52

Diagnosis of Asthma in Infants

and Children
THERESA W. GUILBERT | ROBERT F. LEMANSKE, JR. | DANIEL J. JACKSON

CONTENTS

SUMMARY OF IMPORTANT CONCEPTS

Introduction 861

Childhood asthma is a heterogeneous disease with many phenotypes that may account for different responses to treatment and
varied outcomes.
The severity of asthma in early childhood determines the severity
of the symptoms and loss of lung function in later years.
Typical wheezing patterns in infants or preschool children are
short, recurrent exacerbations of cough and wheeze separated
by symptom-free intervals.
Major factors that may predict risk of persistent asthma are other
allergic diseases, reduced lung function, as well as viral respiratory wheezing illnesses and bacterial colonization in infancy.
A careful history and documentation of risk factors associated
with asthma helps establish the diagnosis.
It is important to evaluate for comorbid diseases that may make
asthma in the young child more difficult to control, including
allergic rhinitis, sinusitis, and gastroesophageal reflux.

Epidemiology 861
Pathogenesis and Etiology 862
Clinical Features: Wheezing Phenotypes 864
Risk Factors for Asthma Development in Childhood
and Adolescence 865
Patient Evaluation and Diagnosis 868
Coexisting Issues in Pediatric Asthma 871
Summary 873

Introduction
The diagnosis and management of pediatric asthma differs
from that of adult asthma. First, the natural history of pediatric
asthma is not fully understood, particularly with respect to the
relationship between risk factors and the subsequent development of asthma in later childhood and adult life. Second,
because asthma is a heterogeneous disease with many phenotypic expressions during childhood, it is challenging to characterize, since the clinical manifestations of asthma are nonspecific.
Third, the evaluation of asthma in children can be complicated
by difficulty in obtaining objective lung function measurements
as well as the lack of definitive biomarkers. Fourth, multiple
wheezing phenotypes are expressed in early childhood, many of
which outgrow their disease with time. Fifth, longitudinal data
that follow the disease from birth to death or disease remission
is lacking. Sixth, asthma may impact lung growth in the developing child, and anatomic differences in children (e.g., smaller
airway size, lower inspiratory flow rate) may impact medication
deposition in the airways. Lastly, it is unclear which therapy is
most effective for a particular wheezing phenotype, or whether
early intervention can alter the course and outcome of this
chronic disease.

Epidemiology
PREVALENCE
In the United States, 12.7% of children younger than 18 years
have been diagnosed with asthma at some point in their lifetime
(9 million children), 70% of whom are reported to have asthma
currently (6.5 million).1 The asthma period prevalence, or the

proportion of the population with asthma over a 12-month

period, as measured by the U.S. National Health Interview
Survey (NHIS) in children up to 17 years of age sharply increased
from 1980 to 1996, from 3.6% in 1980 to 7.5% in 1995. Since
the 2001 NHIS questionnaire change, the Centers for Disease
Control and Prevention (CDC) has reported that asthma prevalence has again risen from 8.7% in 2001 to 9.6% in 2009. The
pattern of childhood asthma prevalence differs by gender. Boys
experience an elevated current asthma prevalence rate until ages
15 to 17 years, when the current prevalence rate in girls is
higher, a relationship that persists through adulthood.1,2
Childhood asthma prevalence rates also vary greatly among
family-reported racial groups. Children of American Indian or
Alaska Native descent have asthma prevalence rates 25% higher
and black children 60% higher than white children. When
reported race and ethnicity are considered, Puerto Rican children have the highest prevalence of all groups, 140% higher
than non-Hispanic white children, whereas Mexican and Asian
children have low reported rates.
The prevalence of asthma has increased over the last 2
decades in many parts of the world but varies between countries
even when using standardized questionnaires. International
Study of Asthma and Allergies in Childhood (ISAAC) phase 3
data show reduced international differences in asthma symptom
prevalence, particularly in the 13- to 14-year-old group, with
decreased prevalence in English-speaking countries and Western
Europe and increased prevalence in regions where prevalence
was previously low. The increases in asthma symptom prevalence in Africa, Latin America, and parts of Asia indicate that
the global burden of asthma continues to rise while differences
in global prevalence decrease.3
861

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SECTION E Respiratory Tract

INCIDENCE
Currently, there are no international measures of asthma incidence, or the risk of developing asthma within a specified time.
A community-based study in Rochester, Minnesota, found that
the yearly incidence of definite and probable asthma in the first
year of life was 3%. The incidence rate dropped to 0.9% and
then to 0.1% in the age group 1 to 4 years and after the age of
15 years, respectively.2 Birth cohort studies provide useful information on the incidence and remission of various asthma phenotypes over time. One birth cohort study of 613 children
enrolled in the mid-1970s is in progress in Dunedin, New
Zealand.2 At age 9 years, 27% of all children had a history of at
least one episode of wheezing, and 4.2% were receiving asthma
therapy; 15% of the cohort had persistent wheezing from the
onset, and 12% had remission, only to relapse; 15% remained
in remission. Although the frequency of children who presumably had asthma is high (27% in persistent and relapse categories), it is similar to that in another birth cohort study in
Tucson.4 A community-based study in Melbourne, Australia,
enrolled children at age 7 and has followed them to age
42 years.2 In all three of these birth cohort studies, the age of
the first reported wheeze was similar, greatest in the first year
and leveling off in the teenage years.
SEVERITY
The severity of asthma symptoms and lung function among
children with persistent asthma appears to track with age. In
the Melbourne cohort study, 60% of children with mild intermittent asthma at age 7 had no symptoms in early adult life,
and only 10% had persistent asthma; 60% with moderate
asthma in childhood continued to have these symptoms as
young adults, whereas 30% had mild symptoms. More than
80% of children with severe asthma had moderate or severe
persistent asthma as young adults.2 Moreover, children who had
persistent asthma at age 10 years had lung function that was
significantly lower than in children with mild or no asthma
at age 10, and the degree of this loss did not change at age
35 years.5 In the New Zealand longitudinal study, lung function
was persistently impaired through childhood and adulthood at
a similar level in those with persistent asthma.2 However, in the
Childhood Asthma Management Program, which follows children with mild-moderate persistent asthma, particular subgroups (younger age of disease onset, male, higher baseline lung
function) appeared to be at risk for significant reduction in
postbronchodilator lung function.6 Thus, patients with persistent asthma whose symptoms start early in life are at the greatest
risk for development of chronic airflow limitation and continued severe symptoms.
Of all children with asthma, only 10% have severe or difficultto-control asthma, but this small subset accounts for a disproportionate use of health care resources.2 Severe asthma can be
distinguished from mild-moderate asthma by higher symptom
burden, more frequent exacerbations, greater allergic sensitization, more airflow obstruction, and increased exhaled nitric
oxide (eNO) despite higher doses of corticosteroids.7,8 Symptoms may also be discernible in early life. Historical data from
children enrolled in the National Institutes of Health (NIH)
Heart, Lung, and Blood Institute (NHLBI) Severe Asthma
Research Program (SARP) indicated that children with severe
asthma had the initiation of symptoms in the first 24 months

of life, versus 60 months in mild-moderate asthma.7 In addition, children with severe asthma had increased prevalence of
atopic dermatitis and positive skin-prick testing to aeroallergens by early childhood.7
In a SARP cluster analysis of children with asthma, four
clusters were identified, all with varying degrees of allergic
disease and a trend of increasing severity: (1) late-onset symptomatic asthma with normal lung function, (2) early-onset
atopic asthma with normal lung function, (3) early-onset atopic
asthma with mild airflow limitation, and (4) early-onset atopic
asthma with advanced airflow limitation.9 The number of controller medications, allergic disease, eNO concentrations, baseline lung function, and duration and onset of asthma were
major predictors of cluster assignment.
AMBULATORY CARE AND HOSPITALIZATION
Morbidity from asthma reflects several factors. In 2008 the
NHIS reported that 8% of children were hospitalized for
asthma,1 and asthma hospitalizations account for approximately 3% of all hospitalizations among children.2 Approximately 57% of children had at least one asthma attack in the
previous year,1 missing an average of 3.8 school days, and 32.5%
had an urgent care or emergency department (ED) visit because
of asthma. Moreover, many children are still not receiving the
recommended asthma care per NHLBI asthma guidelines, such
as receiving a written asthma action plan from their health care
provider (44.3%), using controller medication in the preceding
3 months (31.3%), or being advised to change the home or
school environment (50.6%).
MORTALITY
Asthma death rates climbed from 1980 through the mid-1990s,
although the rate among children has decreased since 1999. In
2004 the asthma mortality rate was 2.5 deaths per 1 million
children, a total of 186 asthma deaths.2 Nevertheless, the majority of these deaths likely could have been prevented through
appropriate asthma therapy and close medical follow-up. Mortality also appears higher in minority and inner-city populations,2 although studies of racial differences in asthma mortality
are greatly confounded by socioeconomic factors.
Risk factors for fatal asthma in children are similar to those
in adults: frequent symptoms, previous severe exacerbations,
and psychosocial problems (Box 52-1).
Other factors associated with asthma deaths in children
include passive smoke exposure or ingestion of foods to which
the child is sensitized. Significant risk factors associated with
intubation in children 5 to 12 years old were: secondhand
smoke exposure, psychosocial problems, family dysfunction,
upper respiratory infection, little formal education, ED visit for
asthma in past year, hospitalization for asthma in past year,
crowding, low socioeconomic status, steroid dependency,
parental history of asthma or allergy, and language barriers.

