Allergr 1993: 48: 119-1.
74
Pnnred in Belgium - all rrghrs reseried
Effects of allergen exposure-avoidance on
inflammation in asthmatic children
Boner AL, Peroni D, Sette L, Valletta EA, Piacentini G. Effects of
allergen exposure-avoidance on inflammation in asthmatic children.
AlleLgy 1993: 48: 119-124. 0 Munksgaard 1993.
Inflammation of the airways has long been known to
be the classic pathologic feature of asthmatics who
have died in status asthmaticus (1, 2). However, it
has recently been appreciated, from studies of bron-
chial lavage and bronchial biopsies, that inflamma-
tory changes are present in even mildly symptomatic
adult patients (3). Experimental evidence has linked
the induction of bronchial hyperresponsiveness
(BHR) to the presence of inflammation (4-7). The
recognition of allergic airways inflammation, as a
cause of both transient and persistent airway hyper-
responsiveness, has led to increased appreciation of
importance of atopy in the pathogenesis of asthma
(4-8). Recently, it has been shown that eosinophil
counts in lavage fluid are correlated with histamine
reactivity in children (9) as well as in adults (3).
Furthermore, ultrastructural examination of the air-
ways of two asthmatic children undergoing open lung
biopsy during clinical remission showed features
similar to lung tissue from two children who had
died in status asthmaticus with the exception of a
larger number of submucosal eosinophils and more
extensivedenudation ofthe epithelium in fatal asthma
(10). Evidence from these findings suggest that
airways-inflammation may play a role also in asth-
matic children. This hypothesis can be further sup-
ported by studies which have shown that allergen
avoidance can improve BHR and asthma symptoms
both in adults (11-12) and children (13-15) with
asthma.
Because of the importance of better understand-
ing the correlation of allergen exposure with B H R
and inflammation we evaluated changes in BHR and
serum markers of inflammation when allergic asth-
Copi nshr 0 Ilunkscuurd 1993
ALLERGY
1SSN 0105-4S38
A. L. Boner, D. Peroni, L. Sette,
E. A. Valletta, G. Piacentini
Pediatric Department University of Verona,
lstituto Pi0 XI1 - Misurina (Belluno), Italy
A.L. Boner
Pediatric Department University of Verona
Istituto Pi0 XI1
Misurina (Belluno)
ltalv
matic children sensitive to house dust mites moved
from an environment rich in allergens (sea level) to
an environment free from mites at a high altitude
(Istituto Pi0 XII, Misurina 1756111) (16-17) and
back again to sea level. The migration of asthmatic
children from sea level to the alpine environment
and back again, offers a natural allergen exposure-
avoidance-exposure challenge model.
Experimental observations
Sentin- and nasal-specific IgE
The relationship between serum-specific IgE and
symptoms has been questioned (18- 19). and direct
correlation between the level of specific IgE and a]-
lergen exposure is not always demonstrable (20-2 1).
It has been suggested that the presence of local spe-
cific IgE may more closely correlate than either skin
prick test or serum RAST with exposure and symp-
toms (22-26). The possibility for a local production
of IgE at the site of the nasal mucosa has been
suggested (24-26).
For this reason, variations of serum- and nasal-
specific IgE to Dennatophngoides prerm?yssinus (Dpt )
during alternate periods of antigen avoidance-
exposure have been evaluated in 18 allergic children
with asthma and rhinitis while guests of the residen-
tial house Istituto Pi0 XII. A method based on di-
rect incubation of allergen coupled substrate on the
nasal mucosa has been employed to measure the
levels of nasal IgE (27). Although serum-specific IgE
showed a decrease during long periods of stay in the
alpine environment and an increase during the short
period of exposure to mites at the sea level those
119
Boner et al.
changes just failed to be significant. In contrast, nasal
1gE.have been significantly (p < 0.001) influenced by
the alternate periods of antigen exposure-avoidance
(28).
