs. There was no relationship between
symptoms and pathology. Next, a cluster analysis was performed. The
authors identified four distinct clusters of severe preschool wheezers
based on allergic sensitization, peripheral eosinophilia, lower airway
neutrophils and presence of bacteria (cluster 1. atopic, high ICS use,
cluster 2. nonatopic, low infection rate, high ICS use, cluster 3.
nonatopic, high infection rate, and cluster 4. nonatopic, low infection
rate, no ICS use). Based on their findings, a quarter of the cohort
expressed an eosinophilic dominant airway inflammation, occasionally
associated with Moraxella predominance in the BAL culture. It was
suggested that when atopic children fail to respond to ICS (despite the
existence of supporting treatable traits), it may be useful to perform
induced sputum culture and if a bacterial infection is identified, a
course of oral antibiotics to be prescribed.
The Individualized Therapy for Asthma in Toddlers (INFANT)
study53 is proof of concept that personalized medicine can be made to
work by targeting ICS to the group of wheezers with eosinophilic
airway disease. Although induced sputum can be performed in
preschool wheezers, sputum and BAL eosinophilia do not correlate,
unlike in school age children.54 Peripheral blood eosinophil count is a
55
surrogate marker of BAL eosinophils and is a biomarker that predicts
clinical response to ICS and the new biologics directed against type 2
56,57
inflammation. The INFANT trial showed that preschool wheezers
more likely to respond favorably to daily ICS are characterized by aero‐
allergen sensitization and/or high blood eosinophil count (more than
| 1993
300/μl). Also, nearly 30% of participants with significant atopy
responded better to high dose intermittent ICS or LTRA rather than
daily ICS.53 So, children with evidence of type 2 inflammation may
have a better clinical response to traditional asthma controller therapy.
Moreover, offline fractional exhaled nitric oxide (FeNO) mea-
surement using tidal breathing has been used to diagnose and
monitor bronchial eosinophilic inflammation in infants with recurrent
wheezing.58 This can be related to single breath FeNO at a steady
flow of 50 ml/s.59 A recent study involving preschool wheezers,
generated reference FeNO values and data on variability within and
between days, which data are essential if the measurements are to be
used clinically.60 This paves the way for systematic FeNO readings in
preschoolers and older patients who are unable to cooperate. More
data are needed before FeNO measurements are recommended for
daily practice, but this is an urgent research need to pursue.61
4.3 | Is there a neutrophilic inflammation (with or
without an infection) present?
Though there is no doubt that eosinophilic preschool asthma exists,
only one‐quarter of wheezy preschoolers belongs to eosinophilic,
allergic‐type 2 high group.12,62,63 The nonallergic group seems to
predominate, and the majority is characterized by lower airway
neutrophilia.14 So, neutrophilic inflammation associated or not with
infection plays an important role in pre‐school wheeze. In one
study64 of BAL, 59% of the wheezy children were culture positive for
Haemophilus influenzae, Streptococcus pneumoniae and Moraxella
catarrhalis at a time of clinical stability. There was also BAL
neutrophilia in 81% of wheezers. Some children had culture negative
neutrophilia, which could of course reflect sampling errors. The
children with neutrophilic inflammation and a bacterial count of 104
colony forming units (cfu)/ml were treated with a prolonged course
of antibiotics and there was a 92% improvement in symptoms.
Strikingly, the improvement lasted more than 6 months in 81% of the
children and 65% of them were able either to reduce or discontinue
asthma treatment. No treatment was given to children with isolated
neutrophilia. These data confirm that there is a group of preschool
wheezers with the treatable trait of airway neutrophilia and infection.
In agreement with these data, in the study of Robinson et al.,11 the
cluster 3 BAL cultured Haemophilus influenzae, Streptococcus pneu-
moniae and Staphylococcus. These data are similar to a previous study
that assessed lower airway microbiota where only two clusters of
preschool wheezers were identified based on lower airway inflam-
mation and microbiota composition. Airway dysbiosis were associ-
ated with airway neutrophilia and antibiotic response in contrast with
the mixed microbiota profile where macrophages and lymphocytes
predominated.12
The presence of bacteria in preschoolers' airway has been shown
to predispose to acute wheezy episodes65 and antibiotic treatment
may be the key to manage this subgroup of wheezy toddlers.
