Wheezing Disorders in the Pre School Child Pathogenesis

and Management 1st Edition

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Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

1. Epidemiology of wheezing in infants and preschool children. . . . . . . . . . . 1

2. Respiratory syncytial virus (RSV) infection and wheezing . . . . . . . . . . . . . 21

3. Immunology of wheezing disorders in infants and preschool children. . . . 31

4. Clinical features of the wheezy infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

5. Lung function in the wheezy infant and preschool child . . . . . . . . . . . . . . 73

6. The wheezy infant and preschool child: differential diagnosis . . . . . . . . . . 97

7. Management of wheezing in infants and preschool children . . . . . . . . . . . 123

8. Proposals for the future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

v
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Preface

One of the most common and yet most challenging problems facing the pediatrician is
the nature and management of the wheezy infant and preschool child. In some coun-
tries, such as the USA and Australia, the incidence of wheezing can reach up to 50%.
Although the incidence is rather less in Europe, the wheezy infant and preschool child
still occupies a very large part of the time of the pediatrician and constitutes a consider-
able burden on the delivery of health care. The parents of the wheezy infant or
preschool child are naturally worried about what is the matter with their child, how the
child should be treated and what is the long-term prognosis. ‘Will he/she have asthma
all his/her life, doctor?’ must surely be one of the most frequent questions posed to the
pediatrician caring for young children. It is little comfort to the parents, or indeed to
the pediatrician, when we admit that we are not sure about the cause of the wheezing
and even less sure about the correct management, if we are honest, in this era of
evidence-based medicine.
This lack of knowledge about wheezing in early life is perplexing, given the large
amount of resources that have been dedicated to research about the pathogenesis and
treatment of asthma during the past decades. There is little doubt that these efforts have
produced medicines that, when used appropriately, allow 90% of school children and
adults with asthma to lead a perfectly normal life. It is also evident, however, that there
is no way to prevent the development of chronic asthma and that many patients with
asthma require continued controller treatment for years. As will be discussed in several
chapters of this book, one of the intriguing recent findings from longitudinal studies of
asthma is that, in most severe cases of the disease, the first asthma-like symptoms occur
during the preschool years. If a strategy for the primary prevention of asthma will ever
be successful, we will need to understand much better which factors determine the
initiation of the most severe forms of the disease during the first years of life.
In view of the challenges posed by the wheezy infant and preschool child, both for
the clinician and the interested researcher, we decided to collaborate on this book in
order to collect and collate as much objective information as possible and present it to
the reader in a manner which will at least lead to a better familiarity with the condition.
We chose to work together rather than to produce a large multi-author book because
we wanted to present the reader with the information in a logical and readable fashion
with the practicing clinician in mind. Between us we have considerable experience in
the clinical, epidemiologic and physiologic aspects of the wheezy infant and preschool

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viii WHEEZING DISORDERS IN THE PRESCHOOL CHILD

