In a Canadian population-based study (Ontario, Canada; population, 12 million) the

burden of asthma-associated comorbidity as measured in rates of hospitalisations,

emergency department visits, and ambulatory care claims was evaluated [28]. Asthma
comorbidity-associated ambulatory claims, emergency department visits, and
hospitalisations were substantial and, in fact, their numbers were much greater than
those due to asthma itself [28]. Interestingly, the health burden due to asthma
comorbidity appeared substantial regardless of age, gender, socioeconomic status, or
living in a rural or urban area [28]. Approximately half of the asthma comorbidity
claims were for other respiratory conditions such as upper respiratory tract infection,
pneumonia, or allergic rhinitis [28]. In a further study by Gershon and coworkers [29]
using the same Ontario data, comorbidity was evaluated as indicated by use of health
service in 14 disease categories. In patients with asthma, comorbidity was 46% (0–4
years old), 40% (5–17 years old), 47% (18–44 years old), 49% (45–64-years old), and
22% (65 years old or more) higher than in those without asthma [29]. In all age groups
most of the 14 disease categories were more common in patients with asthma. The
highest comorbidity (50% or more) was found for respiratory disease other than
asthma, psychiatric disorders, metabolic and immunity disorders, and perinatal
disorders (0–4 years old). Risk of respiratory disease (other than asthma) was
approximately double, and risk of psychiatric disorders and infectious diseases was
approximately 33% to 51% higher in individuals with asthma as compared to those
without asthma. In the oldest age group, physician claims were approximately twice
more common for acute bronchitis and 60% higher for pneumonia in those with
asthma as compared to nonasthmatics [29].

Cell biology of airway epithelium

The airway is covered with a continuous sheet of epithelial cells (Crystal et al., 2008; Ganesan et al.,
2013). Two major airway cell types, ciliated and secretory cells, establish and maintain the
mucociliary apparatus, which is critical for preserving airway patency and defending against
inhaled pathogens and allergens. The apparatus consists of a mucus gel layer and an underlying
periciliary layer. Ciliated cells each project ∼300 motile cilia into the periciliary layer that are
critical for propelling the mucus layer up the airway. In addition, cilia are coated with membrane-
spanning mucins and tethered mucopolysaccharides that exclude mucus from the periciliary
space and promote formation of a distinct mucus layer (Button et al., 2012). Secretory cells
produce a different class of mucins, the polymeric gel-forming mucins. The two major airway gel-
forming mucins are MUC5AC and MUC5B. Some secretory cells, known as mucous or goblet
cells, produce mucins and store them within easilyvisualized collections of mucin granules,
whereas other cells produce and secrete mucins (especially MUC5B) but lack prominent
granules. Gel-forming mucins are secreted into the airway lumen and are responsible for the
characteristic viscoelastic properties of the mucus gel layer.

Airway epithelial injury and remodeling in asthma

A variety of structural changes in the epithelium and other portions of the airway, termed “airway
remodeling,” is frequently seen in individuals with asthma (Elias et al., 1999). These changes
include airway wall thickening, epithelial hypertrophy and mucous metaplasia, subepithelial
fibrosis, myofibroblast hyperplasia, and smooth muscle cell hyperplasia and hypertrophy. Airway
remodeling is thought to represent a response to ongoing tissue injury caused by infectious
agents, allergens, or inhaled particulates and by the host responses to these stimuli. Signs of
frank epithelial injury, including loss of epithelial integrity, disruption of tight junctions, impairment
of barrier function, and cell death, have been identified in some studies and may correlate with
asthma severity (Laitinen et al., 1985; Jeffery et al., 1989; Barbato et al., 2006; Holgate, 2007).
However, in many individuals asthma symptoms and features of airway remodeling, including
mucous metaplasia and subepithelial fibrosis, are seen in the absence of signs of active airway
infection or overt tissue injury (Ordoñez et al., 2000), suggesting that other processes account for
the persistence of asthma in these individuals. Substantial evidence suggests that the
persistence of asthma is driven by ongoing host immune responses that generate mediators
driving airway remodeling and airway dysfunction. The epithelium is both a site of production of
these mediators and a source of cells that respond to mediators produced by immune cells and
other cells within the airway. How airway epithelial cells recognize and respond to viruses,
allergens, and other stimuli has been comprehensively reviewed elsewhere (Lambrecht and
Hammad, 2012). Here we will focus on the contribution of the epithelium to production

