Article

Unraveling the relationship between aeroallergen sensitization, gender, second-hand smoke exposure, and impaired lung function

Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056, USA.
Pediatric Allergy and Immunology (Impact Factor: 3.4). 03/2012; 23(5):479-87. DOI: 10.1111/j.1399-3038.2012.01292.x
Source: PubMed
ABSTRACT
Contradictory findings on the differential effects of second-hand smoke (SHS) on lung function in girls and boys may result from masked relationships between host and environmental factors. Allergic sensitization may augment the relationship between SHS and decreased lung function, although its role in relation to the inconsistent gender differences in children has not been elucidated.
We hypothesize that there will be differences between boys and girls related to early-life allergic sensitization and exposure to SHS on pulmonary function later in childhood.
Participants in this study (n = 486) were drawn from the Cincinnati Childhood Allergy and Air Pollution (CCAAPS) birth cohort study consisting of 46% girls. Allergic sensitization was assessed by skin prick test (SPT) to 15 aeroallergens at ages 2, 4, and 7, while pulmonary function and asthma diagnosis occurred at age 7. SHS exposure was measured by hair cotinine at ages 2 and/or 4. Gender differences of SHS exposure on pulmonary function among children with positive SPTs at ages 2, 4, and 7 as well as first- and higher-order interactions were examined by multiple linear regression. Interactions significant in the multivariate models were also examined via stratification. Comparisons within and between stratified groups were assessed by examining the slope of the parameter estimates/beta coefficients and associated p-values and confidence intervals.
Increased cotinine levels were significantly associated with decreases in FEV(1) (-0.03 l, p < 0.05), peak expiratory flow (-0.07 l/s, p < 0.05), and FEF (25-75%) (-0.06 l/s, p < 0.01). The interaction between cotinine and sensitization at age 2 was borderline significant (p = 0.10) in the FEF(25-75%) model and showed an exposure response effect according to the number of positive SPTs at age 2; zero (-0.06 l/s, p < 0.01), one (-0.09 l/s, p < 0.05), or two or more positive SPTs (-0.30 l/s, p < 0.01). Despite increased polysensitization among boys, the association between cotinine and FEF(25-75%) among girls, with two or more positive SPTs at age 2, showed the greatest deficits in FEF(25-75%) (-0.34 l/s vs. -0.05 l/s and -0.06 l/s for non-sensitized girls and boys, respectively. Girls with two or more positive SPTs showed a twofold greater decrease in FEF(25-5%) (-0.34 l/s; 95% CI: -0.55, -0.13) compared to boys with the same degree of allergic sensitization (-0.18 l/s; 95% CI: -0.41, 0.06), although this difference was not statistically significant.
Reductions in lung function were observed among children exposed to SHS, and the number of aeroallergen-positive SPTs at age 2 modifies this relationship. Girls experiencing early childhood allergic sensitization and high SHS exposure are at greater risk of decreased lung function later in childhood compared to non-sensitized girls and boys and demonstrate greater deficits compared to boys with similar degrees of sensitization.

Full-text

Available from: Gurjit K Khurana Hershey, Dec 27, 2013
ORIGINAL ARTICLE
Unraveling the relationship between aeroallergen sensitiza-
tion, gender, second-hand smoke exposure, and impaired
lung function
Kelly J. Brunst
1
, Patrick H. Ryan
1,2
, James E. Lockey
1
, David I. Bernstein
1
, Roy T. McKay
1
,
Gurjit K. Khurana Hershey
3
, Manuel Villareal
4
, Jocelyn M. Biagini Myers
3
, Linda Levin
1
,
Jeff Burkle
1
, Sherry Evans
5
& Grace K. LeMasters
1
1
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA;
2
Division of Biostatistics and
Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;
3
Division of Asthma Research, Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH, USA;
4
Department of Internal Medicine, University of Cincinnati, College of Medicine, Cincinnati,
OH, USA;
5
Bernstein Clinical Research Center, Cincinnati, OH, USA
To cite this article: Brunst KJ, Ryan PH, Lockey JE, Bernstein DI, McKay RT, Khurana Hershey GK, Villareal M, Biagini Myers JM, Levin L, Burkle J, Evans S,
LeMasters GK. Unraveling the relationship between aeroallergen sensitization, gender, second-hand smoke exposure, and impaired lung function. Pediatric Allergy
Immunology 2012: 00
Keywords
allergic sensitization; gender; child;
spirometry; second-hand smoke.
Correspondence
Grace LeMasters, UC College of Medicine,
3223 Eden Avenue, Cincinnati, OH 45267-
0056, USA.
Tel.: +513 558 0045
Fax: +513 558 6272
E-mail: lemastgj@ucmail.uc.edu
Accepted for publication 1 February 2012
DOI:10.1111/j.1399-3038.2012.01292.x
Abstract
Background: Contradictory findings on the differential effects of second-hand smoke
(SHS) on lung function in girls and boys may result from masked relationships
between host and environmental factors. Allergic sensitization may augment the
relationship between SHS and decreased lung function, although its role in relation
to the inconsistent gender differences in children has not been elucidated.
Hypothesis: We hypothesize that there will be differences between boys and girls
related to early-life allergic sensitization and exposure to SHS on pulmonary func-
tion later in childhood.
Methods: Participants in this study (n = 486) were drawn from the Cincinnati
Childhood Allergy and Air Pollution (CCAAPS) birth cohort study consisting of
46% girls. Allergic sensitization was assessed by skin prick test (SPT) to 15 aeroal-
lergens at ages 2, 4, and 7, while pulmonary function and asthma diagnosis occurred
at age 7. SHS exposure was measured by hair cotinine at ages 2 and/or 4. Gender
differences of SHS exposure on pulmonary function among children with positive
SPTs at ages 2, 4, and 7 as well as first- and higher-order interactions were exam-
ined by multiple linear regression. Interactions significant in the multivariate models
were also examined via stratification. Comparisons within and between stratified
groups were assessed by examining the slope of the parameter estimates/beta coeffi-
cients and associated p-values and confidence intervals.