child, and each chapter represents a joint effort. Despite our desire to produce a book
suitable for the clinician, we have not neglected the basic science aspects of the problem
and we have included extensive referencing to published works with which we are
familiar so that the clinical or basic scientist can refer back to evaluate the original data.
We have limited ourselves very strictly to the preschool years – approximately from
birth to 5 or 6 years of age – because this is the period, especially in the first three years
of life, when wheezing is most difficult to evaluate and manage. We did not intend to
write about asthma in older children, which presents much less of a diagnostic and
management problem and for which there are already many excellent texts. Because of
the pivotal role of viral infection, especially infection by the respiratory syncytial virus,
in causing infants and young children to wheeze, we have devoted a chapter to this
specific cause of wheezing and its management.
Why, then, is there the need for a book such as this and why does wheezing in early
childhood present such difficulties? Perhaps the most pressing reason is that there are
many causes of wheezing in this age group but to all intents and purposes the clinical
presentation is very similar or even identical. Moreover, the clinical findings and diag-
nostic tests available at the present time rarely give a conclusive answer as to the nature
of the problem in what we shall be calling the typical wheezy infant or preschool child,
i.e. those with no specific disease causing the wheezing. Parents, however intelligent
and well meaning, often find it very difficult to describe the nature of the noisy breath-
ing or respiratory distress from which their child suffers and this is particularly prob-
lematic since the child may well be completely asymptomatic by the time he/she reaches
the doctor’s office. During an attack the typical wheezy infant or preschool child will be
distressed with generalized, musical wheezing, hyperinflation and a normal chest radi-
ograph, whatever the origin of the wheeze. However, an almost identical picture can be
due to such important and potentially dangerous atypical causes of wheezing such as
gastroesophageal reflux, cystic fibrosis, primary ciliary dyskinesia and congenital anom-
alies of the airways, lungs or heart. The measurement of lung function or bronchial
responsivity can often help with the evaluation of the older wheezy child or adult, but
lung function testing in infants or very young children is not readily available and is
confined to very specialized centers. Even in these centers, the role of lung function
testing in the management of most wheezy infants or preschool children is far from
clear. The management of the primary disease obviously determines the management of
the atypical wheezy infant with a specific diagnosis such as cystic fibrosis. With the
typical wheezy infant, in whom there is no other underlying disease, suggestions for
management are very confusing. Some published asthma management guidelines rec-
ommend treatment of the wheezy infant as if they were all little asthmatics in terms of
evaluation and management with absolutely no evidence to support this approach, nor,
in many instances, any hope of carrying it out. But parents expect us to be able to help
their wheezy child and are rarely willing to sit by and watch the child without doing
anything therapeutically meaningful. In this book we suggest what we believe to be a
simple, logical and safe approach to management based on trial and error, which also
ensures that children should not continue to receive treatment which is ineffective.
The epidemiology and immunology of the typical wheezy infant and preschool child
provides some clues as to the nature of the conditions causing wheezing in this age
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PREFACE ix

group and we have paid particular attention to these aspects of the problem. For some
years, we and others have been aware that there are at least three main groups of infants
who wheeze in early childhood: (1) those with rather narrow airways to begin with,
(2) those who wheeze in response to viral infections and (3) those with a strong atopic
background. We discuss these types of wheezy children and consider what is known
about the induction of wheezing, its course and the long-term prognosis. Recent epi-
demiologic studies have begun to shed considerable light on the way environmental
factors may influence the developing immune system of the infant in such a way as to
predispose or inhibit the child from becoming wheezy or developing allergic diseases.
Some of this evidence is confusing and even contradictory, and we have paid particular
attention to presenting a fair and balanced account of this fascinating and developing
story. Throughout the book we report what we really do and do not know, and in the
last chapter we present a wish list of suggestions as to what might be done to further
clarify the nature and management of wheezing in infancy and early childhood.
Finally, we wish to express our sincere appreciation of the help we have received
from our publishers. In particular, we thank Martin Dunitz himself for his encourage-
ment and practical support which enabled us to collaborate so easily over a distance of
some 9000 miles. Peter Stevenson was the managing editor of this project and we are
especially grateful to him for his friendship, help and patience throughout.

Fernando Martinez
Simon Godfrey
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1
Epidemiology of wheezing in infants and
preschool children

The past decade has witnessed significant advances in our understanding of the epi-
demiology of wheezing illnesses occurring during the first years of life. Several longitu-
dinal studies initiated either during pregnancy or at birth, and in which follow-up has
been extended beyond the preschool years, have provided a new perspective on the risk
factors for and prognosis of these illnesses. There is now clear evidence indicating that
wheezing in early life is a heterogeneous condition, in which recurrent episodes of
airway obstruction are the final common pathway for the expression of different under-
lying mechanisms and, ultimately, for different diseases. This marked heterogeneity
may explain the difficulty that most clinicians encounter in treating these illnesses
which appear to be less responsive to the usually successful treatment prescribed to
older children and adults with asthma (see Chapter 7). There are also ‘atypical’ forms of
noisy breathing in this age group that contribute to the complexity of their diagnosis
and treatment (see Chapter 4). However, even when confronted with the typical pre-
sentation of this condition the pediatrician is often unable to predict the response to
therapy and to answer the most pressing question of parents, ‘Does my child have
asthma?’. In this review of the epidemiology of wheezing diseases in early life an
attempt will be made to provide a logical basis to explain the nature of the problem.