Pathogenesis and Etiology

PATHOPHYSIOLOGY
The pathophysiologic factors related to reversible airflow
obstruction in asthma are reviewed in depth elsewhere in this
textbook. The pathologic features of asthma in older children

52 Diagnosis of Asthma in Infants and Children

BOX 52-1 RISK FACTORS FOR FATAL ASTHMA

ASTHMA HISTORY
Previous severe exacerbation (e.g., intubation or intensive care
unit admission for asthma)
Two or more asthma hospitalizations for asthma in the past year
Three or more emergency department (ED) visits for asthma in
the past year
Hospitalization or ED visit for asthma in the past month
Use of two or more canisters per month of short-acting bronchodilators (-agonists, SABAs)
Difficulty perceiving asthma symptoms or severity of
exacerbations
Other risk factors: lack of a written asthma action plan, sensitivity to Alternaria
SOCIAL HISTORY
Low socioeconomic status or inner-city residence
Illicit drug use
Major psychosocial problems
COMORBIDITIES
Cardiac disease
Other chronic lung disease
Chronic psychiatric disease
Modified from National Asthma Education and Prevention Program.
Guidelines for the diagnosis and management of asthma: clinical
practice guidelines. Expert Panel Report 3. Bethesda, Md:
National Institutes of Health/National Heart, Lung, and Blood
Institute; 2007.

are similar to those in adults and include tissue eosinophilia,

loss of airway epithelium, smooth muscle enlargement and contraction, bronchial goblet cell hyperplasia, submucosal gland
hypertrophy, vascular congestion, reticular basement membrane (RBM) thickening, airway inflammation, and luminal
mucus.10,11
Bronchial biopsy studies in younger children have shown
variable airway inflammation and airway wall thickness. In
infants with reversible airflow obstruction evaluated for severe
wheezing or cough, bronchial biopsies demonstrated no RBM
(lamina reticularis) thickening or the eosinophilic inflammation characteristic of asthma in older children and adults, even
in the presence of atopic characteristics.2 Other studies found
no evidence of eosinophilic inflammation or remodeling in
wheezing infants in the first year of life, although both were seen
by age 3 years.12,13 Likewise, Barbato and coworkers14 found that
2- to 5-year-old children with asthma had increased epithelial
loss, RBM thickening, and eosinophilia compared with controls
of the same age. However, similar pathologic changes were seen
in atopic children without asthma. A study of 6- to 16-year-old
children with difficult asthma receiving high-dose inhaled corticosteroids (ICS) showed RBM thickening similar to that seen
in adult asthmatic patients and not associated with age,
symptom duration, lung function, or concurrent eosinophilic
airway inflammation. However, unlike in adults with asthma,
no relationship was seen between RBM thickness and bronchial
wall thickening on high-resolution computed tomography
(HRCT) scan in children with difficult asthma.2
Persistent airflow obstruction has been associated with a
greater density of CD4+ T lymphocytes in endobronchial biopsy
specimens in 27 school-age children with difficult asthma after
treatment with systemic corticosteroids compared with controls.2 Conversely, Bossley and colleagues15 demonstrated that

863

school-age children with severe steroid resistant asthma had

evidence of airway remodeling and variable airway eosinophil
counts but not neutrophilia in both bronchoalveolar lavage
(BAL) fluid and biopsy specimens compared with controls.
Further, the Th2 mediators in BAL fluid, induced sputum, or
biopsy specimens were not significantly different between children with severe asthma and controls. Although this study
found a predominance of airway eosinophilia in children with
severe asthma, research in this area is not complete.
Other investigators have found that children with asthma
exhibit three types of airway inflammation: eosinophilic (37%),
paucigranulocytic (46%), and neutrophilic (3% to 50%).16-18
Although airway neutrophils may also be present in a subset of
children with severe asthma19 neutrophils often coexist with
eosinophils in the airway tissue and epithelial lining fluid.20,21
Moreover, these distinct airway inflammatory patterns may
identify specific phenotypes that may have more variable
response to asthma medication.22-24 Children with the eosinophilic inflammation phenotype have increased symptoms, less
controlled disease, more atopy, impaired lung function, greater
airway hyperresponsiveness, and an increased frequency of
exacerbations than other phenotypes.17,25 However, eosinophilic
airway inflammation is typically steroid responsive.2 The neutrophil inflammatory phenotype has been reported to account
for half the burden of asthma at all ages.26 Preschool children
have been shown to have neutrophilic patterns of inflammation
and augmented CXCL8 (IL-8) expression,27-29 perhaps caused
by repeated respiratory viral infection23,30,31 or smoke exposure.32 This noneosinophilic inflammatory phenotype in adults
has been correlated with poor response to corticosteroids.33
Use of BAL in young wheezing children showed a threefold
increase in total cells, most significantly lymphocytes, polymorphonuclear neutrophils, and macrophages/monocytes, compared with normal children. In addition, leukotriene B4 (LTB4),
LTC4, prostaglandin E2 (PGE2), and the potentially epithelialderived 15-hydroxyeicosatetraenoic acid (HETE) were all
increased.34 Moreover, in toddlers with persistent wheezing.27
BAL fluid neutrophilia is common and correlates with CXCL8
concentrations. In children with severe or difficult-to-treat
asthma with persistent airway obstruction despite high-dose
ICS, those with persistent symptoms had greater BAL eosinophil
cationic protein (ECP) concentrations and lower interferon-
and IFN-/interleukin-4 (IL-4) ratio than patients with no or
infrequent symptoms.35 Further, Fitzpatrick and associates21
found that IL-13 and IL-6 in BAL fluid differentiated patients
with asthma from controls, whereas growth-related oncogene
(CXCL1), RANTES (CCL5), IL-12, IFN-, and IL-10 best characterized severe versus moderate asthma in children.
Fractional exhaled nitric oxide (FeNO) can be measured
noninvasively and thus is a well-studied biomarker of airway
inflammation in children and may be a useful diagnostic tool.
FeNO has moderate capability to differentiate young children
with asthma from those without, to identify children likely to
respond to ICS, and to predict children who will experience
an asthma relapse after a reduction in ICS therapy. Also, the
American Thoracic Society (ATS) recently published evidencebased guidelines for the use and interpretation of FeNO.36
It supports the use of FeNO to detect eosinophilic airway
inflammation, determining the likelihood of corticosteroid
responsiveness, monitoring of airway inflammation to determine the potential need for corticosteroid, and unmasking of
otherwise unsuspected nonadherence to corticosteroid therapy.

