Early and late allergic reaction in the nose assessed by whole body plethysmography.

Abstract

Physiological changes during late phase nasal responses after allergen challenge are difficult to establish and different criteria are used for the definition of a positive late phase nasal reaction. The objective of this study was to assess the value of whole body plethysmography in detecting changes in nasal airway resistance after allergen challenge and to suggest criteria for the definition of early and late phase nasal reactions. Nasal challenge with allergen was performed in 15 allergic patients. Nasal resistance was followed until 10 h after allergen challenge and on a control day using whole body plethysmography. The mean percentage changes in the inspiratory nasal resistance during the early phase period (0.25-2 h) and the late phase period (4-10 h) were significantly higher on the allergen challenge day than on the control day (p=0.001 and p=0.01, respectively). The mean percentage change in the inspiratory nasal resistance during the early and late phase period on the control day plus 2 times the standard deviation served as cut-off point for a positive reaction. Using this definition, all patients had early reactions and 7 of the 15 patients (47%) also had late reactions. We conclude that whole body plethysmography is a useful, noninvasive method for the measurement of the physiological changes in the nose following allergen challenge.

Full text

Page 1

Eur Respir J, 1996, 9, 1701–1706
DOI: 10.1183/09031936.96.09081701
Printed in UK - all rights reserved
Copyright ERS Journals Ltd 1996
European Respiratory Journal
ISSN 0903 - 1936
Early and late allergic reaction in the nose assessed by
whole body plethysmography
M.S. de Bruin-Weller*+, F.R. Weller+, A. Scholte*, L.H.M. Rijssenbeek*,
S. van der Baan**, J.M. Bogaard*++, J.G.R. de Monchy*#
Early and late allergic reaction in the nose assessed by whole body plethysmography.
M.S. de Bruin-Weller, F.R. Weller, A. Scholte, L.H.M. Rijssenbeek, S. van der Baan, J.M.
Bogaard, J.G.R. de Monchy. ERS Journals Ltd 1996.
ABSTRACT: Physiological changes during late phase nasal responses after aller-
gen challenge are difficult to establish and different criteria are used for the defi-
nition of a positive late phase nasal reaction. The objective of this study was to
assess the value of whole body plethysmography in detecting changes in nasal air-
way resistance after allergen challenge and to suggest criteria for the definition of
early and late phase nasal reactions.
Nasal challenge with allergen was performed in 15 allergic patients. Nasal resis-
tance was followed until 10 h after allergen challenge and on a control day using
whole body plethysmography.
The mean percentage changes in the inspiratory nasal resistance during the early
phase period (0.25–2 h) and the late phase period (4–10 h) were significantly higher
on the allergen challenge day than on the control day (p=0.001 and p=0.01, respec-
tively). The mean percentage change in the inspiratory nasal resistance during the
early and late phase period on the control day plus 2 times the standard deviation
served as cut-off point for a positive reaction. Using this definition, all patients had
early reactions and 7 of the 15 patients (47%) also had late reactions.
We conclude that whole body plethysmography is a useful, noninvasive method
for the measurement of the physiological changes in the nose following allergen
challenge.
Eur Respir J., 1996, 9, 1701–1706.
*Asthmacentre Heideheuvel, Hilversum,
The Netherlands. +Dept of Pulmonology,
Academic Medical Centre, Amsterdam, The
Netherlands. **Dept of ENT, University
Hospital of Utrecht, The Netherlands. ++Dept
of Pulmonology, University Hospital Dijkzigt,
Rotterdam, The Netherlands. #Dept of
Allergology, University Hospital of Gronin-
gen, The Netherlands.
Correspondence: M.S. de Bruin-Weller
Asthmacentre Heideheuvel
Soestdijkerstraatweg 129
1213 VX Hilversum
The Netherlands
Keywords: Allergic reaction
nose
whole body plethysmography
Received: August 8 1995
Accepted after revision January 27 1996
This study was financially supported by
the Stichting Astma Bestrijding (SAB), The
Netherlands and ALK Benelux.
Allergen challenge in the nose in allergic patients often
results in an early reaction. This reaction can be detec-
ted by various clinical methods, such as evaluation of
symptom scores, rhinomanometry and peak inspiratory
nasal flow [1–4]. The early reaction can also be detec-
ted by the influx of inflammatory cells in nasal secre-
tions [5, 6], or by an increased level of mediators, such
as histamine, prostaglandin D2(PGD2), p-toluenesulfonyl-
L-arginine methylester (TAME) esterase activity and
kinins in nasal lavage fluid [7, 8].
Nasal late phase reactions have been reported in 3–75%
of allergen-challenged allergic patients [8–13]. In con-
trast to the late phase bronchial reaction, no clear crite-
ria have been developed for the definition of the late
nasal response. Although many authors have described
histological and biochemical changes during late nasal
response [8, 14, 15], the follow-up of the late nasal res-
ponse using physical methods has appeared to be very
difficult. In contrast to the changes during the early nasal
response, the changes in nasal obstruction during late
nasal response are quite subtle. The influence of various
factors, such as nasal cycle, posture and unphysiologi-
cal stimulation by nasal instruments, can disturb the regi-
stration of the late nasal response [16, 17].
This is the first study in which the early and late reac-
tions after nasal allergen challenge were monitored with
whole body plethysmography. The aim of the study was
to assess the value of whole body plethysmography in
detecting changes in nasal resistance after allergen chal-
lenge. Furthermore, criteria for the definition of early
and late phase nasal reactions are suggested and discus-
sed.
Patients and methods
Patients
Fifteen atopic, nonsmoking patients with rhinitis (5
males and 10 females; aged 21–55 yrs) participated in
the study. Twelve of the 15 patients also had asthma; and
10 patients regularly used inhaled steroids. The clinical
data are presented in table 1. Three patients had positive
skin tests (≥++) and/or elevated specific immunoglobu-
lin E (IgE) (Pharmacia Cap >0.7 Phadebas radioallergo-
sorbent test (RAST) units (PRU)·mL-1) to house-dust
mite (HDM), and 12 to grass pollen (GP). The pollen
allergic patients were tested outside the pollen season.
None of the patients gave a history of respiratory tract
infections in the 6 weeks prior to the study. All patients
gave informed consent. The study was approved by the
Medical Ethics Committee of Asthmacentre Heideheuvel,
The Netherlands.

