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Abstracts
Atopyas a Risk Factorfor AsthmaSeverity
Sally H Jot*, RA Wood§, Elizabeth Cotton Matsui*, 77" Pero.§, JM
Curtin-Brosnan§, S Kanchanaraksa§, CS Rand§, Karen Callahan*, Lee
Swartz*, Peyton A Eggleston§ *Johns Hopkins Hospital, Baltimore, MD
§Johns Hopkins University, Baltimore, MD
Exposure and sensitization to indoor allergens has shown to be a known
risk factor for the development and persistence of asthma in children. The
objective of this study was to evaluate the relationship between exposure
and sensitization to indoor allergens and asthma severity in a predominantly suburban population. Children with asthma were recruited from 4 pediatric practices in the Baltimore, Maryland area for participation in the
Home Study, a clinical trial evaluating the efficacy of environmental control measures. Upon recruitment, a detailed questionnaire regarding asthma
severity was completed, prick skin tests (PST) to 14 common indoor and
outdoor allergens were performed, and exposure to indoor allergens was
assessed by measuring Bla g 2, Der pl, Der fl, Fel dl and Can fl levels in
dust samples collected from the bedroom, kitchen, and living room. Children were considered to be exposed if levels were >2000ng/g Der pl, Der
fl, Fel dl, and Can fl and > 1U/g for Bla g 2. Asthma severity was measured
based on a composite symptom score, use of inhaled corticosteroids or
other controller medications, and the need for prednisone or emergency
room (ER) visits in the previous 6 months. Data were analyzed to determine
if exposure, sensitization, or the combination of the two affected asthma
severity. The study included 158 subjects with ages ranging from 6 to 17
years. Allergen levels above the threshold occurred in one or more rooms
for Bla g 2 in 57% of homes, Der p I in 15%, Der fl in 36%, Fel d l in 37%.
and Can fl in 48%. 32% of subjects had positive PST to cockroach. 55% to
cat, 70% to one or both dust mites and 11% to dogs. No significant relationship was detected between allergen exposure or sensitization to any specific allergen and any measure of asthma severity. When the combination of
exposure and sensitization to a specific allergen was analyzed, no significant relationships were detected, although there was a trend towards
increased asthma severity as measured by ER visits in those with cockroach
exposure and sensitization (P= 0.1). Significant relationships were detected
between atopy, based on the number of positive PST, and ER visits, but not
with other measures of asthma severity. When subjects with no positive
PST were compared to those with >1 positive PST, there was a significant
difference in the proportion with an ER visit (4.8% vs 33.6%, P=0.007).
When subjects with 0-1 positive PST were compared to those with >2 positive PST, a similar difference was seen (6.7% vs 35.2%, P=0.002). The relationship between the number of positive PST and ER visits continued to be
significant up to 5 positive PST (P=0.009). In summary, while asthma
severity in this population was not significantly associated with specific
allergen exposures or sensitivities, it was clearly associated with the degree
of atopy.
101 Indoor
Allergen Levelsin Homesof Asthmaticand HealthyChildren in Kuwait
Mahdi A1-Mousawwi*, Hermione Lovel*, Nasser Behbehani§, Nermina
Arifhodzick~,, Adnan Custovie~, Ashley A. WoodcockC *Manchester University, Manchester, UK §Kuwait University, Kuwait, Kuwait ¥Kuwait
Allergy Center, Kuwait, Kuwait CWythenshawe Hospital, Manchester,
UK
Indoor allergens exposure in homes may be an important risk factor for
the developement of asthma. We compared the levels of known indoor
allergens (Der p 1, Der f 1, Fel d 1, Can f 1, Bla g 2) in homes of 152 asthma
children and 268 controls. Two samples (living room and bed room) were
obtained from each home. The dust sample was collected from the bedding
and living room floors. A two-site monoclonal antibody-based ELISAs
were used to determine the allergens levels. The geometric mean of Fel d 1
in the living room and bedding of asthmatic and control homes were 0.23,
0.22, 0.22, and 0.19 I-tg/g respectively. The geometric mean of Can f 1 in the
J ALLERGY CLIN IMMUNOL
JANUARY 2002
living room and bedding of asthmatic and control homes were 0.13, 0.16,
0.20. and 0.18 lag/g respectively. The geometric mean of Bla g 2 in the living room and bedding of asthmatic and control homes were 0.32, 0.42,
0.23. and 0.32 ~tg/g respectively, b e r p 1 and Der f 1 were below the limits
of detection in the majority of samples.