INCIDENCE OF FIRST EPISODES OF WHEEZING

In epidemiological terms, incidence is the number of new cases of a certain condition

that occur in a population in a given unit of time. It needs to be distinguished from
prevalence, which is the proportion of all subjects in a population who have a certain
condition at any given time. In this section, incidence of wheezing, regardless of the
mechanism involved, will be described. Incidence and prevalence of different forms of
wheezing will be assessed in the section dedicated to each of these forms.
Wheezing is a very uncommon clinical finding during the first 1–2 months of life.1
Why neonates are spared from the clinical manifestations of airway obstruction is not
understood. Since most wheezing lower respiratory illnesses (LRI) in this age group are
associated with viral infection (see below), it is plausible to surmise that maternal or
developmental factors may determine a different immune response to viruses in the
neonate. However, the data favoring such an assumption are scanty. It has also been
suggested that the structure of the lung during this period of life may protect neonates

1
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2 WHEEZING DISORDERS IN THE PRESCHOOL CHILD

against severe airway obstruction,2 but the lack of solid anatomic data precludes defini-
tive conclusions. The fact remains, however, that apnea and not wheezing is the most
common manifestation of respiratory syncytial virus (RSV) infection before 2 months
of age.
After 2 months of age, incidence of first episodes of wheezing increase markedly,
reaching a peak between 2 and 5 months of age.3 Incidence decreases after the sixth
month of life, and remains low and relatively stable during the second and third years of
life.4 There is no clear explanation for this very consistent pattern for the timing of the
first wheezing episodes. It is possible that it is simply a probabilistic distribution of
events that occur after the refractory newborn period. It is also possible that airway
growth may lag somatic growth during a 4–5-month period in which weight is doubling
and length is increasing by 25%. This may explain why a recent analysis of maximal
expiratory flows obtained with the chest compression technique showed a curvilinear
pattern, with growth of flows becoming faster after 6 months of age, particularly in
males.5 In other words, maximal expiratory flow lags somatic growth for the first few
months of life. The maturation of immune responses in the post-neonatal period may
also increase the risk of developing airway inflammation during viral infections.3

INFECTION AS A FACTOR IN THE ETIOLOGY OF WHEEZING

Several studies have demonstrated that most episodes of wheezing (be it first episode or
subsequent recurrence) during the first three years of life are associated with evidence
of viral infection.4,6,7 Until recently, the most frequent viruses isolated from naso-
pharyngeal samples (either by immunofluorescence or culture) or detected by shifts in
specific immunoglobulin serum titers were RSV, parainfluenza and adenoviruses.7 Up to
80% of all incident episodes of wheezing were thought to be due to infections by these
viruses. In rare cases, influenza viruses, Chlamydia tracomatis or Chlamydia pneumonia,
and Mycoplasma pneumonia, had been isolated during wheezing episodes in this age
group.8 For years, the predominant belief was that rhinoviruses (RV) were rarely associ-
ated with upper or lower respiratory illnesses before the age of 3.4 However, RV are
difficult to isolate with traditional virological techniques requiring antibodies because of
their great genomic variability, giving rise to more than 100 serotypes. The availability
of molecular biology techniques using reverse-transcriptase-polymerase chain reaction
(PCR) has provided a completely new perspective regarding the etiology of wheezing in
early life.9 It has now been reported that RV can be isolated in approximately a quarter
of all infants hospitalized with a diagnosis of LRI during the first year of life, all of
whom were wheezing on admission.10,11 This makes RV the second most frequently iso-
lated virus during wheezing LRI in this age group. In many of these infants, RV isola-
tion occurred in concomitance with detection of RSV, and the great majority of multiple
virus infections were due to the RSV/RV combination. In one study, results suggested
that RV identification was associated with increased severity of bronchiolitis,10 but over
half of all patients with RV had more than one virus detected. Therefore, the indepen-
dent role of RV in determining disease severity could not be distinguished from that of
RV as a co-adjuvant of RSV infection. Nevertheless, these new data on the role of RV in
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EPIDEMIOLOGY OF WHEEZING IN INFANTS AND PRESCHOOL CHILDREN 3