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SECTION E Respiratory Tract

In children (<12 years), FeNO levels above 35 parts per billion

(ppb) suggest the presence of eosinophilic airway inflammation
and likely responsiveness to inhaled corticosteroids. FeNO
levels below 20ppb suggest that eosinophilic airway inflammation is unlikely and that the individual is not likely to respond
to treatment with (or increasing the dose of) inhaled corticosteroids depending on the clinical context.
Exhaled breath condensate (EBC), another noninvasive technique for measuring airway inflammation, is obtained by
cooling exhaled air and is believed to reflect contents of the
airway lining fluid. Hydrogen peroxide, isoprostanes, aldehydes,
and nitrotyrosine are considered markers of oxidative stress,
and these levels are increased in EBC of children with asthma,
suggesting an imbalance between oxidants and antioxidants.
Conversely, glutathione, a protective lung antioxidant, is
decreased in children with acute asthma, suggesting a reduced
antioxidant capacity. The inflammatory mediators, cysteinyl
leukotrienes (cysLTs), are increased in the EBC of children with
atopic asthma even while receiving corticosteroids.37 Robroeks
and colleagues38 demonstrated that patients with asthma had
greater concentrations of multiple chemokines and helper T cell
type 1 (Th1) and Th2 cytokines in EBC than healthy children.
Soluble intercellular (sICAM) and soluble vascular (sVCAM)
adhesion molecule levels were higher in children with asthma
than in healthy children. Also, airway pH balance may have a
role in asthma; reduced EBC pH has been reported in children
with acute or stable asthma.2
Several other mediators of inflammatory cells are significantly higher in very young children with asthma, including the
number of blood eosinophils, serum ECP, eosinophil-derived
neurotoxin (EDN), and urinary EDN.39 In addition, both
increased ECP levels and cysLTs have been obtained from nasal
washings in wheezing children younger than 2 years. These
findings suggest that the inflammatory and structural changes
associated with asthma occur sometime after infancy during the
early preschool years, when children develop more persistent
symptoms of airway dysfunction.
ANATOMIC AND PHYSIOLOGIC FACTORS
The most important anatomic or physiologic factors in early
life predisposing infants and young children to wheezing illnesses are disproportionate narrowing of the smaller peripheral
airways and decreased static elastic recoil properties of the lung.
Peripheral airway conductance is low in the first 5 years of life
but then increases fourfold as the child grows, resulting in a
larger cross-sectional diameter of the smaller airways. Other
causes of decreased static elastic lung recoil include the more
compliant rib cage in infants, decreased collateral ventilation,
and absence of fatigue-resistant skeletal muscle in the diaphragm. All these may contribute to the development of
obstructive airway symptoms in infants and young children.
Further, the relatively small airway diameter predisposes children to airway obstruction from edema, mucous secretion, and
smooth muscle constriction.
In addition to anatomic factors, immune function may play
a role in the development of early childhood wheeze. Reduced
IFN- production by peripheral blood mononuclear cells in the
first year of life is associated with an increased risk of wheezing
in early and later childhood, as shown in an unselected birth
cohort40 and a cohort of children with a family history of allergies and/or asthma.41 Jackson and coworkers42 studied a birth

cohort of 285 children with a family history of allergies/asthma

and found that allergic sensitization precedes rhinovirus wheezing, and that the converse is not true. The authors concluded
that allergic sensitization may lead to more severe rhinovirusinduced lower respiratory illnesses. In contrast, Bosco and
colleagues43 found that activation of Th1-like/cytotoxic and
interferon signaling pathways during acute exacerbations was
decreased in children with both asthma and evidence of chronic
airway obstruction. These associations were independent of the
identification of picornaviruses in nasal secretions or the use of
medications at the time of the exacerbation.

Clinical Features: Wheezing

Phenotypes
Identifying phenotypes of pediatric asthma and the associated
risk factors with each phenotype may help predict long-term
outcomes and identify high-risk children who might benefit
from secondary prevention strategies. Several longitudinal
studies have described wheezing phenotypes in young children.
Tucson Childrens Respiratory Study (TCRS). This study followed 1246 newborns for lower respiratory tract infections in
the first 3 years of life. It identified four different wheezing
phenotypes in childhood by the presence of wheezing symptoms during the first 3 years of life and again at age 6 years:
(1) never (51%); (2) transient early (20%), with onset of wheezing before age 3 years and wheezing resolved by age 6; (3)
persistent (14%), with onset of wheezing before age 3 years with
continued wheezing at age 6; and (4) late onset (15%), with
onset of wheezing between 3 and 6 years of age.4 Further analyses of the TCRS cohort revealed differences in risk factors and
persistence of the disease between atopic and nonatopic persistent wheezers.2
TRANSIENT EARLY WHEEZING
The early transient wheezing phenotype is the most prevalent
form of early wheezing and is characterized by recurrent episodes of wheezing mainly in the first year of life. Of children
who wheeze in the first 3 years of life, 60% have resolution of
their symptoms by 6 years of age.4 Transient wheezing has no
significant relationship to atopy, and maternal smoking during
pregnancy is significantly associated with this phenotype (odds
ratios [OR] 2.2; 95% confidence interval [CI] 1.3-3.7). Interestingly, transient early wheezing was associated with lower levels
of lung function (based on V max FRC) compared with children
who never wheezed when evaluated at age 3 to 6 months.2,4
Subsequent characterization of the transient wheezers from the
TCRS revealed that less than one fourth of transient wheezers
continued to wheeze during adolescence. Other risk factors for
the early transient wheezing phenotype include infants with
school-age siblings, day care attendance, house-dust endotoxin,
and allergen exposure (e.g., cockroach), male gender, and bottle
feeding. Children with transient wheezing do not have increased
methacholine reactivity or peak expiratory flow (PEF) variability at age 11 years.2
NONATOPIC PERSISTENT WHEEZING
The nonatopic persistent wheezing phenotype in children is
associated with the first episode of wheezing occurring before

52 Diagnosis of Asthma in Infants and Children

865

age 1 year. This phenotype represents 20% of wheezy children

younger than 3 years, and the wheezing episodes become less
frequent by the early teenage years. Children with nonatopic
transient wheezing have a lower level of prebronchodilator lung
function and enhanced airway reactivity. It is speculated that
this phenotype may be caused by an alteration in the regulation
of airway tone leading to viral-induced wheeze.2

The Netherlands Prevention and Incidence of Asthma and

Mite Allergy (PIAMA) Study. This longitudinal birth cohort
study demonstrated similar wheezing phenotypes in 2810 children,45 as well as similar associations of these wheezing phenotypes to risk factors associated with the TCRS phenotypes.

IgE-ASSOCIATED ATOPIC PERSISTENT

WHEEZING

The episodic and multi-trigger wheezing phenotype classifications are defined retrospectively; their utility for clinicians to
predict future risk for asthma in preschool wheezers has been
considered suboptimal. Therefore the European Respiratory
Society (ERS) defined two symptom-based phenotypes: episodic and multi-trigger wheeze.46 Children with episodic
(viral) wheeze have discrete symptomatic periods. Children
with multi-trigger wheeze have wheezing both during exacerbations and between episodes in response to various triggers,
including viruses, allergens, exercise, and cigarette smoke. These
children also have lower airway function compared with the
episodic wheezing phenotype.47 Adding an additional layer of
complexity, these phenotypes may not be stable over time. In
one study, more than half the children classified as episodic or
multi-trigger wheezers switched to the other phenotype in the
subsequent year.48

The atopic persistent wheezing phenotype associated with IgE

is found in 20% of children who wheeze during the first 3 years
of life, with symptoms typically first presenting after age 1 year.4
Risk factors associated with atopic wheeze include male gender,
parental asthma, atopic dermatitis, eosinophilia at 9 months,
and history of wheezing with lower respiratory tract infections.
This phenotype is also associated with early sensitization to food
or aeroallergens. Children in the atopic persistent wheezing
group in the Tucson study had normal lung function in infancy
but reduced lung function at age 6 years compared to children
with no history of wheezing with lower respiratory illnesses.
Airway (bronchial) hyperresponsiveness is often observed and
may only be observed after the first episode of wheezing.
As children with these reported phenotypes reached adolescence, the TCRS revealed that persistent wheezers were more
than three times more likely to continue wheezing than never
wheezers and continued to be more atopic than never and
transient wheezers. In addition, persistent wheezers continued
to have lower airflow, but no progressive deficits in lung function were observed in school-age children relative to never
wheezers.2
Italian Studies of Respiratory Disorders in Childhood and
the Environment (SIDRIA). This longitudinal study of 16,333
school-age children had a classification scheme similar to the
TCRS. Two exceptions were an upper age limit of 2 years for
transient early wheezing and a lower frequency of wheeze. In
this study, 83% had never wheezed, 7% had transient early
wheezing, 4% had persistent wheezing, and 6% had late-onset
wheezing.2
Avon Longitudinal Study of Parents and Children (ALSPAC).
This prospective study assessed maternal report of wheezing in
8594 children2 using sophisticated statistical methods. Using
shorter intervals than TCRS, two additional phenotypes were
identified, for a total of six44: (1) never/infrequent wheeze
(59%); (2) transient early wheeze (16%): wheezing typical from
6 to 18 months, but rare after 42 months; (3) prolonged early
wheeze (9%): wheezing typical from 6 to 54 months, but rare
after 69 months; (4) intermediate-onset wheeze (3%): wheezing
rare from 6 to 18 months, but typical thereafter; (5) late-onset
wheeze (6%): infrequent wheezing from 6 to 42 months, but
typical thereafter, and (6) persistent wheeze (7%): wheezing
typical from 6 months onward. The transient early (infant),
late-onset, and persistent wheezing groups had similar risk
factors to the TCRS phenotypes. The prolonged early wheezing
group had increased airway responsiveness and lower schoolage lung function, and the intermediate-onset group demonstrated a higher association with parental history of asthma
(especially maternal) and personal allergic disease compared to
the never/infrequent wheeze phenotype.