In case of true culture negative neutrophilia, gastroesophageal
reflux disease (GERD) may be a factor.14 In the study of Guiddir
1994 | CHATZIPARASIDIS AND BUSH

et al.14 37% of such children (p < 0.001) were given a diagnosis of
GERD (defined as the presence of suggestive symptoms or abnormal
24‐h pH‐monitoring or good treatment response; not all of these
criteria can be said to be rigorous). More studies are needed to
understand if this is another treatable trait.
Lastly, if there is culture‐negative airway neutrophilic inflamma-
tion with no evidence of GERD, the management options are limited.
Macrolides have been proposed as a treatment option66–68 because
of their antibacterial and anti‐inflammatory properties69 but more
research is needed.
It seems that neutrophilic airway inflammation with or without
associated infection is a key feature in preschool asthma and having
an easy, handy and reliable way to obtain lower airway samples
from preschool wheezers is of paramount importance. The
reported data on airway neutrophilic inflammation derived from
studies where bronchoscopy under general anaesthesia performed.
Bronchoscopy can only be used in the investigation of severe
wheeze, whereas most pre‐school wheezers are seen in primary
and secondary care. Induced sputum (IS) could be an attractive
alternative to detect lower airway inflammation and infection. It
has a greater yield of positive bacterial cultures in preschool
children compared to cough swabs and correlates with BAL
70–72
culture. It is safe, feasible and noninvasive. However, though
IS could be used to detect infection in wheezy preschoolers, it does
73
not always reflect BAL and mucosal inflammation
unlike asthmatic adults where sputum inflammatory phenotype
74
is usually stable over time, in older children with asthma IS
differential cell counts showed marked variability in successive
75
visits. This IS instability meant that IS inflammometry was not
successful in preventing exacerbations in older children.
studies in preschool wheezers are lacking. There is an urgent need
for more high‐quality studies to investigate the usefulness of IS to
identify lower airway inflammation in preschool children. In the
meantime, regular utilization of IS to manage preschool wheezing
can only be used in expertize centers.
We need to develop new biomarkers to detect neutrophilic
lower airway inflammation. Studies on serum calprotectin as a
biomarker of neutrophilic inflammation in children are promising, but
more data are needed before calprotectin becomes incorporated in
daily practice.77
4.4 | Is there a noninflamed and noninfectious
airway endotype?
Robinson et al.11 found a cluster of preschool wheezers that
manifested a good response to SABA but had no evidence of allergic
sensitization and no signs of airway inflammation and/or infection in
BAL cytology and culture. They proposed that if a SABA responding
wheezer has <300/μl blood eosinophils, is not sensitized to aero‐
allergens, and has a negative sputum culture/cytology, they could be
managed with SABA or LAMA only treatment, avoiding the use of ICS
or antibiotics.
In the INFANT study53 one‐third of participants appeared to
Moreover, respond to daily ICS despite a low blood eosinophil count and no
aero‐allergen sensitization. The mechanism of ICS action in this
case remains unknown. One likely explanation is that ICS may not be
working on allergic inflammation alone.17 Airway smooth muscles are
shown to respond directly to steroids with downregulation of
76
Similar cytokine release and reduction of bronchial responsiveness,

History & Physical examination

“Verify presence of wheeze”

Atypical pattern of wheeze

Presence of red flags
Yes No

Recurrent wheeze &

Investigate for other disorders that
asthma-like symptoms
present with wheeze and treat
accordingly

Aeroallergen sensitization
confirmed with skin prick or
blood tests AND/OR blood
eosinophils>300/μl
Yes
? No
1. Daily low dose of ICS SABA only use
2. Intermittent high dose ICS
or LTRA
Poor response ? F I G U R E 1 Algorithm of preschool wheeze
management; interrogation marks denote the
Poor response
1. Trial of daily ICS for 6-12 steps where there is need for objective
1. Check inhalation technique weeks biomarkers. ICS, inhaled corticosteroids;
& compliance 2. Anti-reflux treatment LTRA, leukotriene receptor antagonist; SABA,