early wheezing suggest that the proportion of first episodes of wheezing due to viral
infection may far exceed 80% and more likely close to 100%.
Older studies had suggested that viral isolation during wheezing LRI decreased
markedly during the second and third years of life as compared to the very high fre-
quency of isolation during the first year. In fact, viruses could be detected in only
40–50% of 2-year-old children with acute wheezing LRI (Children’s Respiratory Study,
unpublished observations). It is likely that this conclusion will need to be revisited, in
view of the very large proportion of infants in whom RV has been recently detected
even during the first year of life. Further studies will certainly add valuable information
to this field in the near future.
Advances in microbiology have also suggested that other heretofore unknown organ-
isms may play a role in LRI in early life. A new member of the paramyxovirus family
from the Metapneumovirus genus was recently isolated, a genus in which only avian
viruses had been described.12 Children in whom this virus was isolated had clinical
symptoms that strikingly resembled those associated with RSV. Interestingly, serologic
studies showed that, much like for RSV, almost all children are infected by human
Metapneumovirus by the age of 5, and that the virus has been infecting humans at least
for the past 50 years. No comprehensive epidemiological studies have addressed the
public health impact and the incidence of infection due to this virus in large popula-
tion samples. Nevertheless, a preliminary report from Australia suggested that meta-
pneumoviruses may cause wheezing LRI in a small fraction of infants and young
children.13

RECURRENCE OF WHEEZING AND ITS CAUSES

One of the most striking epidemiological characteristics of wheezing episodes in infants

and young children is their tendency to recur. Although many children in this age
group can have a single episode of wheezing not followed by subsequent similar
episodes, no less than 50% of such subjects will present with wheezing at least once
within the next few months. Moreover, parents of 30–40% of children who wheeze
before the age of 3 report current wheezing at 6 years of age.14,15 This type of presenta-
tion thus suggests two potential scenarios: either recurrent wheezing is the result of
underlying predisposing factors that explain both initial and subsequent episodes, or
the initial episode creates the conditions for changes in the host that predispose her/him
to subsequent similar symptoms.
In order to understand better what determines recurrent wheezing, several groups of
investigators have followed infants and young children with this condition and have
assessed risk factors and long-term outcomes of these subjects. Results from these
studies have suggested that recurrent wheezing is a heterogeneous condition and that
different recurrent wheezing phenotypes coexist in this age group. This has been a
rather unexpected finding because the clinical presentation of infants with recurrent
wheezing does not provide clues to the clinician that would suggest the existence of dif-
ferent subgroups of subjects. Nevertheless, the appreciation that recurrent early child-
hood wheezing is not a single entity has helped clinicians and caregivers, both of whom
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4 WHEEZING DISORDERS IN THE PRESCHOOL CHILD

need to provide answers to pressing questions from concerned parents regarding the
prognosis of this condition in their children. In addition, this new knowledge has
suggested new avenues for the primary and secondary prevention of asthma and
asthma-like conditions, as will be discussed in Chapter 8.
What follows is a description of the three most common recurrent wheezing pheno-
types that have been identified in epidemiological studies. It is important to understand
that there may be overlap between these different conditions, simply because it is not
always possible to identify absolute thresholds for complex risk factors and, therefore, no
marker perfectly distinguishes between the different phenotypes described herein.
However, in spite of the many gray areas, efforts are currently under way to better under-
stand the different risk factors that predominate in one phenotype or the other. The
classification described below is also different from the three subdivisions of wheezing in
the first three years of life reported earlier by Martinez et al14 – transient wheezers, late-
onset wheezers and persistent wheezers. The first group is still included in the new classi-
fication, but new data and insights obtained after the publication of that study have driven
us to conclude that although the timing of initiation of symptoms is very important, more
significant in terms of long-term prognosis, risk factors and immunopathogenesis is the
distinction between non-atopic and atopic forms of wheezing. Both late-onset and persis-
tent wheezing can be atopic and non-atopic (Figure 1.1), and the potential role of late or
early initiation of symptoms will be discussed separately for each form below.