Results: Increased cotinine levels were significantly associated with decreases in
FEV
1
()0.03 l, p < 0.05), peak expiratory flow ()0.07 l/s, p < 0.05), and FEF
25–
75%
()0.06 l/s, p < 0.01). The interaction between cotinine and sensitization at age
2 was borderline significant (p = 0.10) in the FEF
25–75%
model and showed an
exposure response effect according to the number of positive SPTs at age 2; zero
()0.06 l/s, p < 0.01), one ()0.09 l/s, p < 0.05), or two or more positive SPTs
()0.30 l/s, p < 0.01). Despite increased polysensitization among boys, the associa-
tion between cotinine and FEF
25–75%
among girls, with two or more positive SPTs
at age 2, showed the greatest deficits in FEF
25–75%
()0.34 l/s vs. )0.05 l/s and
)0.06 l/s for non-sensitized girls and boys, respectively. Girls with two or more posi-
tive SPTs showed a twofold greater decrease in FEF
25–5%
()0.34 l/s; 95% CI:
)0.55, )0.13) compared to boys with the same degree of allergic sensitization
()0.18 l/s; 95% CI: )0.41, 0.06), although this difference was not statistically signifi-
cant.
Pediatric Allergy and Immunology
ª 2012 John Wiley & Sons A/S 1
Page 1
Second-hand smoke exposure (SHS) is widespread among
children in the United States, with nearly one in four children
living in a home with at least one smoker and having cotinine
concentrations (a metabolite of nicotine) more than twice as
high as those among non-smoking adults (1). An extensive
body of evidence has documented that SHS exposure during
childhood is associated with respiratory illness (2), asthma
development and exacerbation (2), and decreased lung func-
tion (3). Biologic evidence for causal relationships may
involve changes in the nervous (4) or immune (5) systems,
airway responsiveness (3), and/or structural changes of the
lungs and airways (4).
The effects of SHS exposure on lung function, however,
may not be uniform among boys and girls or among those with
allergen sensitization and allergic diseases, as these conditions
likely increase the susceptibility of the airways to non-aller-
genic irritants such as SHS (6, 7). Among genetically
predisposed children, atopy has been shown increase a child’s
risk of asthma and bronchial hyper-responsiveness (BHR)
associated with SHS exposure (8). This finding has also varied
by gender. For example, boys without a family history of
atopy exposed to SHS in utero, in the first 2 yr of life, or cur-
rently were at greater risk of asthma or wheeze. The same
study found that the opposite was true among children with a
family history of atopy, demonstrating that girls were more
susceptible to SHS exposure, regardless of the timing of expo-
sure, showing stronger associations for asthma, allergic rhini-
tis, and wheeze (7). Further, it has been shown that only boys
with asthma and girls without asthma exposed to past SHS
experienced decreased flow rates (6).
These varied findings highlight the complex relationships
among host and environmental factors that are seldom exam-
ined concurrently. Because approximately 50% of children
between the ages of 6 and 9 are sensitized (9) and early and
persistent allergic sensitization is recognized as a risk factor
for asthma development (10), the purpose of this study is to
disentangle the relationships related to early childhood sensi-
tization, gender, environmental exposure to SHS as measured
by internal dose of hair cotinine, and the potential long-term
consequences on pulmonary function.
Methods
Study population
The objective of the Cincinnati Childhood Allergy and Air
Pollution Study (CCAAPS) cohort was to determine whether
exposure to indoor and outdoor pollutants during early
childhood is associated with the development of allergic sen-
sitization and allergic diseases and to determine gender sus-
ceptibility. Newborns in the Cincinnati metropolitan area
were identified from birth records from 2001 to 2003 (11).
Infants were eligible for study recruitment if their residence
at birth was either <400 m or >1500 m from a major road
defined as 1000 trucks per day (11). Enrollment criteria
included being born to at least one atopic parent, confirmed
by allergy symptoms and a current skin prick test (SPT) to
15 aeroallergens (11). Parents were also administered a ques-
tionnaire to gather parental and child health information in
the previous year and environmental exposures, including
address history for traffic-related particle exposure. The Uni-
versity of Cincinnati Institutional Review Board approved
the study protocol prior to subject recruitment, and written
informed consent was obtained prior to participating in any
study-related procedures.
Children had a physical examination by trained clinicians
annually at age 1 through 4 and at age 7, including a skin test
for 15 aeroallergens plus cow’s milk and egg. The aeroallergens
tested include seasonal (outdoor) allergens: meadow fescue and
timothy grass pollens, white oak, maple mix, American elm,
red cedar, and short ragweed; and perennial (indoor) allergens:
Alternaria, Aspergillus fumigatus, Penicillium mix, Cladospori-
um, dust mite mix, German cockroach, cat, and dog. A positive
SPT was defined as a reaction producing a wheal at least 3 mm
greater than a saline control after 15 min. Although many
studies define atopy as having one positive SPT, a recent study
found that among patients ranging from 5 to 65 yr of age, hav-
ing two or more positive SPTs was associated with moderate to
severe rhinitis and asthma (12). Therefore, for the purpose of
this study, children were categorized based on the number of
positive SPTs at ages 2, 4, and 7 as follows: negative to all ae-
roallergens, positive to one, or positive to two or more.
Traffic-related particle exposure
Estimated traffic-related air pollution was adjusted for in this
study, as this is a major focus of CCAAPS. An average daily
exposure to traffic-related particles was calculated for each
child using a land-use regression model as previously
described (13). From December 2001 through December
2006, ambient air sampling was performed at 27 sampling
sites in the greater Cincinnati area. The average daily concen-
tration of elemental carbon attributable to traffic (ECAT), a
marker of traffic-related particles, was determined for each
site (13). A land-use regression model was then developed to
relate ECAT with land-use and traffic variables including ele-
vation, truck intensity, and length of bus routes. The final
land-use regression model had an R
2
= 0.73.