The evaluation of the kinetics of changes in nasal-
specific IgE revealed a significant decrease as soon
as after three days of antigen avoidance. Nasal-
specific IgE, therefore, appear to be a more sensitive
index of antigen exposure-avoidance than serum IgE
levels.
Basophil releasability
Basophils may have a significant role in atopic dis-
ease such as allergic rhinitis and atopic dermatitis.
Their role in asthma is however less clear. We have
evaluated in 20 asthmatic children changes in
antigen-induced basophil histamine release (AIHR)
and in spontaneous basophil histamine release
(SHR) during period of antigen avoidance. A sig-
nificant drop in AIHR (p < 0.01), BHR (p < 0.005),
specific IgE serum level (p<O.OOl), but not in S H R
was observed after 40 days of antigen avoidance in
altitude. This trend was confirmed at a further evalu-
ation after 40 more days at the Istituto Pi0 XII. After
40 days of antigen avoidance significant correlations
were found between D . pteronyssinus specific IgE
serum level and PClo-FEV, (rs= -0.4970), AIHR
and PC,,-FEV, (r, = -0.4912), specific serum IgE
and AIHR (r,=0.5643) and S H R and AIHR
(r, = 0.5233). No significant correlation was found
between specific IgE and S H R and between P G 0 -
FEV, and SHR. This study shows that, in allergic
asthmatic children, antigen-induced basophil releas-
ability, BHR, and specific IgE serum levels are modi-
fiable by periods of antigen avoidance or exposure
(29).
Serum markers of eosinophil activation
The eosinophil cationic protein (ECP) levels have
been shown to be related to BHR in asthmatic pa-
tients and to the development of late asthmatic re-
actions after bronchial allergen challenge (30). venge
et al. have also indicated that there is a correlation
between the degree of activity of the eosinophils in
the lungs and the serum levels of ECP (31). In our
study a cohort of 12 asthmatic children was followed
for several months, during which they moved back
and forth to an allergen-free and allergen-rich envi-
ronment at high and low altitude, respectively. Serum
levels of ECP and eosinophil protein X (EPX)
showed a significant increase (p < 0.0 1) when the
children were exposed to the offending allergens.
The total IgE significantly increased during expo-
sure. The serum levels of myeloperoxidase (MPO)
as well as of chemotactic factors for both neutrophils
120
and eosinophils were unaltered during allergen ex-
posure. We confirm that serum eosinophil proteins,
ECP and EPX, are sensitive markers of allergen
exposure in asthmatic atopic children (32). The treat-
ment with sodium cromoglycate during period of
allergen exposure might have prevented the rise of
chemotactic factors in our children during exposure
to the offending allergens.
Eosinophils in rhe sputum
Methacholine PCzoand eosinophil percent count in
blood (Eb%) and in the sputum (Es%) induced by
hypertonic saline inhalation were evaluated in 2 1
asthmatic children within 2 days after admission to
the Istituto Pi0 XI1 (T,) and again after three months
of stay in the allergen-free environment (T,). The
same measurements were reported after two weeks
of allergen exposure at sea level (T3). Methacholine
PC,,-FEV, (mglml), E s % , and Eb% counts are re-
ported in Table 1.
There was a significant decrease in BHR (p = 0.03)
and in Es% count (p = 0.03) between T I and T2.The
increase in BHR and Es% count observed between
T, and T3just failed to be significant (p = 0.06). N o
significant changes were observed in Eb% counts
throughout the study period (33). These results con-
firm that eosinophil counts in the airways of asth-
matic children are important in the development of
BHR as it has been shown in adult patients (34-37).