EPISODIC AND MULTI-TRIGGER WHEEZING

Risk Factors for Asthma

Development in Childhood
and Adolescence
ALLERGIC SENSITIZATION
Many studies have demonstrated the relationship between allergic disease and asthma. In the Tucson cohort, allergic disease
was the key risk factor for development of persistent asthma.4
Children with late-onset and persistent wheezing had a significantly greater rate of allergen sensitization at age 6 years, and
Alternaria sensitization was correlated with an increased rate of
asthma at 22 years.49 In addition, the intermediate-onset, lateonset, and persistent wheezing phenotypes in the Avon cohort
were most strongly associated with allergic sensitization and
childhood asthma.44 In atopic individuals, allergic rhinitis often
precedes the development of asthma and is a known risk factor
for asthma. Several lines of evidence suggest that allergic rhinitis
is associated with more difficult-to-control asthma and greater
use of resources for asthma.2
GENDER
Gender differences are seen in asthma and allergic diseases in
childhood and adolescence, suggesting that gender is an important factor in their development. Boys have a higher risk of
asthma than girls (OR 1.4-1.6).50 This pattern is further complicated by the observation that boys consistently show higher
levels of total IgE51,52 allergic sensitization51,53 than girls. In a
high-risk birth cohort (COAST), gender differences in immune
response profiles included greater mitogen-induced IFN-
responses in boys at ages 1 and 3 years. Among children who
wheezed during the third year of life, boys had increased IFN-,
IL-5, and IL-13 responses at age 3 years. In adolescence the
pattern reverses, and asthma or wheezing is more prevalent in
girls than boys.54-56 Several studies also demonstrated that

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SECTION E Respiratory Tract

obesity or increased body mass index (BMI) is associated with

asthma and atopy in females but not males.57-60
Differential lung/airway growth between genders may play a
role.61 Also, the higher prevalence of wheeze in boys may be
partly explained by a greater prevalence of diagnosed asthma in
boys and comparative undertreatment of girls unless they
develop severe manifestation of disease.62 Possible reasons for
these gender differences include hormonal changes during
puberty, differences in lung growth, and gender-specific differences in environmental exposures.
REDUCED LUNG FUNCTION
Children in higher risk wheezing phenotypes have a greater
degree of lung function impairment compared with other phenotypes.44,63 In the Avon ALSPAC cohort, phenotypes with prolonged early, intermediate-onset, and persistent wheezing had
lowest lung function, and intermediate and late-onset phenotypes had the greatest airway hyperresponsiveness (AHR).44
In the Tucson cohort, children in the persistent wheezing
group had normal lung function in infancy but reduced function at 6 years and into adolescence.4 Furthermore, persistent
wheezing early in life and AHR and low airway function at
6 years were related to both chronic and newly diagnosed
asthma at 22 years.49 Norwegian and Australian cohorts showed
abnormal lung function as young as 1 month in children who
developed persistent wheeze later in childhood.2,64 In addition,
preschool rhinovirus wheezing illnesses are associated with
decreased lung function in later childhood in children with a
family history of allergies or asthma.65
VIRAL AND BACTERIAL UPPER RESPIRATORY
TRACT INFECTIONS
The origins of asthma often begin in early childhood, with the
initial wheezing episodes predominantly linked to infections
with various viral etiologies. It is unclear whether certain viral
respiratory infections cause asthma, or if wheezers with these
illnesses are predisposed to asthma.66 Respiratory syncytial virus
(RSV), human rhinovirus (HRV), influenza, parainfluenza,
metapneumovirus, and other viral pathogens are significantly
associated with wheezing in the first few years of life. During
early childhood, certain viruses have been associated with the
development of the asthmatic phenotype. RSV infection has
been linked to recurrent wheezing in childhood, although data
are inconsistent as to whether infections lead to nonatopic
wheezing that resolves with age or whether these are associated
with development of atopic asthma. Until molecular diagnostic
techniques permitted more comprehensive analyses of specimens for respiratory pathogens, it has been difficult to isolate
the effects of RSV from those induced by other viral infections,
particularly effects caused by HRV strains. In addition, almost
one third of preschool children may test positive for more than
one virus when hospitalized for wheezing.2
Rhinovirus has recently been reported to be the most frequent cause of asthma exacerbations in both young and older
children with asthma, involving all three subclasses of the virus
but especially clade C.67,68 Moreover, children who experience
wheezing episodes with rhinoviruses in the first few years of life
may be at greatest risk for persistent wheezing and asthma later
in childhood.42,69 Given the rapid developmental processes that
occur during early childhood, particularly in the pulmonary
system, the effects of an acute inflammatory response to a viral

lower respiratory tract infection during this period might have

long-term detrimental consequences for lung structure and
function. These infections may amplify the asthma risk with
allergic disease and reduce lung function during early childhood.70,71 Further, an individual with immune function biased
toward atopy may have both altered host defenses that increase
susceptibility to bacterial and viral infections and increased risk
of developing asthma.72-75 Indeed, recent findings indicate a
causal relationship between allergic sensitization in early life
and the subsequent development of HRV-induced wheezing.76
Other host-specific factors (genetic, environmental, immunologic, developmental) may influence the initial response or subsequent development of an asthma phenotype following viral
respiratory tract illnesses, because the majority of children have
been infected by these viruses by 2 years of age.
Bisgaard and coworkers77 demonstrated that neonates (1
month of age) colonized in the hypopharyngeal region with
Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis or a combination of these organisms are at
increased risk for recurrent preschool wheezing and asthma at
age 5 years. Moreover, Schwerk and colleagues78 studied 42 preschool children with severe persistent wheezing using bronchoscopy and BAL and found that 81% had neutrophilic
inflammation, 59% of whom had increased bacterial counts
of S. pneumoniae, H. influenzae, or M. catarrhalis. After 2 to
6 weeks of antibiotic treatment, 92% of these children showed
marked improvement in symptoms.78
Paradoxically, some infections have also been proposed to
prevent the development of asthma. This is suggested by the
hygiene hypothesis, which proposed that early life exposures to
protective factors (e.g., larger family size) that lead to more
infections might protect against development of atopic disease.
Early exposures to microbial agents such as livestock and probiotics have been studied to assess their ability to influence
development of atopic disease. Furthermore, the gastrointestinal microbiome or commensal bacteria may also influence a
childs risk of developing allergy and asthma.79 Some have
attributed these findings to an effect on the critical balance
between the expression of Th1 and Th2 cytokines producing an
exuberant Th1 response, or an effect on T regulatory lymphocytes mitigating atopic immune development and responses79,80
(see Chapters 1 and 49).
ASTHMA PREDICTIVE INDEX
The most common scoring system used to predict asthma is the
Asthma Predictive Index. The API was derived from the Tucson
cohort study to predict future wheezing in children 3 years of
age with at least one previous episode of wheezing2,81,82 (Table
52-1). Original major criteria were clinician-diagnosed eczema
(dermatitis) and parental asthma. Minor criteria were cliniciandiagnosed allergic rhinitis, wheezing apart from colds, and
eosinophilia in peripheral blood (4% or more eosinophils).
Children with wheezing and either one major or two minor
criteria at 3 years of age were four to seven times more likely to
have asthma during later childhood. The API was validated in
a population-based birth cohort of 1954 children in Leicester,
UK, with similar results.83 In addition, these results were comparable using a simpler definition.
The greatest value of the API may lie in the identification of
children who are unlikely to develop persistent asthma. With
low sensitivity (15% to 57%), the API is a poor predictor of
development of asthma.2,81-84 However, with a high negative

52 Diagnosis of Asthma in Infants and Children

TABLE

52-1

Modified versus Original Asthma Prevention

Index (API)

1. A history of four or more wheezing episodes, with at least one

diagnosed by a physician.
2. In addition, the child must meet at least one of the following
major conditions or at least two of the following minor criteria.
Modified API
MAJOR CRITERIA
Parental history of asthma
Physician-diagnosed atopic
dermatitis
Allergic sensitization to at least
one aeroallergen*
MINOR CRITERIA
Allergic sensitization to milk, egg,
or peanuts*
Wheezing unrelated to colds
Blood eosinophils 4%

Original API
Parental history of asthma
Physician-diagnosed atopic
dermatitis

Physician-diagnosed allergic
rhinitis*
Wheezing unrelated to colds
Blood eosinophils 4%