CONCLUSION: Low levels of mite, cat, dog and cockroach allergens
were found in Kuwaiti homes. There was no significant differences
between asthmatic and control homes.
102
Oral Delivery of Cromolyn:Bioavailability and BioactivityAfter
Oral Administrationin Animal Models
Donald Sarubbi*, Puchun Liu*, Ehud Arbit*, William Abraham§, Steven
Dinh* *Emisphere Technologies, Tarrytown, NY §University of Miami at
Mount Sinai Medical Center, Miami Beach, FL
Cromolyn is used to treat mild to moderate bronchial asthma. While an
oral dosage form can offer significant therapeutic advantages, it has been
limited by its low oral bioavailability (<1%). This work demonstrates that
oral delivery of cromolyn is feasible using Emisphere's oral drug delivery
technology. Preliminary data in animal models show that significantly
enhanced oral bioavailability can be achieved, and the absorbed cromolyn
is biologically active. Rodent Pharmacokinetic Studies: Fasted male
Sprague-Dawley rats were anesthized by intra-muscular injection with ketamine and thorazine, Experimental groups were dosed by oral gavage or by
intravenous injection. For intravenous administered cromolyn (1.5 mg/kg),
the area under the serum concentration-time curve (AUC), peak serum concentration (Cmax) and time of peak serum concentration (Tmax) were 20.4
mg-min/ml, 1.3 mg/ml and 0 min, respectively. When a delivery agent and
cromolyn (30 mg/kg) are co-administered orally, the AUC, Cmax and
Tmax were 18.3 mg-min/ml, 0.65 mg/ml and 15 min, respectively. No
detectable serum cromolyn concentrations were observed in the control
groups of delivery agent alone and cromolyn alone. An absolute oral
bioavailability of 4.5% was achieved in rats. Primate Pharmacokinetic
Studies: Serum concentrations of cromolyn lbllowing capsule administration of the delivery agent and cromolyn were measured in conscious male
and female Cynomolgus monkeys. The AUC, Cmax and Tmax from dosing
capsules containing the delivery agent and cromolyn (25 mg/kg) were 48.8
mg-min/ml, 0.30 mg/ml and 120 rain, respectively. Sheep Pharmacodynamic Studies: The early (EAR) and late (LAR) changes in specific lung
resistance following inhalation challenge to Ascaris suum antigen were
measured in unsedated sheep after oral gavage of the delivery agent and
cromolyn (100 mg/kg). Responses to antigen challenge were compared to
each animal's historical control. A significant protective effect on EAR
(84% protection) and LAR (78% protection) was observed. Airway responsiveness to inhaled carbachol 24 hr after antigen challenge was also measured. In the oral cromolyn treatment group, the airway responsiveness was
unchanged from baseline, as compared to the significant increase in airway
responsiveness (i.e. the development of airway hyperresponsiveness)
observed in the untreated control group.