Transient early wheezing (60% of wheezers < 3 years of age)

The existence of a group of infants and young children who present with recurrent
wheezing episodes during the first year of life and show apparent remission of these

No wheeze

% Whole cohort (n = 826)

Persistent
wheeze VmaxFRC < 1yr ml/sec

IgE IU/ml age 6

Late-onset
wheeze % Atopic age 6

Transient
early
wheeze

6 3 0 20 40 60 80 100 120
years values

Figure 1.1
Asthma and wheezing in the first six years of life (from Martinez et al14).
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EPIDEMIOLOGY OF WHEEZING IN INFANTS AND PRESCHOOL CHILDREN 5

symptoms by the early school years has been known for a long time.16,17 However, a more
thorough identification of this phenotype has only become available more recently, the
result of longitudinal studies starting at birth. These studies have demonstrated that no
less than 60% of all wheezing babies and young children have stopped all wheezing by
3–6 years of age. These children are not more likely to have a family history of asthma or
to have personal or family history of allergic conditions such as eczema or skin-test reac-
tivity to allergens than children who do not wheeze during the first six years of life.14,18
Symptoms usually begin during the first year of life and may either subside or continue
into the second and third years of life.15 Although longitudinal studies have shown that
children belonging to this group tend to have symptoms almost exclusively during viral
infections, the severity of each of these episodes does not appear to be less prominent in
this particular group as compared with those observed in persistent wheezers. This is
important from a clinical point of view because transient early wheezers cannot be identi-
fied with those young children who in the past were called ‘happy wheezers’. Moreover,
studies in older atopic wheezers have demonstrated that the severity of symptoms during
the early school years is a very important predictor of subsequent persistence and severity
of wheezing. However, this does not hold true for wheezing during the first years of life.
It is very important for the clinician to understand these differences in the natural history
of recurrent wheezing at different ages because prognosis is an important concern for
parents, and labeling an infant or preschool child as having asthma (with its associated
stigma of a lifelong, chronic disease) simply because her/his symptoms are quite severe
may be misguided in this age group.

Risk factors for transient early wheezing

Infants of mothers who smoke during pregnancy are much more likely to have transient
wheezing episodes during the first years of life.19 This is one of the most consistent
findings in all pediatric epidemiologic studies.20
Another factor that seems to be strongly associated with transient infant wheezing is
the level of lung function measured shortly after birth and before any wheezing episode
occurs.21,22 The consistency of this finding in many epidemiologic studies suggests that
either a functional or structural alteration of the lung is present in many of the children
that predisposes them to wheezing. This makes physiologic sense because resistance to
the flow of a gas through a tube is proportional to the fourth power of the radius. Thus,
it is plausible to suggest that in airways with a smaller initial diameter, larger increases
in resistance will occur with the same amount of airway mucus or edema during a viral
infection. In favor of the hypothesis that this may be a structural alteration are studies
showing that transient infant wheezers did not have an increased prevalence of metha-
choline hyperresponsiveness or positive peak flow variability at 11 years of age.23 This,
in spite of the fact that levels of lung function, especially indices related to forced expi-
ratory flows at low lung volumes, were significantly lower in transient infant wheezers
both at 11 and 16 years of age.
It is interesting to stress here that when lung function measured shortly after birth
was compared in different groups of wheezing infants and young children, only those
who would be later classified as transient wheezers showed diminished maximal
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6 WHEEZING DISORDERS IN THE PRESCHOOL CHILD