Antigen avoidance and allergen-induced bronchial
hyperresponsiveness
The beneficial effect of antigen avoidance on BHR
is well-known ( 1 1-15). In this study the effects of a
prolonged stay in a house dust mite (HDM) free
environment at high altitude, on BHR and H D M
specific challenge was evaluated in 23 moderately
severe H D M allergic asthmatic children. The chil-
dren were in the residential house of Misurina for 9
consecutive months, October to June. BHR was
evaluated by a histamine challenge, followed the day
after by a D.pteronyssinus (Dpt)-specific bronchial
challenge and after 2 days by another histamine
Table 1. Bronchial hyperresponsivenessIPC,,-FEV I methacoiine)and eosinophil% count
m sputum (Es%) and blood IEb%) heanfSEM) at different times dunng allergen ex-
posure or avoidance
lime
TI T, T,
PC,,-FEV, methacholine 5.20t1.72 7.43A2.11 5.97k1.79
Es% 14.43t3.32 7.28t-2.31 8.09A2.87
Eb% 4.23t0.56 3.4t0.36 6.47f0.63
 Child asthmatic inflammation & allergen avoidance

challenge. There was a significant (p<O.OOl) in- obtained by the administration of aqueous antigen
crease in Dpt PD2,-FEV, after 6 (March) and 9 extract (44).
(June) months, with a decrease of the late reaction T o reproduce the natural allergen exposure pat-
measured by FEV,. Also histamine PD,,-FEV, sig- tern as much as possible, a single antigen challenge
nificantly increased after 6 and 9 months stay at high (only one cap) was performed every day successively
altitude: this improvement was particularly evident and the test was considered positive when FEV,
in the histamine challenges performed after the Dpt- values dropped below 20% of the baseline value
specific bronchial response (p < 0.0 1). Our data sup- obtained immediately before the inhalation of the
port the evidence that H D M avoidance decreases antigen. The administration of a single increasing
not only non-specific B H R but also allergen sensi- antigen dose every 24 h reflects the natural allergen
tivity, late-allergen induced bronchial reactions and exposure timing, from mattress the natural habitat of
the enhancement of BHR induced by allergen chal- house dust mites. This method offers the possibility
lenge (38). The magnitude of improvement is less of showing a late reaction and the consequent in-
than can be achieved by pharmacotherapy alone and, crease in BHR in absence of the early reaction. All
therefore, emphasizes the importance of the allergen the tests started at 9 a.m. FEV, values were recorded
avoidance as part of the effective treatment of aller- hourly after each challenge, for 12 h to detect the
gic asthma. early, as well as the late, reaction. A methacholine
challenge was performed on the day preceding the
Importance of allergen exposure in the pathogenesis start of the antigen challenge and the day following
of asthma: evidence from an antigen challenge
the early and/or the late reaction. Twenty-three asth-
matic children allergic to D . preronyssinus have been
The recent recognition of allergic airway inflamma- studied during their stay at the Istituto Pi0 XI1 on
tion as a cause of BHR has led to increased appre- the Italian Alps. Seven asthmatic children, skin prick
ciation of the importance of atopy as a major cause test-negative for Dpt, performed the same challenge
of asthma (4-8). as controls (45). The results of the study are reported
The patterns and the pathogenesis of allergen- in Table 2 and Fig. 1. As can be seen, 3 (13%) chil-
induced asthmatic responses have been documented dren (Pts. 5, 10 and 19) had an isolated early reac-
by allergen provocation test in the laboratory (39). tion, 10 (43.5%) patients (Pts. 1, 3, 4, 6 , 8, 9, 11, 12,
Allergen inhalation challenges are generally followed
by a dual reaction: an early bronchospastic response
Table 2. Individual response to antigen and rnethacholine challenge
followed by a late response due to edema and in-
flammation within the airways (39-41). Late re- Reactmn Methacholine
sponses are associated with an increased BHR (42) Antigen dose rnax % FEV, fall PD,,-FEV, (mcgl
and are likely much more important in the patho- associated with
genesis of asthma. Subject a positive response Early Late PreBPTs PostBPTs
The clinical equivalent of the early response may 1 200 52 23 105 92
not be recognised particularly in patients allergic to 2 200 - 30 50 23