An individual time-weighted average daily exposure was
calculated for each year of a child’s life for all subjects
enrolled in CCAAPS. This exposure was determined by
Conclusions: Reductions in lung function were observed among children exposed to
SHS, and the number of aeroallergen-positive SPTs at age 2 modifies this relation-
ship. Girls experiencing early childhood allergic sensitization and high SHS exposure
are at greater risk of decreased lung function later in childhood compared to non-
sensitized girls and boys and demonstrate greater deficits compared to boys with
similar degrees of sensitization.
Girls, allergic sensitization, tobacco, and lung function Brunst et al.
2 ª 2012 John Wiley & Sons A/S
Page 2
geocoding all addresses where the child was reported to have
spent more than 8 h/wk in the previous 12 months and calcu-
lating a time-weighted estimate of exposure (14). Geocoding
and geographic information systems were conducted using
EZLocate (TeleAtlas) and ArcGIS 9.3 (Environmental Sys-
tems Research Institute, Redlands, CA, USA).
Pulmonary function and asthma diagnosis
At age 7, all children had spirometry testing according to
ATS-ERS guidelines (15). Spirometers had their volume accu-
racy verified daily, and each child performed at least four
acceptable maneuvers. A random sample of five percent of
the pulmonary function tests was examined for any significant
measurement artifact that would invalidate the reported
forced vital capacity (FVC) or forced expiratory volume in 1-s
(FEV
1
) or significantly influence the reported forced expira-
tory flow between 25% and 75% of FVC (FEF
25–75%
). The
best FEV
1
, FVC and peak expiratory flow (PEF) were
recorded, whereas FEF
25–75%
was derived from the best curve,
defined as the greatest sum of FEV
1
and FVC. In addition,
FEV
1
as a percentage of FVC was calculated (FEV
1
/FVC).
A diagnosis of asthma first required parental report of
asthma symptoms in the previous 12 months (tight or
clogged chest or throat, difficulty breathing or wheezy after
exercise, wheezing or whistling in the chest, or a prior physi-
cian diagnosis of asthma). Second, the child had to exhibit
BHR. BHR was first defined by a 12% increase in baseline
FEV
1
following bronchodilator administration of 2.5 mg of
levalbuterol (15). Children who did not have a 12% increase
in FEV
1
were tested for BHR by methacholine challenge test-
ing (MCCT). The four-dose protocol began with a saline
control followed by sequential doses of 0.0625, 0.25, 1.0, and
4.0 mg/ml of methacholine chloride. BHR by MCCT was
defined as a 20% or greater decline in baseline FEV
1
post-
saline diluents challenge. If there was a <20% decline in
FEV
1
at 4 mg/ml, the MCCT was considered negative and
not diagnostic for BHR.
Hair collection and analysis
At ages 2 and 4, hair was collected by cutting approximately
20 strands of hair from the root end in the occipital region of
the scalp. The samples were washed prior to analysis to
remove surface nicotine, adjusted by weight, and analyzed
for the quantity of cotinine by radioimmunoassay at the Hos-
pital for Sick Children in Toronto, Canada (16). Children
with concentrations below the limit of detection (0.02 ng/mg)
were assigned a cotinine value of 0.01 ng/mg (17). Cotinine
values for the two time periods were highly correlated
(r
2
= 0.71). For this reason and to decrease missing values,
the average value of age 2 and 4 was calculated, and if one
time period was available, that was used.
Statistical analysis
Explanatory analyses were performed to identify important
variables for predicting lung function among boys and girls.
Univariate associations with the primary exposure variable
(cotinine) and possible predictor variables were evaluated by
chi-square contingency tables for categorical variables and by
t-tests for continuous variables. Predictor variables included
race [African American (AA), non-African American
(NAA)], sex, age (yr), height (cm), weight (kg), chest circum-
ference (cm), child asthma status (yes/no), aeroallergen sensi-
tization (0, 1, 2, or more positive SPTs) and food (milk and
egg) sensitization (yes/no) at ages 2, 4, and 7, ECAT (lg/m
3
),
riding in a school bus (yes/no), gas stove present in home
(yes/no), prenatal SHS exposure (yes/no), and maternal edu-
cation (non-high school graduate, graduated high school,
attended college, or was a college graduate). The correlation
and distribution of hair cotinine were examined at ages 2 and
4. Cotinine was skewed and subsequently log transformed
using the natural log.
Linear regression was performed to assess univariate asso-
ciations between each pulmonary function outcome and coti-
nine, modified by other predictor variables. Accordingly,
first- and higher-order interactions between cotinine, gender,
and allergic sensitization were modeled. Multiple linear
regression models were then built for each pulmonary func-
tion outcome separately. A priori, hair cotinine, ECAT, and
variables related to pulmonary function testing (PFT) out-
comes (race, gender, and height) were included in all multi-
variate models. ECAT was included as it is a source of
particulate matter exposure and could be a potential con-
founder. Other predictor variables and interactions significant
at the 15% level were initially included in multivariate mod-
els.
A deterministic approach to model reduction was used to
reduce the initial multivariate model of each pulmonary func-
tion outcome. Variables were removed one at a time, begin-
ning with the highest p-value. If a change in the parameter
estimate of cotinine exceeded 10% after removal, the variable
remained in the model. The final models included variables
and interactions significant at the 15% level. The variance
inflation factor (VIF) values of each final model were then
assessed to quantitate multicollinearity. If an interaction was
significant, the model was repeated after stratification by the
variable that interacted with cotinine. The slope of the
parameter estimates/beta coefficients and associated p-values
and confidence intervals were used to assess differences
between stratified models. Statistical analyses were performed
using sas 9.2 (SAS Institute Inc., Cary, NC, USA).
Results
Population description
Of the 762 children enrolled at age 1, 81% (n = 617) were
evaluated at age 7, and 591 successfully completed the PFT.
Sufficient hair samples were available for 82% (n = 486) of
those children and were included in this analysis. There were
no significant differences between those who did or did not
complete the pulmonary function with respect to race, gen-
der, or allergic sensitization nor did gender or allergic sensiti-
zation differ for those with or without hair cotinine results.