expiratory flows. These results suggest that persistent wheezers do not start life with an
altered lung function but acquire these alterations postnatally. This issue will be
discussed in more detail later in this chapter. However, it is reasonable to surmise that if
children with diminished lung function at birth are also at risk for atopic wheezing
then they are more likely to have increased severity of wheezing in early life and
increased likelihood of persistence of symptoms thereafter.
Environmental exposures also seem to play an important role as risk factors for
transient infant wheezing. Children who attend daycare during the first months of life
or who live with older siblings at home are more likely to wheeze in early life, but this
increased risk does not seem to extend beyond the age of 4–6.24 Exposure to increased
levels of house dust endotoxin has also been shown to be associated with increased risk
of wheezing during the first years of life, but this risk does not seem to extend beyond
the first three to six years of life either.25 Moreover, endotoxin exposure in early life
appears to decrease the risk of subsequent development of atopic wheezing and allergic
sensitization during the school years. This apparent contradiction is discussed in more
detail in Chapter 3. Exposure to allergens such as cockroaches26 is also associated with
significant increased risk of wheezing during the first years of life, without concomitant
increased risk of developing allergic sensitization to these or other allergens before the
age of 3. It is therefore possible that factors that increase irritation of the airways or
upregulate immune responses to viruses may increase the incidence of transient
wheezing in early life, but this issue requires further elucidation.
Male sex is also very strongly associated with the risk of transient infant wheez-
ing.15,18 This finding is of great interest because a recent, very large, multicenter analysis
of lung function during the first year of life confirmed that girls have larger size-
corrected maximal expiratory flows obtained with the chest compression technique
than males.5 The hypothesis that airway structure may be an important determinant
factor for transient infant wheezing is supported by this correspondence between levels
of lung function, gender and risk for this condition.
An intriguing finding of three longitudinal studies15,18,27 is that children of younger
mothers are more likely to have transient infant wheezing than children of older
mothers. There is no clear explanation for this finding but children of younger mothers
are also of a lower birthweight than those of older mothers.27 It is thus possible that,
much like for somatic growth, airway growth may also be related to maternal age. There
indeed appears to be some evidence that children of younger mothers have lower levels
of lung function than those of older mothers.27
Finally, bottle-feeding is also associated with transient infant wheezing.15,18,28 The
mechanisms by which breastfeeding may decrease the risk of transient infant wheezing
may have to do with protection against the development of more severe viral infections.
The protective effect of breastfeeding disappears with age and is not observed for
persistent wheezing.

Non-atopic persistent wheezing (20% of wheezers < 3 years of age)

As explained earlier, approximately 40% of all children who wheeze during the first
three years of life have parental reports of continued wheezing at the age of 6.
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EPIDEMIOLOGY OF WHEEZING IN INFANTS AND PRESCHOOL CHILDREN 7

Only about half of these persistent wheezers have evidence of sensitization against local
aeroallergens, which contrasts with > 90% of allergic children among those who have
current wheezing at age 13.29 For years, the issue remained unresolved as to whether
these non-atopic wheezers of the toddler and early school years were to become the
future allergic asthmatics or if these children were a different phenotype of childhood
wheezing. This is certainly not an academic matter because it is a common belief among
experienced pediatricians and specialists that toddlers do not respond as well as older
children to the most widely used anti-inflammatory and bronchodilator therapies
successfully used in older children and adults with asthma. Moreover, many children
presenting with wheezing in this age group have symptoms mainly during the winter
months, a time when viral infections are most prevalent in the community. It was thus
suspected, but never substantiated in controlled studies, that there was a group of
preschoolers who had airway obstruction mainly during viral infections, that their
symptoms, much like those of transient wheezers, were not associated with increased
prevalence of allergic sensitization and that their prognosis was better than that of
atopic wheezers.
Recent longitudinal studies have confirmed this suspicion. When preschool wheezers
were followed up to the school years, it was found that by early adolescence most of those
who were non-atopic were no longer wheezing.30 The main factor associated with
this form of wheezing was the age at which their wheezing had started: the majority of
these children had objective evidence of wheezing LRI during the first year of life,
whereas those with atopy-associated wheezing were more often reported to have their
first wheezing episodes during the second or third years of life. This pattern of presenta-
tion of non-atopic wheezing was confirmed when the data were analyzed in a different
way: the outcome up to the age of 13 of the first episode of LRI occurring before 3 years
of age was assessed prospectively according to its etiology.31 A consistent pattern was
observed for children who had confirmed RSV-LRI, most of these occurring during the
first year of life as described earlier: these children were three to four times more likely to
wheeze at the age of 6 than their peers without RSV-LRI. However, this increased risk
withered markedly with age and the risk of wheezing in children with RSV-LRI was only
marginally increased by the age of 13. Children with confirmed RSV-LRI were not more
likely to be atopic or to have elevated serum IgE levels at the age of 11. Thus, both retro-
spective and prospective analysis of the data gave the same result: a group of children,
most of whom wheezed during RSV infection in early life, were more likely to wheeze,
especially during the toddler years, and this form of wheezing was unrelated to allergic
sensitization. The natural trend of this form of wheezing was to remit with age, and thus
the decreasing association between RSV-LRI and wheezing between the ages of 6 and 13.
Although in studies performed in developed English-speaking countries non-atopic
wheezers are already a minority among children who wheeze during the early school
years, the same does not appear to hold true in all populations and in all latitudes.
Likewise, empirical observations suggest that the generally good long-term prognosis of
non-atopic wheezing in toddlers raised in developed societies may not be observed in
underdeveloped countries. Recent studies from Australia, Peru and Ethiopia illustrate this
point. In Australia, comparisons of the prevalence of asthma symptoms and atopy were
made between Aboriginal and non-Aboriginal children between the ages of 7 and 12
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8 WHEEZING DISORDERS IN THE PRESCHOOL CHILD