Modified from Guilbert TW, Morgan WJ, Zeiger RS, etal. Atopic
characteristics of children with recurrent wheezing at high risk for
the development of childhood asthma. J Allergy Clin Immunol
2004;114:1282-7.
*Differences in indices.

predictive value, the API can identify children with a low likelihood of developing asthma later when their API is negative.49,81,82
The U.S. National Asthma Education and Prevention Program
Expert Panel Report 3 (EPR-3) supports use of a modified API
(allergic skin testing replaces clinician-diagnosed allergic rhinitis) in the diagnosis of asthma, although the sensitivity and
specificity has yet to be determined.85 The API may help identify
preschoolers who respond to inhaled corticosteroids.86,87 For
example, in a study of preschool children with recurrent wheeze
and a positive API, ciclesonide modestly reduced wheeze exacerbation rates and improved lung function.87
Other asthma risk scores use combinations of factors that
confer significantly greater risk for a preschooler with wheeze
to have persistent asthma in later childhood, including recurrent chest infections at age 2 years, family history of asthma,
positive skin-prick test to at least one food or inhalant allergen
at age 4, recurrent nasal symptoms at 1 year,88 greater severity
of obstructive airway disease during the first 2 years of life,89
male gender, postterm delivery, medium-low parental education, wheezing frequency, wheezing/dyspnea apart from colds,
parental report of serious infections, and physician-diagnosed
eczema.90 In one study, children with high scores had 46% risk
of later persistent asthma compared to 3% risk of later asthma.90
The API and other predictive scores have not been validated in
diverse populations.
GENETICS
Although the molecular basis of several mendelian diseases has
been described, genetic studies of common diseases with
complex causes have met with less success. In asthma, these
evaluations are complicated by multiple childhood asthma phenotypes, inability to replicate significant results, early life exposure assessments, and the complexity of gene-by-environment
and gene-by-gene interactions. As a result, important associations might have been missed. Because the relationship between
genotype and phenotype is more complex than previously
thought, accurate study of age-related genetic relationships in

867

asthma requires long-term, longitudinal studies. To date, two

major groups of genes have been explored: (1) those related to
increased risk of developing asthma or particular phenotypes
and (2) those associated with corticosteroid response.91,92
TGFB1 polymorphisms correlate with disease severity,93 whereas
the C-C chemokine receptor 5 (CCR5) 32 polymorphism is
associated with decreased asthma susceptibility in children but
not adults. A promoter polymorphism for IL-12b has been
associated with impaired lung function (FEV1) in girls but not
boys, in childhood only. Three longitudinal studies have examined the role of 2-adrenoceptor polymorphisms in asthma
susceptibility and suggest that the Arg16 allele can be associated
with decreased airway function in infancy and the Gly16 allele
with asthma symptoms in childhood.2
The CC16 polymorphisms are associated with the development and persistence of childhood asthma.94 CD14 polymorphisms have been linked to early-onset atopy and early-onset
increased airway responsiveness in childhood, but not in young
adults, and asthma pathogenesis and lung function in smokers.95
The ORMDL3 gene product correlates with susceptibility to
early-onset asthma, particularly through interaction with early
life exposure to environmental tobacco smoke.96,97 GSTM1 null
and GSTP1 genotypes are linked to a greater risk of asthma98
and rapid decline of lung function among smokers.99 The
ADRB2 receptor gene correlates with increased risk of wheezing
among children with in utero and early childhood tobacco
smoke exposure.100 Finally, three genes (CHRH1, TBX21, and
FCER2) are associated with response to corticosteroids, and
these findings were replicated in several cohorts.101-103
Several cross-sectional studies of genetic polymorphisms
associated with asthma in children have been confirmed in
adult studies. Eighteen genetic polymorphisms in the IL-4,
IL-4R, IL-13, and the signal transducer and activator of transcription 6 (STAT6) pathway have been strongly associated with
both asthma and atopy (IgE) when all four genes have been
considered using stepwise statistics, however, when each gene
was analyzed separately, the significance of these relationships
was much smaller. Polymorphisms in the asthma susceptibility
gene ADAM33 (coding for a metalloproteinase) and others on
chromosome 20p13 have been associated with impaired lung
function in early childhood and confirmed in adult studies. The
C_7947 polymorphism in T-bet (TBX21 or T-box 21) on chromosome 17q21, which regulates Th1 lineage development, is
associated with AHR in white children with asthma and a
cohort of adult males. Polymorphisms in the G proteinrelated
receptor for asthma gene (GPRA) located on chromosome 7p
have been linked to asthma susceptibility and allergy in children
and adults.2
OTHER RISK FACTORS
Socioeconomic Factors
Several lines of evidence indicate low socioeconomic status
(SES) in the United States is a risk factor for asthma morbidity
and mortality. It is unclear whether race, ethnicity, or SES is the
principal risk factor associated with excessively high asthma
morbidity and mortality. Recent evidence suggests that minority residents of inner-city areas are particularly affected by high
rates of asthma morbidity and mortality. Racial and ethnic differences for asthma prevalence are well documented (see Prevalence, earlier). Among school-age children, increased asthma
prevalence in black children compared with white children
remained after adjustment for socioeconomic factors. A similar

868

SECTION E Respiratory Tract

pattern of racial and socioeconomic disparities are also seen in

the rates of ambulatory care visits, ED visits, and hospitalizations. These racial and ethnic disparities may be caused by
increased cockroach allergen sensitization in inner-city children
and ongoing exposure in those sensitized. Also, low SES may
also be associated with other problems that can impact asthma
control, such as family dysfunction, low literacy levels, stress,
crime, and substance abuse.2
Psychological Factors
Depression, stress, and anxiety are important risk factors for
asthma-related ED visits and mortality.85 Several studies found
a higher incidence of both anxiety and depression in children
and adults with asthma than in the general population.104-106
These psychological disorders may correlate with asthma
because this chronic pediatric disease increases the risk of
developing anxiety and depression. Also, however, children
with mood and anxiety disorders or those exposed to parents
with these disorders may be at increased risk of developing
asthma.107-109

Patient Evaluation and Diagnosis

HISTORY
The presence of multiple key indicators increases the probability that a child has asthma (Box 52-2). However, documenting
at least partially reversible airflow obstruction is helpful in
establishing a diagnosis of asthma, through a greater than 12%
increase in forced expiratory volume in 1 second (FEV1) from
baseline or a greater than 10% increase in predicted FEV1 after
inhalation of a short-acting -agonist (SABA). Although
eczema, hay fever, or a family history of asthma or atopic disease
is often associated with asthma, these are not key indicators.
Each key indicator is not diagnostic by itself, but the presence

BOX 52-2 KEY SYMPTOM INDICATORS

FOR CONSIDERING A DIAGNOSIS
OF ASTHMA
1. Wheezinghigh-pitched wheezing sounds when breathing out
(normal chest exam without wheezing does not exclude asthma)
2. History of any of the following:
Cough (worse particularly at night)
Recurrent wheeze
Recurrent difficulty breathing
Recurrent chest tightness
3. Symptoms occur or worsen in the presence of:
Exercise
Viral Infection
Inhalant allergens (e.g., animals with fur or hair, house-dust
mites, mold, pollen)
Irritants (tobacco or wood smoke, airborne chemicals)
Changes in weather
Strong emotional expression (laughing or crying hard)
Stress
Menses
4. Symptoms occur or worsen at night, waking the patient
Modified from National Asthma Education and Prevention Program.
Guidelines for the diagnosis and management of asthma: clinical
practice guidelines. Expert Panel Report 3. Bethesda, Md:
National Institutes of Health/National Heart, Lung, and Blood
Institute; 2007.

of multiple key indicators increases the probability of a diagnosis of asthma.