Brunst et al. Girls, allergic sensitization, tobacco, and lung function
ª 2012 John Wiley & Sons A/S 3
Page 3
AA, however, were less likely to provide hair samples (data
not shown). Of the final cohort used for analysis, 46% were
girls, 14.5% AA, and 14.9% met the clinical criteria for
asthma.
The overall geometric mean cotinine concentration in hair
(±1 s.d.) was 0.15 ng/mg (±0.28) ranging from 0.01 to
2.80 ng/mg. Girls (0.16 ng/mg) and boys (0.15 ng/mg) had
similar concentrations (Table 1). Asthmatic (0.20 ng/mg)
compared to non-asthmatic children (0.14 ng/mg) had higher
cotinine concentrations although this difference was not sta-
tistically significant. Cotinine values did not differ between
asthmatic and non-asthmatic children by gender. AA had, on
average, four times the concentration of cotinine, 0.49 ng/mg
compared to 0.09 ng/mg for NAA (p < 0.05), but this
difference did not vary by gender. Based on our question-
naire data, AA also had more SHS exposure compared to
NAA while riding in a car.
Allergic sensitization
At age 2, 4, and 7, 37.7%, 52.6%, and 44.9% of children
were SPT positive, respectively (Table 1). The number of chil-
dren with only one positive SPT initially increased from age
2 (20.8%) to 4 (26.1%) but then decreased at age 7 (15.7%).
A continual increase in those with two or more SPTs
occurred as the children aged from 2 (16.9%) to 4 (26.5%)
and to 7 (29.2%). Overall, the number of positive SPTs was
evenly distributed between genders at ages 2 and 4. At age 7,
Table 1 Participant characteristics by gender (n = 486)
Total
n = 486
Girls
n = 224
Boys
n = 262
African American n (%) 70 (14.5) 32 (14.3) 38 (14.5)
Asthmatic n (%) 72 (14.9) 28 (12.5) 44 (16.8)
Allergic sensitization age 2 (n = 461)
0 SPT+ n (%) 287 (62.2) 132 (58.9) 155 (59.2)
1 SPT+ n (%) 96 (20.8) 48 (21.4) 48 (18.3)
2 or more SPT+ n (%) 78 (16.9) 33 (14.7) 45 (17.1)
Allergic sensitization age 4 (n = 464)
0 SPT+ n (%) 220 (47.3) 102 (45.5) 118 (45.0)
1 SPT+ n (%) 121 (26.1) 56 (25.0) 65 (24.8)
2 or more SPT+ n (%) 123 (26.5) 53 (23.7) 70 (26.7)
Allergic sensitization age 7 (n = 472)
0 SPT+ n (%) 260 (55) 122 (54.5) 138 (52.7)*
1 SPT+ n (%) 74 (15.7) 47 (20.9) 27 (10.3)*
2 or more SPT+ n (%) 138 (29.2) 46 (20.5) 92 (35.1)*
Maternal education
Non-high school graduate n (%) 23 (4.85) 12 (5.43) 11 (4.35)
High school graduate n (%) 68 (14.35) 29 (13.12) 39 (15.42)
Attended college or college graduate n (%) 383 (80.8) 180 (81.45) 203 (80.24)
Mean age in years (s.d.) 6.9 (0.47) 6.9 (.46) 6.9 (0.48)
Mean height in cm (s.d.) 124.0 (7.36) 123.3 (7.47) 124.6 (7.23)
Mean weight in kg (s.d.) 25.29 (4.76) 25.00 (4.27) 25.53 (51.4)
Mean chest circumference in cm (s.d.) 61.91 (5.14) 61.23 (4.96) 62.49 (5.22)
Mean ECAT in lg/m
3
0.36 (0.12) 0.36 (0.14) 0.35 (0.10)
Mean cotinine in ng/mg (s.d.) 0.15 (0.28) 0.16 (0.31) 0.15 (0.26)
African American 0.49 (0.54)* 0.54 (0.57) 0.43 (0.51)
Non-African American 0.09 (0.14)* 0.08 (0.13) 0.09 (0.15)
Asthmatics 0.20 (0.25) 0.24 (0.32) 0.16 (0.19)
Non-asthmatic 0.14 (0.29) 0.14 (0.30) 0.13 (0.28)
Mean FEV
1
in l (s.d.) 1.42 (0.23) 1.38 (0.22) 1.46 (0.23)
Mean FVC in l (s.d.) 1.60 (0.27) 1.54 (0.24) 1.65 (0.27)
Mean FEV
1
/FVC % (s.d.) 0.89 (0.06) 0.89 (0.06) 0.89 (0.06)
Mean FEF
25–75%
in l/s (s.d.) 1.74 (0.42) 1.72 (0.41) 1.75 (0.44)
Mean PEF in l/s (s.d.) 3.16 (0.55) 3.09 (0.51) 3.23 (0.58)
SPT, skin prick test; 0 SPT+, tested negative to all aeroallergens; 1 SPT+, one positive skin prick test; 2 or more SPT+, two or more positive
skin prick tests; ECAT, elemental carbon attributable to traffic; FEV
1
, Forced expiratory volume in 1 s; FEF
25–75%
, Forced expiratory flow
between 25% and 75% of forced vital capacity; PEF, peak expiratory flow; FVC, Forced vital capacity; FEV
1
/FVC%, FEV
1
as a percentage of
FVC; s.d., standard deviation.
Bolded values represent significant differences by gender (*p < 0.05; p < 0.01) using chi-square contingency tables for categorical variables
and by T-tests for continuous variables.
Girls, allergic sensitization, tobacco, and lung function Brunst et al.
4 ª 2012 John Wiley & Sons A/S
Page 4
there was a significant association between the number of
positive SPTs and gender (p = 0.03) as 35% of boys and
only 21% of girls had two or more positive SPTs (Table 1).