living in the same rural communities.32 As a group, Aboriginal children were signifi-
cantly less likely to be atopic and to have allergic rhinitis than non-Aboriginal children,
but were equally likely to wheeze (31.0 versus 27.3%) and to have a diagnosis of asthma
(39.4 versus 39.3%). Among Aboriginal children, having had bronchitis before the age
of 2 was a strong risk factor for wheeze (adjusted odds ratio of 9.3) and asthma
(adjusted odds ratio of 19.3). This contrasted with what was observed in Caucasian
children in whom, much like in the Tucson study described earlier, bronchitis before
the age of 2 was only weakly associated with current asthma and wheezing between the
ages of 7 and 12. In the Peruvian study, 8–10-year-old children living in a deprived
urban area of Lima were studied.33 Those with reported wheezing during the previous
year had mild symptoms and were not more likely to be atopic than those without
wheezing, but they did have diminished levels of lung function and were more likely to
have exercise-induced falls in lung function. Finally, in Ethiopia, schoolchildren living
in rural areas who wheezed were not more likely to be atopic than those who did not
wheeze, whereas those living in urban areas showed a significant association between
asthma symptoms and allergic sensitization.34 Therefore, the natural history and prog-
nosis of non-atopic wheezing differs by socioeconomic status of the population, by
environmental exposures, by ethnic group and likely by genetic background. Certainly,
increased exposure to viral infection in children of lower socioeconomic status
increases the likelihood of viral-associated wheezing. But the increased prevalence of
non-atopic wheezing relative to atopic wheezing must also be due to a decreased likeli-
hood of the form of allergic sensitization which is characteristic of atopic wheezing
among children living in rural areas or in deprived social conditions. It is possible that
increased exposure to microbes in general, which is characteristic of small children
living in poverty, may have a dual effect. On the one hand, it would be associated with
an increase in the incidence of viral and bacterial infection, with consequent more
severe airway damage and persistence of wheezing associated with viral infection into
the late school years. On the other hand, the same infections that increase the risk of
non-atopic persistent wheezing in susceptible individuals may decrease the likelihood
of allergic sensitization and of atopic wheezing, the mechanisms of which will be
explained in greater detail in Chapter 3.

Risk factors for non-atopic persistent wheezing

We are only beginning to understand what determines non-atopic wheezing in toddlers
and schoolchildren. The suspicion that functional characteristics of the lung are
involved was suggested many years ago when it was found that children with a history
of RSV-LRI had lower levels of lung function and increased prevalence of bronchial
hyperresponsiveness (BHR) during the school years than those without such a
history.35,36 This hypothesis was confirmed by two recent longitudinal studies. Data from
the Tucson Children’s Respiratory Study showed that those with a history of RSV-LRI
have diminished lung function at the age of 11, independent of current wheezing at that
age.31 However, a history of RSV-LRI was also associated with marked increase
responses to a bronchodilator.31 As a consequence, post-bronchodilator lung function
was not significantly different between children with and without a history of RSV-LRI.