Typical wheezing patterns in infants or preschoolers are
short, recurrent exacerbations of cough and wheeze of varying
severity and duration, usually triggered by viral upper respiratory symptoms and separated by long symptom-free intervals.
It is important to obtain history regarding timing and pattern
of wheezing (acute or chronic), relationship of episodes to viral
illness and feeding, history of comorbidities, response to previous treatments, family and patient history of atopic disease, and
socioenvironmental factors contributing to morbidity. Box 52-3
provides guidelines for obtaining a history pertinent to establishing a diagnosis of asthma.110
Features of atypical wheezing that should alert the physician
to a diagnosis other than asthma include symptoms starting at
or shortly after birth, continuous wheezing, failure to thrive,
complete failure to respond to antiasthmatic medications, and
no association with typical triggers such as viral upper respiratory infections or exposure to allergens after sensitization. Box
52-4 lists the differential diagnosis of asthma and comorbid
diseases, and Table 52-2 shows their relative frequency by age.
PHYSICAL EXAMINATION
A complete examination for asthma must focus on both the
upper and the lower respiratory tract, chest, and skin. Physical
findings that increase the probability of asthma are hyperexpansion of the thorax (use of accessory muscles, appearance of
hunched shoulders, barrel configuration to chest indicating
chronic air trapping), sounds of wheezing during normal
breathing or forced expiration, evidence of chronic rhinitis
(allergic shiners, allergic crease), and atopic dermatitis. Unilateral wheezing may indicate foreign body aspiration or development of a pneumothorax. Sinusitis (malodorous breath)
should be assessed because it may contribute to instability of
lower airway symptoms.39 Poor growth is often an ominous sign
of other diseases, such as congenital heart disease, cystic fibrosis,
and underlying immunodeficiency. Extremities should be
examined for clubbing and cyanosis that could be associated
with cystic fibrosis or other chronic lung diseases. Neurologic
examination should include signs of microcephaly or evidence
of weakness that might result in inadequate cough and aspiration, leading to wheezing.
In the acutely ill asthmatic patient, complaints of chest or
neck pain may indicate the dissection of air along the blood
vessels through the mediastinum into the neck. A crunching
sound is heard on auscultation of the chest, particularly over
the sternum, and crepitus is felt in the subcutaneous tissues
around the shoulders. The presence of a normal examination
does not rule out asthma because the disease is variable, and
signs of airflow obstruction are often absent between attacks.
RADIOGRAPHIC STUDIES
First-tier evaluation of the child with recurrent wheeze should
include a chest radiograph to evaluate for infiltrates, masses,
great vessel abnormalities, radiopaque retained foreign body,
and signs of asymmetry. Posteroanterior (PA) and lateral chest
radiographs are usually indicated in the initial evaluation of a
child with asthma, particularly if none has been performed
previously. In mild asthma the chest radiograph is normal. As
the child ages or the disease becomes more severe, radiographic

52 Diagnosis of Asthma in Infants and Children

869

BOX 52-3 SUGGESTED MEDICAL HISTORY FOR ASTHMA DIAGNOSIS

A detailed medical history of the new patient who is known or
thought to have asthma should address the following items:
1. Symptoms
Cough
Wheezing
Shortness of breath
Chest tightness
Sputum production
2. Pattern of symptoms
Perennial, seasonal, or both
Continual, episodic, or both
Onset, duration, frequency (number of days or nights, per
week or month)
Diurnal variations, especially nocturnal and on awakening in
early morning
3. Precipitating and/or aggravating factors
Viral respiratory infections
Environmental allergens, indoor (e.g., mold, house-dust mite,
cockroach, animal dander or secretory products) and
outdoor (e.g., pollen)
Characteristics of home, including age, location, cooling/
heating system, wood-burning stove, humidifier, carpeting
over concrete, presence of molds or mildew, characteristics
of rooms where patient spends time (e.g., bedroom and
living room with attention to bedding, floor covering, stuffed
furniture)
Smoking (personal and others in home or day care)
Exercise
Occupational chemical or allergens
Environmental change (e.g., moving to new home; going on
vacation; alterations in workplace, work processes, or materials used)
Irritants (e.g., tobacco smoke, strong odors, air pollutants,
occupational chemicals, dusts and particulates, vapors,
gases, aerosols)
Emotions (e.g., fear, anger, frustration, hard crying or
laughing)
Stress (e.g., fear, anger, frustration)
Drugs (e.g., aspirin and other NSAIDs; -blockers, including
eye drops)
Food, food additives, and preservatives (e.g., sulfites)
Changes in weather; exposure to cold air
Endocrine factors (e.g., menses, pregnancy, thyroid disease)
Comorbid conditions (e.g., sinusitis, rhinitis, gastroesophageal
reflux disease)
4. Development of disease and treatment
Age of onset and diagnosis
History of early life injury to airways (e.g., bronchopulmonary
dysplasia, pneumonia, parental smoking)

Progression of disease (better or worse)

Present management and response, including plans for managing exacerbations
Frequency of using (SABAs)
Need for oral corticosteroids and frequency of use
5. Family history
History of asthma, allergy, sinusitis, rhinitis, eczema, or nasal
polyps in close relatives
6. Social history
Day care, workplace, and school characteristics that may interfere with adherence
Social factors that interfere with adherence, such as substance
abuse
Social support/social networks
Level of education completed
Employment
7. History of exacerbations
Usual prodromal signs and symptoms
Rapidity of onset
Duration
Frequency
Severity (need for urgent care, hospitalization, ICU
admission)
Life-threatening exacerbations (e.g., intubation, ICU
admission)
Number and severity of exacerbations in the last year
Usual patterns and management (what works?)
8. Impact of asthma on patient and family
Episodes of unscheduled care (ED, urgent care,
hospitalization)
Number of days missed from school/work
Limitation of activity, especially sports and strenuous work
History of nocturnal awakening
Effect on growth, development, behavior, school or work performance, and lifestyle
Impact on family routines, activities, or dynamics
Economic impact
9. Assessment of patients and familys perceptions of disease
Knowledge of patient, parent, and spouse or partner about
asthma and their belief in chronicity of asthma and efficacy
of treatment
Patients perception and beliefs regarding use and long-term
effects of medications
Ability of patient, parents, and spouse or partner to cope with
disease
Level of family support and capacity of patient, parents, and
spouse or partner to recognize severity of an exacerbation
Economic resources
Sociocultural beliefs

Modified from National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma: clinical practice
guidelines. Expert Panel Report 3. Bethesda, Md: National Institutes of Health/National Heart, Lung, and Blood Institute; 2007.
ED, Emergency department; ICU, intensive care unit; NSAIDs, nonsteroidal antiinflammatory drugs; SABAs, short-acting -agonists.

signs of air trapping may be seen, such as hyperlucency, flattening of the diaphragms, increased anteroposterior (AP) diameter, or horizontal positioning of the ribs. Peribronchiolar
inflammatory changes and atelectasis are often observed in children with persistent asthma. The right middle lobe tends to be
a common target for loss of lung volume. A routine chest radiograph does not contribute significantly to the successful management of children with an acute exacerbation of asthma
unless the history or physical examination indicates the presence of a pneumothorax, pneumomediastinum, or other atypical complications. Barium esophography might demonstrate a
filling defect caused by a vascular ring, whereas a swallow study
might disclose microaspiration.

Chest computed tomography (CT) allows for detection of

thoracic masses, adenopathy, bronchiectasis, and delineation of
vascular structures. The role of HRCT for lung imaging in
infants and children with obstructive lung disease is a subject of
ongoing research. In patients with asthma, CT may show several
structural changes related to small-airway disease, including
cylindrical bronchiectasis, bronchial wall thickening, and air
trapping; an indirect marker for bronchiolar obstruction.
PULMONARY FUNCTION TESTS
Pulmonary function testing is important in the diagnosis and
management of asthma. The results should be reproducible and

870

SECTION E Respiratory Tract

BOX 52-4 DIFFERENTIAL DIAGNOSIS FOR

ASTHMA IN INFANTS AND CHILDREN

TABLE

52-2

Age-Related Differential Diagnosis

for Wheezing

Upper Airway Diseases

Allergic rhinitis and sinusitis

RELATIVE FREQUENCY OF
OCCURRENCE

Obstructions Involving Large Airways

Foreign body in the trachea or bronchus
Vocal cord dysfunction
Vascular rings or laryngeal webs
Laryngotracheomalacia, tracheal stenosis, or bronchostenosis
Enlarged lymph nodes or tumor

Condition

Obstructions Involving Small Airways

Viral bronchiolitis or obliterative bronchiolitis
Cystic fibrosis
Bronchopulmonary dysplasia (chronic lung
prematurity)
Heart disease

disease

of

Other
Recurrent cough not caused by asthma (infection, habit cough,
postnasal drip)
Aspiration from swallowing mechanism dysfunction or gastroesophageal reflux disease

Infancy

Childhood

Adolescence

Asthma

+++

+++

Airway malacia

++

Cystic fibrosis

+++

Foreign body

++

+++

Airway infection

+++

++

Bronchopulmonary
dysplasia

+++

Primary ciliary dyskinesia

++

Bronchiectasis

Congenital anomalies
(vascular ring)

+++

Vocal cord dysfunction

++

Tumors

Aspiration syndromes

Pulmonary edema

Modified from National Asthma Education and Prevention Program.