The most common aeroallergen sensitization at age 2 was
timothy grass (8.5%) (Table 2). Similarly at age 4 and 7, tim-
othy grass remained one of the most common allergies
(11.6% and 15.7%) along with maple mix (12.1% and
17.2%), respectively, with dust mite (12.1%) and cat (10.8%)
sensitization increasing at age 4. A shift in the pattern of
allergic sensitization was observed at age 7, with short rag-
weed and white oak allergies becoming more prevalent
(Table 2). Among children with two or more positive SPTs,
timothy grass and maple pollen allergies were the most com-
mon at all ages (Table 2). While the prevalence of egg and
milk allergies was the highest at age 2 (7.9% and 1.9%,
respectively), their frequency sharply decreased with increas-
ing age (Table 2). Further, food allergies were not associated
with decreases in lung function (data not shown).
Pulmonary function
Significant reductions in FEV
1
()0.03 l; 95% CI: )0.04,
)0.01), FEF
25–75%
()0.06 l/s; 95% CI: )0.09, )0.03), and
PEF ()0.07 l/s; 95% CI: )0.11, )0.03) were observed for
every unit change of log cotinine, but this was not true for
FVC and FEV
1
/FVC (Table 3). Neither gender nor allergic
sensitization at age 2, 4, or 7 independently modified the rela-
tionship between cotinine and FEV
1
, FVC or FEV
1
/FVC
outcomes.
The interaction between cotinine and allergic sensitization
at age 2 was borderline significant in the FEF
25–75%
(p = 0.10) and PEF model (p = 0.15). For both genders of
the non-sensitized children ()0.06 l/s; 95% CI: )0.09, )0.02)
and those children with two or more positive SPTs ()0.30 l/s;
95% CI: )0.41, )0.18), the effect of cotinine on FEF
25–75%
was highly significant (p < 0.01) (Table 3). These data also
showed a dose–response effect of allergic sensitization at age
2 on FEF
25–75%
and PEF among children with zero, one, or
two or more positive SPTs (Table 3). Reductions in FEF
25–
75%
()0.06, )0.09, and )0.30 l/s, respectively) were three and
five times greater among children positive to one or two or
more aeroallergens compared to non-sensitized children
(p < 0.05) (Table 3). A similar dose–response reduction in
PEF related to the number of positive SPTs at age 2 was
observed from those who were non-sensitized ()0.07 l/s; 95%
CI: )0.11, )0.02), had one ()0.15 l/s; )0.33, 0.04), or had
two or more positive SPTs ()0.20 l/s; 95% CI: )0.35, )0.04).
Although not statistically significant, those children with two
or more positive SPTs had a three times greater decrease in
PEF compared to non-sensitized children (Table 3). Allergic
sensitization at age 4 or 7, however, did not modify the rela-
tionship between hair cotinine and FEF
25–75%
or PEF.
The interaction between gender and cotinine was signifi-
cant (p = 0.03) in the FEF
25–75%
model. After stratification
by gender, it was evident that similar and significant reduc-
tions in FEF
25–75%
were observed between boys and girls as
hair cotinine concentrations increased, suggesting that coti-
nine was driving the observed interaction between gender and
cotinine (Table 3). Interestingly, the combined interaction
between cotinine, gender, and allergic sensitization at age 2
was also significant in the FEF
25–75%
model (p = 0.05).
Figure 1 shows the six to sevenfold increased effects of coti-
nine on FEF
25–75%
when stratified by both gender and aller-
gic sensitization while controlling for other covariates. The
Table 2 Prevalence of sensitization to individual aeroallergens and food allergens at ages 2, 4, and 7*
Category Individual allergens
%Yr2
Total
(n = 461)
%Yr2
2 or more SPT+
(n = 78)
%Yr4
Total
(n = 464)
%Yr4
2 or more SPT+
(n = 123)
%Yr7
Total
(n = 472)
%Yr7
2 or more SPT+
(n = 138)
Pollen Meadow fescue 3.7 21.8 7.3 22.8 13.1 43.5
Timothy 8.5 37.2 11.6 36.6 15.7 51.4
White oak 4.6 21.8 9.7 30.1 14.8 48.6
Maple mix 5.6 26.9 12.1 36.6 17.2 51.4
American elm 3.7 16.7 8.4 27.6 12.7 41.3
Red cedar 7.4 25.6 5.0 16.3 4.4 12.3
Short ragweed 3.7 14.3 7.8 24.4 15.7 50.0
Mold Alternaria 3.7 14.3 5.8 16.3 2.8 7.2
Aspergillus fumigatus 4.6 17.9 1.9 5.7 2.3 7.2
Penicillium 2.6 14.1 3.7 11.4 2.1 5.8
Cladosporium 3.0 17.9 3.0 8.1 2.1 5.8
Dust Dust mite 6.5 20.5 12.1 26.0 12.3 25.4
German cockroach 4.3 19.2 6.9 17.1 4.0 13.8
Animal Cat 6.1 19.2 10.8 26.8 11.2 30.4
Dog 3.9 12.8 5.8 17.9 4.9 15.2
Food Milk 1.9 5.1 1.1 1.3 0.42 1.2
Egg 7.9 11.7 3.4 5.3 2.3 2.6
SPT, skin prick test.
*All prevalence values are per total number tested at each year.
Brunst et al. Girls, allergic sensitization, tobacco, and lung function
ª 2012 John Wiley & Sons A/S 5
Page 5
greatest significant effect was observed for girls with two or
more positive SPTs ()0.34 l/s; 95% CI: )0.55, )0.13) com-
pared to non-sensitized girls ()0.05 l/s; 95% CI: )0.11, 0.01)
and non-sensitized boys ()0.06 l/s; 95% CI: )0.01, )0.12)
(Fig. 1). The difference between girls with one or two or
more positive SPTs or between boys with one or two or more
positive SPTs was not significant (Fig. 1). A trend, however,
was observed among girls and boys with two or more posi-
tive SPTs, as girls showed a twofold greater decrease in
FEF
25–75%
compared to boys with a similar degree of sensiti-
zation.