103
An AnthroposophicLifeStyleand IntestinalMicroflora in Infancy
Johan Aim*, Jackie Swartz§, Bengt Bjorksten~, Lars Engstrand~, Gunnar
Lilja~, Roland MOllby~, GOran Pershagen~, Annika Scheynius~ *Sachs
Children's Clinic, Karolinska Institute, Stockholm, Sweden §Vidar Clinic, Jarna, Sweden ¥Center for Allergy Research, Karolinska Institute,
Stockholm, Sweden ~Karolinska Institute, Stockholm, Sweden
The intestinal flora is supposed to have an impact on the development of
the immune system. In the anthroposophic life style a diet comprising vegetables spontaneously fermented by lactobacilli, and a restrictive use of
antibiotics, antipyretics and vaccinations is typical. The aim of this study
was to assess the gut flora in infants in relation to certain life style characteristics associated with anthroposophy. Sixty-nine children below two
years of age with an anthroposophic life style and 59 similarly aged infants
J ALLERGY CLIN IMMUNOL
VOLUME 109, NUMBER 1
Abstracts
with a traditional life style were clinically examined and questionnaire
replies assessed. Faecal samples were analysed by bacterial enumeration,
bacterial typing through biochemical fingerprinting and by measuring
microflora-associated characteristics (MACs). The numbers of colony
forming units (Cfu) per g of faeces were significantly higher for enterococci and lactic acid bacteria in children who had never been exposed to antibiotics (5.5x10"7 vs 2.1×10"7; p<0.001) and (10×10"7 vs 4.1×10"7;
p<0.01), respectively. Furthermore, the number of enterococci was significantly higher in breastfed and vegetarian infants (p<0.01). The diversity
(Simpson's diversity index) of lactobacilli, as determined by biochemical
fingerprinting, was higher in infants born at home, than in those born in
hospital (p<0.01). Several MACs were related to specific life style features,
and infants with an anthroposophic life style had a higher proportion of
acetic acid and a lower proportion of propionic acid in their stool, as compared to the control children. In conclusion, life style factors related to the
anthroposophic way of life influenced the composition of the gut flora in
the infants. These differences may contribute to the lower prevalence of
atopic disease previously observed in children in anthroposophic families.
1 f~J~l Lower Prevalence of Asthma, Rhinitis and Atopy in Rural India
IJr'lr Is Associated With Higher House-Dust Endotoxin Levels
Pudupakkam K Vedanthan*, PA Mahesh§, AD Holla§, Rajesh Vedanthane Andrew H Liu~ *University of Colorado, Fort Collins, CO §Allergy, Asthma and Chest Center, Mysore, India ¥School of Medicine, University of Caifornia, San Francisco, San Francisco, CA ~National Jewish
Medical and Research Center, Denver, CO
OBJECTIVES: (1) To determine the prevalence of asthma, rhinitis and
allergen sensitization in rural vs. urban cohorts of children in India; (2) to
determine if household endotoxin exposure differs in these locales.
METHODS: The study took place in two locations: Mysore, an urban
center in south India; and Vinobha, a rural village 25 miles from Mysore.
Included in this study were 164 children (97 rural, 67 urban), ages 6 to 16
years, from 103 randomly selected households (50 urban, 53 rural). Data
was collected from three sources: (1) parents of the children were interviewed using a modified version of the International Study of Asthma &
Allergies in Childhood (ISAAC) questionnaire; 2) children underwent
prick allergy skin testing to common indoor inhalant antigens (cockroach,
dust mite, cat, dog, cattle); and 3) house-dust samples were analyzed for
endotoxin content using a standardized Limulus Amebocyte Lysate assay.
RESULTS: All ISAAC questions related to asthma and rhinitis revealed
a significantly lower prevalence of these airways atopic diseases in the rural
India cohort. For example, reported wheezing and sneezing were more
common among urban children compared to the rural group (Table). Rural
children were also less likely to be atopic based on skin test sensitivity,
especially for dust mite and cockroach antigens (Table). There were no
urban vs. rural differences in the prevalence of animal dander sensitization
(i.e. cat, dog, cattle). House dust endotoxin levels were significantly higher
in the rural vs. urban homes (geometric mean: 297 vs. 201 EU/mg dust,
p=0.03, t-test).
CONCLUSIONS: Rural living conditions in India are associated with
lower prevalences of childhood asthma, rhinitis and atopy, and greater
endotoxin exposure, when compared with an urban India locale. [AH Liu is
supported by AAAAI (ERT) and NIH (HL04272-01A1)]
Asthma, Rhinitis & Atopy are Less Common in Rural India
Wheezing
Sneezing
PST+ Dust mite**
PST+ Cockroach
Rural
Urban
OR (CI)*
13%
17%
17%
22%
34%
45%
46%
43%
0.30 (0.14, 0.64)
0.26 (0.13, 0.53)
0.23 (0.11, 0.48)
0.37 (0.18, 0.73)
*Odds Ratio (5-95% confidence intervals); **Prick skin test + if 3ram or greater
wheal (skin test data missing for one subject).