If a participant did not speak English, they were asked to complete the questionnaire with the
help of an English-speaking family member or friend, or to contact the research coordinator
for translation services. Translation services (via a three-way teleconference between the
study coordinator, translator and participant) were available to all those who required
assistance. A second distribution of questionnaires was made to all children two to three
weeks after the first distribution. Recent new federal privacy legislation forbids access to
classroom name lists to aid in directed recruitment procedures. To have the most accurate
information for questionnaire distribution and response-rate calculations, the total number of
grade 1 and two students currently registered in each school was provided by the school
principal. Completed questionnaires were either returned to the school in person or mailed
directly to the T-CHEQ study team using a self-addressed, stamped envelope.
The questionnaires were printed on a computer-scannable form. All returned surveys were
checked by research assistants for stray marks and errors that could impede computer
scanning. To improve data accuracy, the questionnaires were scanned twice; any
discrepancies in data agreement were manually resolved, if possible, or replaced with a
missing value. Once the full data set was obtained, it was systematically ‘data cleaned’ using
algorithms to replace impossible or extreme values of variables with a missing data point.
Questions defining variables related to demographics and asthma or allergic symptoms and
disease were transcribed directly from either the ISAAC questionnaires (for asthma and
allergy outcomes and risk factors) (15), or Canadian national surveys (including individual
level household income, education, dwelling type, household size and environmental tobacco
smoke exposure) (20,21) to enable national and international comparisons of the data.
‘Lifetime asthma’ was defined as an affirmative response to the question “Has your child
ever had asthma”? ‘Doctor-diagnosed lifetime asthma’ also required an affirmative response
to the question “Was this diagnosed by a doctor”? ‘Current asthma’ was a derived variable
defined as doctor-diagnosed lifetime asthma and report of wheeze and/or taking
medication(s) for asthma or wheezing in the past 12 months. Lifetime hayfever and eczema
were defined by affirmative responses to core ISAAC questions: “Has your child ever had
hayfever”? and “Has your child ever had eczema?”, respectively, with a subsequent question
restricting the disease to being doctor diagnosed. Detailed information regarding medication
use for asthma or wheeze in the previous 12 months was parent-reported, with the aid of a
coloured chart, which included pictures of all currently labelled asthma medications available
in Canada.
Data regarding ethnicity were not collected at the individual level. However, school board-
level data on the five most common languages (other than English) spoken by children, and
individual school data on percentage of students speaking English as a second language, were
collected from the school board databases.
All statistics were computed using SAS version 9.1 (SAS Inc, USA). School- and individual-
level response rates were calculated using denominators of the total number of eligible
schools approached and the total number of grade 1 and 2 students in each participating
school, respectively. The target sample size of 20,000 was calculated to yield risk estimates
of environmental exposures that would be significantly precise to be explored in future
analyses. The prevalence rates calculated took into account missing responses for each
variable. Many T-CHEQ participants were from the same school. Schools, therefore, may
also be viewed as clusters of students. There may exist some characteristics that are common
to all children in one school and differentiates them from those in others. To account for
possible school clustering effects, prevalence and 95% CIs were calculated using the cluster
option of the SURVEYFREQ procedure, which identifies each school as a cluster of students.
To evaluate the representativeness of the sample, data on demographic, health determinant
and asthma outcome variables from two national surveys were obtained: the 2001 census,
which had at least one child five to 17 years of age (essentially a 100% response rate because
participation is mandatory), and Cycle 4 (2000/2001) of the National Longitudinal Survey of
Children and Youth (NLSCY), restricted to children five to nine years of age (22,23). The
NLSCY is a voluntary childrens health survey conducted by Statistics Canada, with an 84.8%
household response rate. The NLSCY uses the same ISAAC questions to ascertain asthma
and wheeze prevalence as the T-CHEQ survey. The census and NLSCY data were restricted
to households in the Toronto census metropolitan area for comparability purposes. The
Toronto metropolitan census area extends beyond the T-CHEQ geographical borders and
includes a slightly higher proportion of the suburban population.
Ethics approval was obtained from both The Hospital for Sick Children (Toronto, Ontario)
and the Health Canada Research Ethics Boards. Permission to conduct the T-CHEQ study in
the schools was obtained first from the Toronto District and Catholic School Boards’ research
committees, followed by permission from each school’s principal. The T-CHEQ cover letter
sent to parents explained that parental consent was implied by completing and returning the
questionnaire.