2. Increase ICS dose 3. Prolonged course of antibiotics
short acting beta agonist [Color figure can be
3. Use of antibiotics?
viewed at wileyonlinelibrary.com]
CHATZIPARASIDIS AND BUSH
suggesting a possible direct action of ICS on airway smooth muscle,
but this is speculative.78–84
5 | TR E A TME N T
Although a pragmatic approach to preschool wheezing management
with the use of treatable traits is the future goal, to date the only
practical objective biomarkers are those reflecting airway eosinophilic
inflammation. Neutrophilic inflammation with or without an associ-
ated infection is hard to detect in daily practice and for which we
need reliable and easy to use biomarkers. Figure 1 offers a summary
of current knowledge and gives one proposed for it algorithm for
preschool wheezing management. Since more work needs to be done
in the field of objective biomarkers, the present algorithm represents
summary of the data presented in this review and is not a guideline
for current practice.
6 | C ONC LUS I ON S
Preschool wheezers are highly heterogenous with still poorly
understood endotypes. There is no correlation between symptom
patterns and underlying pathology, so it is imperative that we move
beyond history taking as a guide to therapy. We are moving towards
much more objective, personalized treatment strategies. Cystic
fibrosis is a wonderful example of what personalized, endotype‐
based medicine can achieve.85 We need to develop new biomarkers
of airway phenotypes, but more importantly, move to understanding
underlying endotypes.
A U T H O R C O N TR I B U T I O N S
Grigorios Chatziparasidis: conceptualization (lead); data curation
(supporting); validation (supporting); writing—original draft (lead);
writing—review and editing (lead). Andrew Bush: data curation
(supporting); resources (equal); supervision (lead); validation (lead).
A C KN O W L E D G M E N T
“I would like to express my deep gratitude to Professor Andy Bush
for his enthusiastic encouragement and useful critiques in writing this
paper.”
D A TA A V A I L A B I L I T Y S T A T E M E N T
Data openly available in a public repository that issues datasets
with DOIs.
ORCID
Grigorios Chatziparasidis http://orcid.org/0000-0003-4308-4710
REFERENCES
1. Bloom CI, Franklin C, Bush A, Saglani S, Quint JK. Burden of
preschool wheeze and progression to asthma in the UK: population‐
| 1995
based cohort 2007 to 2017. J Allergy Clin Immunol. 2021;147(5):
1949‐1958.
2. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M,
Morgan WJ. Asthma and wheezing in the first six years of life. N Engl
J Med. 1995;332(3):133‐138.
3. Mallol J, Garcia‐Marcos L, Sole D, Brand P. International preva-
lence of recurrent wheezing during the first year of life: variability,
treatment patterns and use of health resources. Thorax.
2010;65(11):1004‐1009.
4. Bui AL, Dieleman JL, Hamavid H, et al. Spending on children's
personal health care in the United States 1996‐2013. JAMA
Pediatrics. 2017;171(2):181‐189.
5. Fleming L, Murray C, Bansal AT, et al. The burden of severe
asthma in childhood and adolescence: results from the paediatric
U‐BIOPRED cohorts. Eur Respir J. 2015;46(5):1322‐1333.
6. Deliu M, Belgrave D, Sperrin M, Buchan I, Custovic A. Asthma
phenotypes in childhood. Expert Rev Clin Immunol. 2017;13(7):
705‐713.
7. Howard R, Rattray M, Prosperi M, Custovic A. Distinguishing asthma
phenotypes using machine learning approaches. Curr Allergy Asthma
Rep. 2015;15(7):38.
8. Saglani S, Custovic A. Childhood asthma: advances using machine
learning and mechanistic studies. Am J Respir Crit Care Med.
2019;199(4):414‐422.