Discussion
This study is the first to investigate the differential gender
effects of SHS exposure using hair cotinine, while exploring
the importance of timing and extent of allergic sensitization
on lung function. Significant associations were observed
Table 3 Effects of cotinine on pulmonary function outcomes at ages 2, 4, and 7 in total population and stratified by gender and allergic sen-
sitization
FEV
1
(95% CI) FVC (95% CI) FEV
1
/FVC (95% CI) FEF
25–75%
(95% CI) PEF (95% CI)
Total
population
)0.03 ()0.04, )0.01)* )0.02 ()0.04, 0.003) )0.26 ()0.78, 0.25) )0.06 ()0.09, )0.03) )0.07 ()0.11, )0.03)
Gender
Girls )0.02 ()0.05, 0.004) )0.02 ()0.05, 0.01) )0.81 ()1.63, 0.013) )0.06 ()0.11, )0.01)* )0.08 ()0.13,)0.02)*
Boys )0.01 ()0.03, 0.003) )0.01 ()0.04, 0.02) )0.02 ()0.69, 0.64) )0.05 ()0.09, )0.01) )0.07 ()0.12, )0.01)*
Allergic sensitization age 2
0 SPT+ )0.02 ()0.04, 0.004) )0.02 ()0.04, 0.001) )0.11 ()0.71, 0.50) )0.06 ()0.09, )0.02) )0.07 ()0.11, )0.02)
1 SPT+ )0.03 ()0.10, 0.04) )0.02 ()0.10, 0.05) )0.59 ()2.78, 1.61) )0.09 ()0.17, )0.01)* )0.15 ()0.33, 0.04)
2 SPT+ )0.05 ()0.11, 0.01) )0.06 ()0.12, 0.01) )1.36 ()3.30, 0.59) )0.30 ()0.41, )0.18) )0.20 ()0.35, )0.04)*
Allergic sensitization age 4
0 SPT+ )0.004 ()0.019, 0.012) )0.007 ()0.022, 0.008) )
0.0004 ()0.0084, 0.0074) )0.015 ()0.19, 0.16) )0.04 ()0.11, 0.04)
1 SPT+ )0.01 ()0.02, 0.01) )0.005 ()0.021, 0.011) )0.008 ()0.0183, 0.0019) )0.04 ()0.09, 0.01) )0.06 ()0.12, 0.01)
2 SPT+ )0.03 ()0.06, 0.01) )0.02 ()0.04, 0.01) )0.006 ()0.017, 0.005) )0.04 ()0.10, 0.02) )0.09 ()0.25, 0.07)
Allergic sensitization age 7
0 SPT+ )0.01 ()0.04, 0.02) )0.01 ()0.05, 0.03) 0.24 ()0.48, 0.95) )0.04 ()0.09, 0.01) )0.11 ()0.16, )0.05)
1 SPT+ )0.02 ()0.05, 0.01) )0.02 ()0.05, 0.002) )0.75 ()1.99, 0.50) )0.04 ()0.12, 0.04) )0.04 ()0.13, 0.04)
2 SPT+ )0.03 ()0.06, 0.003) )0.02 ()0.06, 0.02) )0.23 ()1.4, 0.90) )0.07 ()0.14, 0.01) 0.01 ()0.10, 0.11)
FEV
1
, Forced expiratory volume in 1 s measured in l; FEF
25–75%
, Forced expiratory flow between 25% and 75% of forced vital capacity mea-
sured in l/s; PEF, peak expiratory flow measured in l/s; FVC, Forced vital capacity measured in l; FEV
1
/FVC, FEV
1
as a percentage of FVC;
SPT, skin prick test.
Bolded values represent significant associations: *p-value < 0.05; p-value < 0.01; p-values represent the effect of cotinine on outcome
within each model.
Models are adjusted for age, race, gender, height, elemental carbon attributable to traffic and any covariates remaining in the model with a
p < 0.15. Parameter estimates represent the change in the pulmonary function outcome per 1 unit change in log cotinine. 95% Confidence
intervals of each outcome’s predicted mean values are shown for each model.
Figure 1 Combined effect of gen-
der and allergic sensitization at age
2 on the reduction of FEF
25–75%
at
age 7. FEF
25–75%
, Forced expiratory
flow between 25% and 75% of
forced vital capacity; 95% Confi-
dence intervals for FEF
25–75%
pre-
dicted mean values are shown.
Models are adjusted for age, race,
height, elemental carbon attribut-
able to traffic and any covariates
remaining in the model with a
p < 0.15.
Girls, allergic sensitization, tobacco, and lung function Brunst et al.
6 ª 2012 John Wiley & Sons A/S
Page 6
between hair cotinine levels and reductions in FEV
1
,
FEF
25–75%
, and PEF. The results varied by allergic sensitiza-
tion status, suggesting that sensitization as early as age 2
increases a child’s susceptibility for reductions in FEF
25–75%
at age 7. This was not observed for allergic sensitization at
age 4 or 7. The extent of allergic sensitization also plays a
vital dose–response role in susceptibility. The reduction in
FEF
25–75%
among children with two or more positive SPTs
at age 2 was five times greater compared to non-sensitized
children and three times greater compared to children with
one positive SPT. We support previous findings that allergic
sensitization in the first 3 yr of life is associated with a loss
of lung function at age 6 that persisted into puberty (18).
Although the exact mechanism of this modification is
unclear, it is possible that this finding reflects a heightened
Th2 immune response. Independently, both SHS and poly-
sensitization create a Th-2-biased environment. For instance,
it has been shown that SHS enhances the immune response
to allergens and that multi-allergic children experience sub-
clinical asthma-like changes in their lung function (19, 20).
SHS exposure among the more sensitized children may
potentiate the effect SHS has on pulmonary function reflect-
ing a combined adjuvant effect on the allergic inflammation
response to the specific allergens or a heighted general irritant
effect impacting the airways. Further, there are three mecha-
nisms that may explain why the modification effect was only
observed at age 2. First, it has been suggested that the most
important steps toward the development of mature systemic
immune responses occur prior to age 3 (21). Second, the tim-
ing of atopy, which directly ties into the development of the
systemic immune response, appears to have an important role
in not only this study but also others (18). Lastly, between
36 wk and prior to age 3, proliferation of alveolar is com-
pleted (4). Our results confirm the importance of this critical
window and suggest that very early-life allergic sensitization,
especially if positive to two or more aeroallergens, increases a
child’s risk of pulmonary function loss at age 7 when exposed
to SHS. This finding appears to be particularly true among
girls.