Guidelines for the diagnosis and management of asthma: clinical
practice guidelines. Expert Panel Report 3. Bethesda, Md:
National Institutes of Health/National Heart, Lung, and Blood
Institute; 2007.

Modified from Bierman CW, Pearlman DS, editors. Allergic diseases

from infancy to adulthood. 2nd ed. Philadelphia: Saunders; 1988.
, Unlikely to present in this age group; +, likely to present in this age
group; +/ may present in this age group.

comparable to established norms and should provide objective

assessment of the disease over time. Childrens perception of
asthma symptoms and airflow obstruction is variable, and pulmonary function tests (PFTs) can reveal obstruction much
more severe than estimated from history or physical examination, resulting in the child being placed in a more severe asthma
category than using symptom frequency alone.
As recommended by EPR-3, peak expiratory flow (PEF) is a
valuable, easily available measurement, well suited for monitoring trends in asthma control over time in children age 4 years
and older, but less useful in diagnosing asthma or classifying
severity.110 However, although PEF rates can correlate with
asthma trends over time, the limitations need to be recognized.
PEF monitoring is effort dependent, so low values obtained in
children may reflect effort, increasing airway obstruction, or
technical problems with the device. Also, PEF data may not
predict use of medical services as strongly as symptom scores
alone.
Spirometry is helpful in the evaluation of wheezing, with
reversible airflow obstruction highly suggestive of asthma. Spirometry is recommended by EPR-3 for any child older than
4 years in whom the diagnosis of asthma is being considered,
or for disease management. It measures forced vital capacity
(FVC), FEV1, forced vital capacity (FVC), maximum forced
expiratory flow (FEFmax), and forced expiratory flow at 25%,
50%, 75%, and 25% to 75% of FVC (FEF25, FEF50, FEF75, and
FEF25-75, respectively). When published performance standards
are followed,111,112 the results are accurate, reproducible measurements that objectively reflect the patients airway function.
FEV1 is independently associated with future asthma symptoms
and health care utilization in children with mild to moderate
asthma.2 Also, FEV1 is generally normal in children with

asthma,113 even in severe persistent childhood asthma, whereas

FEV1/FVC decreases as asthma severity increases. Pre- and postbronchodilator determinations can be obtained in children,
with improvements of 12% or greater for FVC and FEV1 and
25% for FEF25-75 considered clinically significant, although
many children with asthma may not reach this degree of reversibility.114 The presence of low FEV1/FVC indicates intrathoracic
airflow obstruction, which can be seen in patients with asthma
and most other disorders associated with diffuse lower airway
inflammation, including cystic fibrosis, bronchiectasis, and
primary ciliary dyskinesia.
Spirometry also provides both inspiratory and expiratory
flow-volume loops, which are helpful in detecting other types
of airflow obstruction. Fixed airway obstruction, as seen with a
mediastinal mass resulting in extrinsic airway compression, will
cause abnormalities of both the inspiratory and the expiratory
loop. Extrathoracic airflow obstruction, which is detectable as
flattening or blunting of the inspiratory loop, suggests vocal
cord dysfunction. Flow-volume loops include both a maximal
forced expiratory (as in spirometry) and inspiratory maneuver.
Analysis of the shape of the flow-volume curve is important in
the diagnosis of static and dynamic large-airway obstruction, as
well as diffuse airway obstruction in asthma. Flow-volume
curves can be used to measure flow rates during infancy and
facilitate the diagnosis of vocal cord dysfunction in older
children.39
Specialized PFTs include body plethysmography, impulse
oscillometry, and infant testing and are available in most pediatric medical centers. Plethysmography allows the measurement of lung volumes and airway mechanics (resistance,
conductance, specific conductance). Lung volume measurements include thoracic gas volume (TGV), which is combined

with spirometric measurements to yield residual volume (RV)

and total lung capacity (TLC). The RV/TLC ratio measures air
trapping and is a sensitive measure of pulmonary dysfunction
in children with mild, intermittent asthma. Specific airway conductance has been demonstrated as sensitive measurement of
mild airway obstruction, even in younger children. The pressureflow curves generated during the measurement of airway
mechanics provide further insights into airway dysfunction.
Impulse oscillometry (IOS) measurements are noninvasive
and based on signals of respiratory system resistance and reactance produced by a loudspeaker on the childs respiratory
system during quiet tidal breathing. Abnormalities have been
demonstrated in groups of preschool and young children with
asthma. The Childhood Asthma Research and Education
(CARE) network demonstrated improved lung function in preschool children at high risk for asthma treated with ICS compared with placebo using IOS values as outcome measures;
normative values are available for Canadian children age 3 to
10 years. A recent study in children with a family history of
allergies or asthma showed that similar numbers of children can
successfully perform spirometry and IOS at 4 to 8 years of age.65
Infant PFTs provide information from partial flow-volume
curves and measurements of pulmonary resistance/compliance
and functional residual capacity. A PFT using rapid thoracoabdominal compression has similar results in infants as produced
by voluntary maneuvers performed by adults and older children.2 These tests require sedation but are well tolerated.
Specialized PFTs should probably be reserved for select,
high-risk patients in infancy and early childhood because spirometry can often be performed by age 6 years in experienced
centers. Children that might benefit include those infants that
respond poorly to therapy, those in whom further management
might be warranted if abnormal lung function is found, or in
the preschool child in whom establishing the presence of AHR
may help support the diagnosis of asthma.
BRONCHIAL PROVOCATION
If a diagnosis of asthma in a child is not clear because of an
atypical history, persistent symptoms, an abnormal physical
exam, or documented airway obstruction, the use of bronchial
provocation testing might elicit evidence of AHR and may be
useful in establishing the diagnosis. Common bronchial provocateurs are methacholine, mannitol, histamine, exercise, adenosine monophosphate (AMP), and cold air.115 Allergen
bronchoprovocation is rarely performed outside a research
setting. It should be emphasized that response to chemical
stimuli such as methacholine and histamine indicates AHR.
Although a characteristic feature of asthmatic patients, AHR
can also be present in other chronic lung diseases and in patients
with allergic rhinitis. However, some data suggest that an exercise or AMP challenge may be more specific for asthma.
Methacholine inhalation challenge in children is safe when
carried out according to published recommendations and with
appropriate monitoring. As a result, it has been widely used in
epidemiologic and genetic studies. In fact, recent studies suggest
that responses to bronchial challenges may predict subsequent
asthma in later childhood both in normal infants and in children with chronic cough, or allergic rhinitis.116 Mannitol dry
powder challenge has recently been correlated with exercise
challenge results in children and is a feasible alternative for
bronchial challenge in children.117

52 Diagnosis of Asthma in Infants and Children

871

LABORATORY EVALUATION
Although the majority of children with asthma may be diagnosed and managed with the testing previously discussed, other
laboratory tests may be informative as well. The presence of
eosinophilia or an elevated total serum IgE level is supportive
but not diagnostic of asthma; further, normal results do not rule
out the diagnosis of asthma. Other tests may be helpful in select
situations, particularly in children with recurrent pneumonia,
failure to thrive, an atypical pattern of symptoms, or poor
response to usual asthma therapy. Evaluation of immune competence might disclose an immune deficiency that predisposes
the child to recurrent infections. Sweat chloride testing, a biopsy
to evaluate ciliary structure and function, and bronchoscopy
with BAL to evaluate pulmonary anatomy and infection are
important in diagnosing other chronic respiratory diseases. An
intermediate-strength purified protein derivative test (5-TU
PPD) is important if tuberculosis is possible.
DETERMINATION OF SPECIFIC IgE ANTIBODIES
Antigen-specific IgE to aeroallergens (e.g. mites, tree pollen,
grass pollen, animal dander) is uncommon during the first year
of life but increases during the preschool years. Although
aeroallergen-induced asthma thus is uncommon during the
first year of life, 60% of children at high risk for development
of asthma were sensitized to aeroallergen and/or food allergen
by ages 2 and 3 years.2 Further, sensitization to indoor (dust
mites, cockroaches, pets, molds) or outdoor (pollens, molds)
allergens are a major contributor to both chronic airway inflammation and acute asthmatic symptoms and should be considered when evaluating children or adolescents with asthma.
Aeroallergen-induced asthma then begins to increase in prevalence during later childhood and adolescence, peaking in the
second decade of life. The presence of antigen-specific IgE antibody can be determined using in vitro methodology, such as
the radioallergosorbent test (RAST) or a quantitative enzymelinked immunosorbent assay (ELISA) that measures serum IgE
antibody levels, or a skin-prick test that measures the actual
reaction to the allergen, including mediator release from mast
cells. Skin testing is more sensitive, less expensive, and can
provide the pertinent information more rapidly than in vitro
tests for allergen-specific IgE antibody. However, in vitro IgE
testing is more widely available, carries no risk of systemic reactions, and can be performed in patients with severe eczema or
dermographism, and results can be interpreted even if the child
is taking antihistamines.