9. Oksel C, Granell R, Mahmoud O, Custovic A, Henderson AJ. Causes
of variability in latent phenotypes of childhood wheeze. J Allergy Clin
Immunol. 2019;143(5):1783‐1790.
10. Savenije OE, Granell R, Caudri D, et al. Comparison of childhood
wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA.
J Allergy Clin Immunol. 2011;127(6):1505‐1512.
11. Robinson PFM, Fontanella S, Ananth S, Martin Alonso A, Cook J.
Kaya‐de vries D, et al. recurrent severe preschool wheeze: from
prespecified diagnostic labels to underlying endotypes. Am J Respir
Crit Care Med. 2021;04(5):523‐535.
12. Robinson PFM, Pattaroni C, Cook J, et al. Lower airway microbiota
associates with inflammatory phenotype in severe preschool
wheeze. J Allergy Clin Immunol. 2019;143(4):1607‐1610.
13. Fainardi V, Santoro A, Caffarelli C. Preschool wheezing: trajectories
and Long‐Term treatment. Front Pediatr. 2020;12:8.
14. Guiddir T, Saint‐Pierre P, Purenne‐Denis E, et al. Neutrophilic
steroid‐refractory recurrent wheeze and eosinophilic steroid‐
refractory asthma in children. The. Journal of Allergy and Clinical
Immunology: In Practice. 2017;5(5):1351‐1361.
15. Bush A. Pathophysiological mechanisms of asthma. Front Pediatr.
2019;19:7.
16. Global Initiative for Asthma. Global Strategy for Asthma Mangement
and Prevention. 2019. Available from www.ginaasthma.org
Accessed December 3, 2020.
17. Anthracopoulos MB, Everard ML. Asthma: a loss of post‐natal
homeostatic control of airways smooth muscle with regression
toward a pre‐natal state. Front Pediatr. 2020;16:8.
18. Douros K, Everard ML. Time to say goodbye to bronchiolitis, viral
wheeze, reactive airways disease, wheeze bronchitis and all that.
Front Pediatr. 2020;5:8.
19. Visness CM, Gebretsadik T, Jackson DJ, et al. Asthma as an
outcome: exploring multiple definitions of asthma across birth
cohorts in the environmental influences on child health outcomes
children's respiratory and environmental workgroup. J Allergy Clin
Immunol. 2019;44(3):866‐869.
20. Moral L, Vizmanos G, Torres‐Borrego J, et al. Asthma diagnosis in
infants and preschool children: a systematic review of clinical
guidelines. Allergol Immunopathol. 2019;47(2):107‐121.
21. Ducharme FM, Dell SD, Radhakrishnan D, et al. Diagnosis and
management of asthma in preschoolers: a Canadian Thoracic Society
1996 | CHATZIPARASIDIS
and Canadian Paediatric Society Position Paper. Can Respir J.
2015;22(3):135‐143.
22. Just J, Nicoloyanis N, Chauvin M, Pribil C, Grimfeld A, Duru G. Lack
of eosinophilia can predict remission in wheezy infants? Clinical &
Experimental Allergy. 2008;38(5):767‐773.
23. Bisgaard H. The Copenhagen prospective study on asthma in
childhood (COPSAC): design, rationale, and baseline data from a
longitudinal birth cohort study. Ann Allergy Asthma Immunol.
2004;93(4):381‐389.
24. Belgrave DCM, Buchan I, Bishop C, Lowe L, Simpson A, Custovic A.
Trajectories of lung function during childhood. Am J Respir Crit Care
Med. 2014;189(9):1101‐1109.
25. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ,
Martinez FD. Tucson children's respiratory study: 1980 to present.
J Allergy Clin Immunol. 2003;1(4):661‐675.
26. Horak E. Longitudinal study of childhood wheezy bronchitis and
asthma: outcome at age 42. BMJ. 2003;326(7386):422‐423.
27. Phelan PD, Robertson CF, Olinsky A. The Melbourne asthma study:
1964‐1999. J Allergy Clin Immunol. 2002;109(2):189‐194.