Although nearly 45% of girls and boys in the CCAAPS
cohort, with a family history of atopy, had at least one posi-
tive SPT prior to age 7, boys were more sensitized than girls
at all ages; this finding has been previously confirmed (22).
Interestingly, although boys and girls had similar exposures,
the effect of SHS on FEF
25–75%
loss was six times greater
among girls with two or more positive SPTs compared to
non-atopic girls and boys. Prior studies have found conflict-
ing results but also provide very intriguing hypotheses need-
ing further exploration. For instance, Chen et al. (23)
concluded that current or recent tobacco smoke exposure, as
measured by questionnaire, had a larger effect on FEV
1
and
FEF
25–75%
in girls than in boys. Earlier findings, also based
on questionnaire data, documented opposing gender effects
showing boys experiencing greater lung function deficits as a
result of SHS exposure (24). Recently, it has become evident
that girls with a family history of atopy may be at greater
risk of respiratory diseases and respiratory symptoms result-
ing from exposure to SHS (7). Further, Li et al. (6) found
that boys with asthma and reported SHS exposure showed
significant decreases in FEV
1
, while only girls without asthma
showed decreases. It is possible that the gender discrepancy
in the relationship between SHS exposure and flow rates of
airways may have a physiological foundation because females
tend to have smaller absolute airways after adjusting for
height (25). However, another interesting hypothesis is the
possible role of sex hormones. Although CCAAPS is unable
to address this hypothesis, there have been intriguing studies
that support this theory. Girls prior to menarche have been
shown to have detectable levels of progesterone in their saliva
(26). Prenatal and SHS exposure has been associated with
earlier menarche (27), and progesterone (a hormone involved
in the female menstrual cycle) has been shown to illicit a Th2
immune response similar to that seen in allergic asthma; this
effect is enhanced by exposure to SHS (28). Despite the
inconsistencies in the literature, it is compelling that gender
plays a fundamental role especially in a girl’s risk of
decreased lung function with SHS exposure. Whether or not
hormones are responsible is appealing but remains unknown.
This study’s major findings center on FEF
25–75%
, suggest-
ing that the small airways may be a particular target for
SHS. What is clear is that airway development and final alve-
olarization occur at different stages. Therefore, depending on
when SHS exposure occurs, there may be differing dimen-
sions of lung damage. It is noted, however, that the guide-
lines of the American Thoracic Society (15) do not suggest
the use of FEF
25–75%
to define airway obstruction because of
its variability, dependence on length of forced expiratory
time, and level of FVC achieved. Confidence can be found in
our data, however, as those children diagnosed with asthma
also had a lower FEF
25–75%
. Further, we found no signs of
measurement artifact that would invalidate the reported
FVC, FEV
1
, or FEF
25–75%
after review by a pulmonary toxi-
cologist (RM). Other recent studies (29, 30) have demon-
strated that FEF
25–75%
measurement in children with allergic
disease and/or asthma may be beneficial where FEV
1
is not
yet affected. FEF
25–75%
has been demonstrated to correlate
better with air trapping and bronchodilator responsiveness
than FEV
1
in asthmatic children (30). FEF
25–75%
has also
been suggested as a possible early indicator of bronchial
impairment, and early allergic or inflammatory involvement
of the small airways in subjects with allergic disease (29).
Further, FEF
25–75%
has predicted the presence of clinically
relevant reversible airflow obstruction in children (30). There-
fore, changes in FEF
25–75%
within population studies, espe-
cially for children, may give insight toward airflow
modifications or remodeling in the small airways that are
undetected by parameters such as FEV
1
or FEV
1
/FVC,
which are affected primarily by alteration of central and lar-
ger airway function. Further research exploring the clinical
predictability of FEF
25–75%
in detecting early or smaller air-
way obstruction, especially in children, is warranted.
We feel that these findings are also generalizable to a non-
high-risk cohort. Two of the major risk factors for childhood
asthma are family history of asthma and allergies and early
and persistent allergic sensitization to environmental allergens
(10). It has been shown previously that nearly 50% of children
Brunst et al. Girls, allergic sensitization, tobacco, and lung function
ª 2012 John Wiley & Sons A/S 7
Page 7
between the ages of 6 and 9 are atopic (9). In the CCAAPS
cohort, the frequency of SPT positivity to at least one aeroal-
lergen (15 evaluated) is approximately 45%. Hence, these
results are likely applicable to a large portion of children in the
United States presenting with allergic sensitization. This study
addresses the limitations of previous studies using question-
naire data rather than internal dose data for SHS exposure as
it controls for potential sources of bias and confounding asso-
ciated with parental reporting of smoking, passive smoking
outside of the child’s home, and exposure misclassification. It
is acknowledged that prenatal exposure to SHS and other
sources of indoor/outdoor particulate matter is relevant to
lung function and may be potential confounders. However,
during univariate analyses, prenatal exposure to SHS, riding a
school bus, and the use of a gas stove in the home, all accord-
ing to parental report, were examined and were not associated
with the pulmonary function outcomes at age 7 and therefore
were not included in the models.
Based on our results, and those of others, gender and the
extent of allergic sensitization are significant factors in sus-
ceptibility to SHS. Our study identified sensitized girls as
being a high-risk group for the damaging effects of SHS on
FEF
25–75%
. The discordant results on lung function deficits
presented in the literature, however, complicate and highlight
the complexity of the underlying mechanisms for gender dif-
ferences in children exposed to SHS. It is likely that the mul-
tifarious relationship between SHS and pulmonary function
loss among boys and girls is ultimately dependent on not
only timing of exposure but also the child’s ‘total load’ in
relationship to cumulative risks (i.e., exposures + allergic
sensitization + asthma status + genetic susceptibility + sex
hormones). Hence, it is overdue for researchers to extend
analyses to include these more complex interactions between
exposures and multiple simultaneous determinants to fully
understand a child’s risk for lung damage especially during
the early stages of lung development.