Coexisting Issues in Pediatric Asthma

SINUSITIS-ASTHMA RELATIONSHIP
Sinusitis and asthma often coexist, with up to 50% of children
with asthma demonstrating sinusitis by endoscopy. Nasal congestion and cough that are either particularly severe or do not
resolve after 10 days increase the probability of sinusitis. Additional symptoms often include purulent nasal discharge, maxillary facial or dental pain, fever or chills. Physical examination
often reveals swollen and hyperemic nasal mucosa surrounded
by purulent mucus. However, the history and physical examination usually do not provide definitive diagnostic information.
Thus, sinus radiographs may be helpful adjuncts in establishing

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SECTION E Respiratory Tract

the diagnosis of sinusitis. There are few studies of the impact

of sinus treatment on asthma outcomes in children. Tosca and
associates118 explored the effect of medical treatment for rhinosinusitis on asthma outcomes, treating 18 children with a combination of amoxicillin-clavulanate and fluticasone propionate
aqueous nasal spray for 14 days with a short course of oral
steroids. Asthma symptoms and lung function significantly
improved after treatment and was sustained 1 month later. Tsao
and associates119 demonstrated that the intensive treatment of
sinusitis with amoxicillin-clavulanate and nasal isotonic saline
solution irrigation improves asthma symptoms in children, but
not lung function (see Chapter 43).
Gastroesophageal Reflux Disease and Asthma
Asthma and gastroesophageal reflux disease (GERD) is common
in infancy and might be associated with chronic or recurrent
respiratory symptoms, including wheezing,120,121 although there
remains uncertainty as to whether gastroesophageal reflux is
actually causative of wheezing in childhood or represents the
unrelated coexistence of two relatively common problems
(wheezing and GERD). As many as 45% to 65% of children with
asthma have GERD.122 Proposed mechanisms for the effect of
GERD on asthma might be microaspiration or irritation of the
esophagus leading to bronchospasm. The child may exhibit dysphagia or regurgitation or may be asymptomatic. GERD can
lead to nighttime exacerbations, postprandial symptoms, or
poorly controlled symptoms despite asthma therapy.
A recent trial in school-age children with poorly controlled
asthma receiving ICS without symptoms of GERD demonstrated that treatment with proton pump inhibitors (PPIs)
improved neither symptoms nor lung function compared with
placebo, but PPI use was associated with increased respiratory
infections.123 On pH probe testing, 43% of these children had
GERD. However, PPI therapy reduces nocturnal symptoms and
exacerbations and improves quality of life. One potential diagnostic approach may be the use of a 3-month trial of a PPI,
typically at a higher, twice-daily dose for 2 to 3 months in children with significant GERD symptoms.2 Other diagnostic tests
for GERD include a barium esophagram to help diagnose swallowing difficulties, anatomic abnormalities, or pathologic
reflux; esophageal pH monitoring; esophageal manometry;
radionuclide studies for reflux/aspiration; and esophagoscopy
with biopsy for esophagitis. Pharmacotherapy in symptomatic
children may include antacids, H2 blockers, PPIs, and prokinetic
agents.39 Other therapies include small, frequent, thickened
feedings for infants and utilizing gravity by elevating the head
of the bed. Antireflux surgery should be reserved for children
with persistent GERD symptoms despite a generous PPI dose
and those who cannot adhere to therapy.2
Growth of Asthmatic Children
Children with persistent asthma of at least moderate severity
may exhibit impaired growth and often have a temporary
decrease in growth velocity, although the eventual adult height
attained is likely to be normal. This decreased growth is typically associated with delay in pubertal development and marked
growth deceleration in late childhood, perhaps caused by
growth-suppressing influences of endogenous cytokines and
glucocorticoids resulting from illness and inflammation. Also,
growth delay can be associated with ICS therapy. A study of
toddler-age children with recurrent wheeze at high risk for
asthma found that those treated for 2 years with fluticasone

(176g/day) resulted in a 1.1-cm reduction in height at the end

of the 2 years compared with the placebo group.86 Similarly,
school-age children with persistent asthma treated with
budesonide (400g/day) for an average of 4 years had gained
1.1cm less in height at the end of the 4 years than the placebo
group. Also, school-age children with persistent asthma treated
with beclomethasone (400g/day) for 1 year gained 1.1cm less
in height than those receiving placebo.2 In these studies the differences in height gain between the ICS-treated and placebo
groups were not progressive after the first 3 to 4 months of ICS
therapy, apparently because of a temporary decrease in height
velocity. However, other studies in preschool children have
found no statistically significant effects of ICS therapy124,125 on
growth velocity. These conflicting findings may be explained
by the observation that linear growth in children younger than
3 years is influenced by factors other than growth hormone
(e.g., nutrition).126 Moreover, Amirav and colleagues127 recently
highlighted the many factors that affect the efficacy and safety
of ICS in young children, including anatomic and emotional
factors along with differences in airway physiology and aerosol
delivery.
The effect on growth velocity may also be age and weight
dependent. Guilbert and colleagues128 reported that although a
1.1-cm difference in growth was found during 2 years of treatment with fluticasone propionate, 88g twice daily, 2 years
after discontinuation of ICS there was no longer a significant
difference overall in linear growth relative to placebo-treated
preschool-age children. However, children who entered the trial
at a younger age (2 years), weighed less than 15kg, and received
ICS during the trial continued to have less linear growth
(1.9cm) 2 years after stopping ICS therapy than the placebo
group, perhaps from a higher relative exposure to ICS. These
findings emphasize that the growth-suppressive effects of ICS
therapy in preschool children are small on average and improve
over time in most children; nevertheless, there may be subgroups of children who experience larger-than-expected effects
on linear growth. Accordingly, regular monitoring of growth in
children receiving ICS therapy is important, along with continued attempts to titrate ICS therapy to the minimally effective
dose.
Antibiotics and Childhood Asthma
Continued controversy surrounds the use of antibiotics in the
care of children with asthma. Because most exacerbations of
asthma are related to viral illnesses, little evidence exists to
support a beneficial effect of adding an antibiotic to an asthma
treatment plan. Nevertheless, oral antibiotics are frequently
prescribed for wheezing illnesses in preschool children (650
antibiotic prescriptions/1000 wheezing children). These prescriptions are dominated by azithromycin, which increased
15-fold between 1995 and 2001. In children with stable asthma,
5.2% were found to have a coexisting infection with Mycoplasma pneumoniae, suggesting that there may be potential
benefit from treatment of atypical organism infection.2 An antiinflammatory effect of macrolides may also play a role. Viral
infections, particularly caused by rhinovirus (RV), are associated with neutrophilic inflammation and increased IL-8
expression.129-131 Neutrophils are relatively insensitive to the
therapeutic effects of corticosteroids,132 but interestingly,
azithromycin can attenuate immunoinflammatory responses
and may reduce the ensuing destructive neutrophilic inflammation. In addition, recent data demonstrate that azithromycin

52 Diagnosis of Asthma in Infants and Children

reduces RV replication and increases interferon gene expression

in human bronchial epithelial cells.133 These findings are especially important because in children, viral infections are the
major etiologic agent in episodes of clinically significant lower
respiratory symptoms.2,30 These studies now strongly suggest
that macrolides have antiinflammatory mechanisms of action
unrelated to their antimicrobial properties. Additional prospective studies are needed to help determine the appropriate positioning of antibiotics in the treatment regimen of children with
asthma.

Summary
Transient and persistent wheezing phenotypes have been identified, with allergic disease, reduced lung function, and viral

873

respiratory infection in infancy the major risk factors for persistence of asthma. A careful history and examination for risk
factors can help establish the diagnosis of asthma. Consideration is given to other comorbid diseases (e.g., allergic rhinitis,
sinusitis, gastroesophageal reflux) that can make asthma more
difficult to control. In the future, refining clinical phenotypes
of asthma using a combination of molecular virology, imaging,
genetic, and clinical factors will further elucidate its pathogenesis and may ultimately help predict outcomes and improve
prevention and treatment.
Acknowledgment
Chapter research and writing supported by NIH grants
1RO1HL61879,
1PO1AI50500,
2P50HL56396,
and
1UL1RR025011.

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