28. Quanjer PH, Stanojevic S, Cole TJ, et al. Multi‐ethnic reference
values for spirometry for the 3–95‐yr age range: the global lung
function 2012 equations. Eur Respir J. 2012;40(6):1324‐1343.
29. Lange P, Celli B, Agustí A, et al. Lung‐Function trajectories leading to
chronic obstructive pulmonary disease. N Engl J Med. 2015;373(2):
111‐122.
30. Tai A, Tran H, Roberts M, et al. Outcomes of childhood asthma
to the age of 50 years. J Allergy Clin Immunol. 2014;133(6):
1572‐1578.
31. Bui DS, Lodge CJ, Burgess JA, et al. Childhood predictors of lung
function trajectories and future COPD risk: a prospective cohort
study from the first to the sixth decade of life. The Lancet Respir Med.
2018;6(7):535‐544.
32. Bisgaard H, Nørgaard S, Sevelsted A, et al. Asthma‐like symptoms in
young children increase the risk of COPD. J Allergy Clin Immunol.
2021;147(2):569‐576.
33. Bush A. Impact of early life exposures on respiratory disease.
Paediatr Respir Rev. 2021;40:24‐32.
34. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F.
Intermittent inhaled corticosteroids in infants with episodic wheez-
ing. N Engl J Med. 2006;354(19):1998‐2005.
35. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A.
Secondary prevention of asthma by the use of inhaled fluticasone
propionate in wheezy INfants (IFWIN): double‐blind, randomised,
controlled study. The Lancet. 2006;368(9537):754‐762.
36. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long‐Term inhaled
corticosteroids in preschool children at high risk for asthma. N Engl J
Med. 2006;354(19):1985‐1997.
37. Chatziparasidis G, Priftis KN, Bush A. Breath Sounds. Wheezing as a
respiratory sound. Vol 00. Springer International Publishing; 2018:
207‐223.
38. Michel G, Silverman M, Strippoli MP, et al. Parental understanding of
wheeze and its impact on asthma prevalence estimates. Eur Respir J.
2006;28(6):1124‐1130.
39. Yang CL, Gaffin JM, Radhakrishnan D. Question 3: can we diagnose
asthma in children under the age of 5 years? Paediatr Respir Rev.
2019;29:25‐30.
40. Bacharier LB, Guilbert TW, Jartti T, Saglani S. Which wheezing
preschoolers should be treated for asthma? J Allergy Clin Immunol
Pract. 2021;9(7):2611‐2618.
41. Bacharier LB, Guilbert TW. Diagnosis and management of early
asthma in preschool‐aged children. J Allergy Clin Immunol.
2012;130(2):287‐296.
42. Al‐Shamrani A, Bagais K, Alenazi A, Alqwaiee M, Al‐Harbi AS.
Wheezing in children: approaches to diagnosis and management. Int
J Pediatr Adolesc Med. 2019;6(2):68‐73.
AND BUSH
43. Brand PLP, Baraldi E, Bisgaard H, et al. Definition, assessment and
treatment of wheezing disorders in preschool children: an evidence‐
based approach. Eur Respir J. 2008;32(4):1096‐1110.
44. Bush A, Grigg J, Saglani S. Managing wheeze in preschool children.
BMJ. 2014;348(feb04 16):g15.
45. Dundas I. Diagnostic accuracy of bronchodilator responsiveness in
wheezy children. Thorax. 2005;60(1):13‐16.
46. Busi LE, Restuccia S, Tourres R, Sly PD. Assessing bronchodilator
response in preschool children using spirometry. Thorax. 2017;72(4):
367‐372.
47. Bickel S, Popler J, Lesnick B, Eid N. Impulse oscillometry. Chest.
2014;146(3):841‐847.
48. Mochizuki H, Hirai K, Tabata H. Forced oscillation technique and
childhood asthma. Allergol Int. 2012;61(3):373‐383.
49. Jorge PPDO, de Lima JHP, Silva DCCE, et al. Impulse oscillometry in
the assessment of children's lung function. Allergol Immunopathol.