Acknowledgments
The authors thank Bridget Whitehead, Christopher Schaffer,
and the clinic staff for their efforts in study coordination,
recruitment, data management, and data collection. We
also thank all of the CCAAPS families for their time and
commitment.
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Page 9
  • Source
    • "Exposure to second-hand smoke (SHS) in children is associated with respiratory problems such as lower respiratory illness (CDC, 2006; Fuentes-Leonarte et al., 2014); middle ear disease and otitis media (CDC, 2006; Fuentes-Leonarte et al., 2014); increased risk of sinusitis (Hur et al., 2014), chronic rhinitis and allergic rhinitis (Higgins and Reh, 2012), asthma (CDC, 2006; Tinuoye et al., 2013) and lower lung function level (CDC, 2006; Brunst et al., 2012; Merghani and Saeed, 2013 ); increased risk of invasive meningococcal disease (Murray et al., 2012); and higher blood pressure (Simonetti et al., 2011 ). Furthermore, sudden infant death syndrome and childhood cancer, as leukaemias, lymphomas and brain tumours, could be related to SHS exposure (CDC, 2006). "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Second-hand smoke exposure (SHS) in children remains as a major pollution problem, with important consequences for children's health. This study aimed to identify the sources of exposure to SHS among 4-year-old children, comparing self-reports to a urinary biomarker of exposure, and characterize the most important variables related to SHS exposure in this population. Methods: 4-year-old children's exposure to SHS was assessed by a parental-reported questionnaire and by urinary cotinine (UC) measurements in 1757 participants from 4 different areas of the Spanish INMA (INfancia y Medio Ambiente - Environment and Childhood) Project. The questionnaire about SHS included information about smoking habits at home by household members, and about exposure to SHS in other places including other homes, bars, restaurants or transportation. The association between quantified UC levels (>4ng/ml) and sociodemographic variables and the different sources of SHS exposure was examined using logistic regression. Results: Based on parental reports, 21.6% of the children were exposed to SHS at home and 47.1% elsewhere; making a total 55.9% of the children exposed to SHS. In addition, 28.2% of the children whose parents reported being not regularly exposed to SHS had quantified UC values. Children from younger mothers (<34 vs. ≥39.4 y) had a higher odds of exposure to SHS [OR (95% CI): 2.28 (1.70-3.05) per year], as well as from families with a lower educational level [OR secondary: 2.12 (1.69-2.65); primary or less: 2.91 (2.19-3.88)]. The odds of quantifiable UC in children dropped after the smoking ban in public places [OR=0.59 (0.42-0.83)]. Regarding the sources of SHS exposure we observed that quantifiable UC odds was increased in children whose parents smoked at home in their presence [OR mother occasionally: 13.39 (7.03-25.50); mother often: 18.48 (8.40-40.66); father occasionally: 10.98 (6.52-18.49); father often: 11.50 (5.96-22.20)] or in children attending other confined places, mainly other houses where people smoked [OR: 2.23 (1.78-2.80)]. Conclusions: Children's SHS exposure is nowadays an unresolved major public health problem in Spain. After the ban of smoking in public places health care professionals should put more emphasis to the parents on the importance of controlling the exposure of their children in private spaces.
    Full-text · Article · Feb 2016 · Environmental Research
  • Source
    • "Asthma caused by ETS during puberty is more pronounced in girls (Strong and Chang, 2013). Girls exposed to ETS and allergic sensitization during prepuberty are at greater risk of decreased lung function later in adulthood compared to non-sensitized girls and boys (Brunst et al., 2012). As no gender differences in cotinine levels were detected in our study, it could be hypothesized that cotinine, as an aromatase inhibitor, may have gender related differences in its effects on the respiratory system. "
    [Show abstract] [Hide abstract] ABSTRACT: a b s t r a c t Susceptibility to environmental stressors has been described for fetal and early childhood development. However, the possible susceptibility of the prepubertal period, characterized by the orchestration of the organism towards sexual maturation and adulthood has been poorly investigated and exposure data are scarce. In the current study levels of cadmium (Cd), cotinine and creatinine in urine were analyzed in a subsample 216 children from 12 European countries within the DEMOCOPHES project. The children were divided into six age–sex groups: boys (6–8 years, 9–10 years and 11 years old), and girls (6–7 years, 8–9 years, 10–11 years). The number of subjects per group was between 23 and 53. The cut off values were set at 0.1 mg/L for Cd, and 0.8 mg/L for cotinine defined according to the highest limit of quantification. The levels of Cd and cotinine were adjusted for creatinine level. In the total subsample group, the median level of Cd was 0.180 mg/L (range 0.10–0.69 mg/L), and for cotinine the median wet weight value was 1.50 mg/L (range 0.80–39.91 mg/L). There was no significant difference in creatinine and cotinine levels between genders and age groups. There was a significant correlation between levels of cadmium and
    Full-text · Article · Dec 2014
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    • "Furthermore, passive tobacco smoke’s influence is even stronger when it interacts with other risk factors, such as atopic sensitization. Among 486 children from the CCAAPS birth cohort, lung function was impaired at the ages 2, 4 and 7 years in atopic polysensitized girls exposed to tobacco smoke [44]. The effect of tobacco smoke seems to be partially affected also by genetic predisposition. "
    [Show abstract] [Hide abstract] ABSTRACT: The epidemic of childhood allergic disorders has been associated to the decline of infectious disease. However, exposure to many triggers (airborne viruses, tobacco smoke, pollution, indoor allergens, etc.) contribute to the disease. Breast feeding practices, nutrition, dietary and obesity also play a multifaceted role in shaping the observed worldwide trends of childhood allergies. Guidelines for treatment are available, but their implementation is suboptimal. Then developed countries are slowing learning integrating the development of suitable guidelines with implementation plans. Awareness, psychosocial and family factors strongly influence asthma and food allergy control. Moreover, monitoring tools are necessary to facilitate self-management. By taking into consideration these and many other pragmatic aspects, national public health programs to control the allergic epidemic have been successful in reducing its impact and trace the need for future research in the area.
    Full-text · Article · Dec 2013 · Italian Journal of Pediatrics
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