house dust mites and this may be one of the causes 3 200 24 37 80 33
of under appreciation of the importance of allergen 4 400 33 22 1150 70
5 800 21 - 90 18
exposure in the pathogenesis of asthma. It has been 6 200 31 48 63 9.5
suggested that intermittent or chronic low grade al- 7 200 - 43 11 I
lergen exposure in some patients might not provoke 8 200 24 40 70 12
severe enough mediator release to produce an early 9 100 26 22 15 8.5
10 200 38 - 18 17
asthmatic reaction yet may be responsible for gradual
11 200 48 45 65 1
onset chronic late responses and increased airway 12 200 37 24 65 1
hyperresponsiveness and asthma symptoms (4). 13 200 - 30 145 20
To confirm this possibility we performed specific 14 100 - 28 80 6
bronchial challenge using a micronized, freeze-dried 15 400 - 54 115 7
16 400 30 60 185 18
allergen extract administered as a powder (Hy- 17 100 - 28 750 292
poinhal Method, Lofarma) (43). A cromolyn spin- 18 400 26 29 340 34
haler (Fisons Inc) was used as the delivery system 19 400 32 - 96 80
for serial titrated doses of D . preronyssinus (Lofar- 20 200 - 23 615 19
ma) in increasing concentrations of 0 (placebo), 100, 21 100 - 35 127 17
22 - - - 119 99
200, 400, 600, 800, and 1000 allergenic units (AU), 23 100 - 34 71 15
evaluated by the RAST inhibition method as previ- -
X 250 32.5 35.5 215.9 36.05
ously described (43). This method showed a good DS 162.6 9.3 11.2 300 6 66. I
specificity as well as comparable results with those

121
Boner et al.
3 .zoo
-I 7 months) of allergen avoidance, asthmatic children
undergoing specific bronchial challenge develop
fewer late reactions and the enhancement of BHR by
late reaction to allergen is far less marked. It is also
400 evident, from antigen challenge, that in some pa-
tients intermittent or chronic low-grade allergen ex-
posure might not provoke enough mediator release
-8 a

eoor--
n* p.Il.nl1 3/23 10123 9/21 1/23

I to produce an early asthmatic response yet may be

-
E I
T
I r I responsible for an isolated late response and increase
in BHR. Although it is not possible from these stud-
ies to conclude that inflammation of the airways and
BHR are linked and consequent phenomena, it is
reasonable to regard them as parallel pathological
n processes (5 1) which may be differently modulated
Early Dual Late No by different drugs but which are always and con-
Fig. 1. Above: mean ( 5 SD) dose of antigen that caused a 20% comitantly reduced by antigen avoidance. This strat-
fall in FEV, in subjects with early, dual or late reaction, respec- egy should therefore be considered a main stay step
tively. In one subject no reaction was observed after administra- in the management of asthma in allergic children.
tion of 1000 allergenic units of the antigen. Below: mean ( t SD)
PD,,-methacholine before ( A ) and after (*) the antigenic provo-
cation in subjects with early, dual, late or no reaction, respectively. References
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123
Boner et al.
P. VENGE
Did you prophylactically treat the patients on whom
you performed the sputum examinations?
A. BONER
Prophylactic treatment was used during the first
month of admission to the residential house, Istituto
Pi0 XII, Misuriiia (a house dust mite-free home at
a high altitude), but I have to check the patients’
records in order to be absolutely sure.
R. DAHL
Was it possible to predict the single LAR by RAST
value, serum-ECP level or reactivity? Do you con-
sider early- and late-phase reactions as separate or
dependent reactions?
124
A. BONER
No, it was not possible to predict those children who
presented isolated late-phase reactions by RAST
test. Serum-ECP was not evaluated in this study. I
think early and late reactions are biologically differ-
ent from each other. In isolated late reactions it is
very probable that pulmonary function studies are
not sensitive enough “to see” what is going on in the
lung.
J. WARNER
The detection of an EAR depends on measured
changes in lung functions but events may occur in
the airways without changes in lung function. Fur-
thermore, the patients were studied in a perfect en-
vironment where those factors which increase non-
specific BHR have been considered. This will reduce
the likehood of producing low dose allergen induced
EAR but presumably has less effect on the LAR.