05
$51
Sick Building Syndrome, Chemical Sensitivity, and Irritant Rhinosinusitis
William Joel Meggs Brody School of Medicine at East Carolina University, Greenville, NC
OBJECTIVE: To assess for airway abnormalities and the multiple
chemical sensitivity syndrome (MCS) in a cohort with Sick Building Syndrome (SBS).
METHODS: Standardized histories and physical examinations, rhinomanometry, PFT's, and fiberoptic rhinolaryngoscopy were performed.
Medical records and industrial hygiene reports were reviewed. Two case
definitions (Cullen and Kipen) were used to screen for MCS.
RESULTS: 38 patients with building related illness associated with a
poorly ventilated office building (CO2>4,000 ppm) were examined. Mean
age was 36.5_+12 yrs (range 18 to 61 yrs), with 8 men and 30 women. Complaints associated with the workplace included rhinosinusitis (100%), asthma (97%), fatigue (95%), headache (95%), difficuhies with memory
(71%), and mental confusion (42%). Prior or current treatment with beta
agonist inhalers, steroid inhalers, and montelukast was almost universal.
PFF's were abnormal in 60% without discontinuation of medications.
Nasal resistance was abnormal in 93% (mean right 1.32_+0.96 Pa/cm3/sec,
range 0.45 to 4.41 Pa/cm3/sec, left 1.15_+0.75 Pa/cm3/sec, range 0.32 to
4.41 Pa/cm3/sec). Rhinolarygoscopy was abnormal in all 35 of 38 who
underwent the evaluation, with findings characteristic of chemical irritant
rhinitis. Discoloration of mucosa with injection, cobblestoning, edema, and
injection of the uvula and soft pallet were common. 13% were still
employed in the building, 13% were employed elsewhere, 74% were not
currently employed. Irritant sensitivity was reported by 100%. 92% met the
Cullen criteria for MCS, and 68% met the Kipen criteria.
CONCLUSION: Rhinosinusitis, irritant sensitivity, asthma, fatigue,
headaches, difficulty with memory, and objective measures of airway
inflammation were found in association with employment in a sick building. These findings suggest a relationship between SBS and MCS, and irritant rhinosinusitis and asthma may underlie these disorders.
I N ~ Exposure to Ambient Particulate Spikes increases Exhaled eN0
U ~ I I Levels in Asthmatic Schoolchildren With a Clinical Sensitivity
to Air Pollution
Nathan Rabinovitch, Steven Dutton, Erwin W Gelfand National Jewish
Medical and Research Center, Denver, CO
Epidemiological and cohort studies have repeatedly demonstrated that acute
exposure to ambient particulate less than 2.5 microns in diameter (PM2.5) is
associated with increased asthma morbidity and mortality. Nevertheless, it
remains unclear how PM2.5 may exert its effects on the airway and which asthmatics may be clinically susceptible to PM2.5. Twenty-six schoolchildren with
moderate to severe asthma were initially enrolled in this 2-year study. Forced
expiratory volume (FEV 1) measurements and rescue medication usage were
recorded daily and were used to define sensitivity. Following Year 1, 7 children
from the cohort were selected who demonstrated clinical sensitivity to PM2.5
levels (sensitive group) and were compared to 7 children who did not (control
group). Urinary leukotriene FA (LIE4) and exhaled nitric oxide (eNO) were
obtained from these 14 children on days when ambient PM2.5 was above the
90th percentile ("spike days") and below the 25th percentile ("baseline days").
Mean LTE4 levels did not significantly differ between spike and baseline days,
regardless of whether data from the entire cohort or from the sensitive group
alone was analyzed. Mean eNO levels, however, were significantly (p=0.0092)
increased on spike days among the entire cohort. Subset analysis revealed that
this finding was due to a highly significant (p<0.0001) increase in mean eNO
levels (>60%) in the sensitive group. The control group demonstrated no such
differences. Ambient PM2.5 particulate spikes are associated with increased
levels of the airway inflammatory marker eNO in asthmatic children with a
demonstrated clinical sensitivity to air pollution, eNO may serve as a marker of
clinical sensitivity to air pollution spikes in children with asthma, Sponsor: EPA
# R825702-05; GCRC# NJC 160.