2019;47(3):295‐302.
50. Morrow Brown H. Treatment of chronic asthma with prednisolone
significance of eosinophils in the sputum. The Lancet. 1958;272(7059):
1245‐1247.
51. Saglani S, Payne DN, Zhu J, et al. Early detection of airway wall
remodeling and eosinophilic inflammation in preschool wheezers.
Am J Respir Crit Care Med. 2007;176(9):858‐864.
52. Turato G, Barbato A, Baraldo S, et al. Nonatopic children with
multitrigger wheezing have airway pathology comparable to atopic
asthma. Am J Respir Crit Care Med. 2008;178(5):476‐482.
53. Fitzpatrick AM, Jackson DJ, Mauger DT, et al. Individualized therapy
for persistent asthma in young children. J Allergy Clin Immunol.
2016;138(6):1608‐1618.
54. Lex C, Payne DNR, Zacharasiewicz A, et al. Sputum induction in
children with difficult asthma: safety, feasibility, and inflammatory
cell pattern. Pediatr Pulmonol. 2005;39(4):318‐324.
55. Lex C, Ferreira F, Zacharasiewicz A, et al. Airway eosinophilia
in children with severe asthma. Am J Respir Crit Care Med.
2006;174(12):1286‐1291.
56. Busse W, Chupp G, Nagase H, et al. Anti–IL‐5 treatments in patients
with severe asthma by blood eosinophil thresholds: indirect treatment
comparison. J Allergy Clin Immunol. 2019;143(1):190‐200.
57. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety
in Moderate‐to‐Severe uncontrolled asthma. N Engl J Med.
2018;378(26):2486‐2496.
58. Gabriele C, de Benedictis FM, de Jongste JC. Exhaled nitric oxide
measurements in the first 2 years of life: methodological issues,
clinical and epidemiological applications. Ital J Pediatr. 2009;35(1):21.
59. van Mastrigt E, de Groot RCA, van Kesteren HW, Vink ATJ,
de Jongste JC, Pijnenburg MWH. Tidal breathing FeNO measure-
ments: a new algorithm. Pediatr Pulmonol. 2014;49(1):15‐20.
60. Daniel PF, Klug B, Valerius NH. Exhaled nitric oxide in healthy young
children during tidal breathing through a facemask. Pediatr Allergy
Immunol. 2007;18(1):42‐46.
61. Oh MA, Shim JY, Jung YH, et al. Fraction of exhaled nitric oxide and
wheezing phenotypes in preschool children. Pediatr Pulmonol.
2013;48(6):563‐570.
62. Tang HH, Teo SM, Belgrave DC, et al. Trajectories of childhood immune
development and respiratory health relevant to asthma and allergy.
eLife. 2018;7:1‐31.
63. Bacharier LB, Beigelman A, Calatroni A, et al. Longitudinal
phenotypes of respiratory health in a High‐Risk urban birth cohort.
Am J Respir Crit Care Med. 2019;199(1):71‐82.
64. Schwerk N, Brinkmann F, Soudah B, Kabesch M, Hansen G. Wheeze
in preschool age is associated with pulmonary bacterial infection and
resolves after antibiotic therapy. PLoS One. 2011;6(11):e27913.
65. Bisgaard H, Hermansen MN, Bønnelykke K, et al. Association of
bacteria and viruses with wheezy episodes in young children:
prospective birth cohort study. BMJ. 2010;341(oct04 1):c4978.
CHATZIPARASIDIS AND BUSH
66. de Benedictis FM, Carloni I, Guidi R. Question 4: is there a role
for antibiotics in infantile wheeze? Paediatr Respir Rev. 2020;33:
30‐34.
67. Beigelman A, Isaacson‐Schmid M, Sajol G, et al. Randomized trial to
evaluate azithromycin's effects on serum and upper airway IL‐8 levels
and recurrent wheezing in infants with respiratory syncytial virus
bronchiolitis. J Allergy Clin Immunol. 2015;135(5):1171‐1178.
68. Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of
azithromycin and prevention of severe lower respiratory tract
illnesses in preschool children with a history of such illnesses.
JAMA. 2015;314(19):2034‐2044.
69. Grigg J. Antibiotics for preschool wheeze. The Lancet Respir Med.
2016;4(1):2‐3.
70. Gaillard EA, Grigg J, Tellabati A, McNally T, Whittaker A,
Beardsmore CS. Isolation of cells from the lower airways in infants
with wheeze by sputum induction. Eur Respir J. 2013;41(2):483‐485.
71. D'sylva P, Caudri D, Shaw N, et al. Induced sputum to detect lung
pathogens in young children with cystic fibrosis. Pediatr Pulmonol.
2017;52(2):182‐189.
72. Mussaffi H, Fireman EM, Mei‐Zahav M, Prais D, Blau H. Induced
sputum in the very young. Chest. 2008;133(1):176‐182.
73. Jochmann A, Artusio L, Robson K, et al. Infection and inflammation
in induced sputum from preschool children with chronic airways
diseases. Pediatr Pulmonol. 2016;51(8):778‐786.
74. Simpson JL, McElduff P, Gibson PG. Assessment and reproducibility
of Non‐Eosinophilic asthma using induced sputum. Respiration.
2010;79(2):147‐151.
75. Fleming L, Tsartsali L, Wilson N, Regamey N, Bush A. Sputum
inflammatory phenotypes are not stable in children with asthma.
Thorax. 2012;67(8):675‐681.
76. Fleming L, Wilson N, Regamey N, Bush A. Use of sputum eosinophil
counts to guide management in children with severe asthma. Thorax.
2012;67(3):193‐198.
77. Chatziparasidis G, Kantar A. Calprotectin: an ignored biomarker of
neutrophilia in pediatric respiratory diseases. Children. 2021;8(6):
428.
| 1997
78. Lakser OJ, Dowell ML, Hoyte FL, et al. Steroids augment
relengthening of contracted airway smooth muscle: potential
additional mechanism of benefit in asthma. Eur Respir J. 2008;32(5):
1224‐1230.
79. Banerjee A, Damera G, Bhandare R, et al. Vitamin D and
glucocorticoids differentially modulate chemokine expression in
human airway smooth muscle cells. Br J Pharmacol. 2008;155(1):
84‐92.
80. Sun HW, Miao CY, Liu L, et al. Rapid inhibitory effect of
glucocorticoids on airway smooth muscle contractions in Guinea
pigs. Steroids. 2006;71(2):154‐159.
81. Goldsmith AM, Hershenson MB, Wolbert MP, Bentley JK. Regula-
tion of airway smooth muscle α‐actin expression by glucocorticoids.
Am J Physiol Lung Cell Mol Physiol. 2007;292(1):L99‐L106.
82. Boivin R, Vargas A, Lefebvre‐Lavoie J, Lauzon AM, Lavoie JP. Inhaled
corticosteroids modulate the (+) insert smooth muscle myosin heavy
chain in the equine asthmatic airways. Thorax. 2014;69(12):
1113‐1119.
83. Holden NS, Bell MJ, Rider CF, et al. β2‐adrenoceptor agonist‐
induced RGS2 expression is a genomic mechanism of bronchopro-
tection that is enhanced by glucocorticoids. Proc Natl Acad Sci USA.
2011;108(49):19713‐19718.
84. Espinoza J, Montaño LM, Perusquía M. Nongenomic bronchodilating
action elicited by dehydroepiandrosterone (DHEA) in a Guinea pig
asthma model. J Steroid Biochem Mol Biol. 2013;138:174‐182.
85. de Boeck K, Amaral MD. Progress in therapies for cystic fibrosis. The
Lancet Respir Med. 2016;4(8):662‐674.
How to cite this article: Chatziparasidis G, Bush A. Enigma
variations: the multi‐faceted problems of pre‐school wheeze.
Pediatric Pulmonology. 2022;57:1990‐1997.
doi:10.1002/ppul.26027