Page 2

Nasal challenge
Allergen solutions were prepared from stock solutions
of Dermatophagoides pteronyssinus and mixed grass
pollens, diluted in phosphate-buffered saline (PBS) with
0.03% human serum albumin and containing 0.0125%
benzalkonium chloride (SQ 503 resp. SQ 293; ALK Bene-
lux), to produce a range of 10 fold increasing concentra-
tions from 100 to 10,000 biological units (BU)·mL-1. The
allergen solutions were administered with a pump spray,
delivering a volume of 0.102 mL (ALK Benelux). Both
nostrils were challenged. Before allergen challenge, pati-
ents waited 15 min to allow the nasal mucosa to become
acclimatized. Increasing doses of allergen were given at
15 min intervals; no further dose was given when the nasal
resistance, measured with whole body plethysmography
(see below), had doubled. Following the final dose, nasal
resistance was measured after 15 min and thereafter every
hour until 10 h after challenge. On a control day, nasal
resistance was recorded until 10 h after the inhalation of
a control solution, a phosphate buffer solution with 0.03%
human serum albumin and containing 0.0125% benzal-
konium chloride.
On the allergen challenge day and on the control day,
the mean percentage changes in inspiratory nasal air-
way resistance compared to preinhalation, in the periods
0.25–2 h and 4–10 h post inhalation, were calculated in
order to characterize early and late allergic reaction.
Whole body plethysmography
Whole body plethysmography is often used to deter-
mine airway resistance in routine practice [18]. In this
study, a volume constant body plethysmograph (Jaeger,
Wuerzburg Germany) was used. In this procedure air-
way resistance (Raw) is measured with open airways
(mouth open), and is defined as the quotient of mean alveo-
lar pressure (PA) and the corresponding gas flow (V') so
that Raw=PA/V'. The gas flow is measured at the mouth
with a pneumotachometer. The conversion factor for the
determination of alveolar pressure from box pressure
fluctuations follows from measurements of mouth pres-
sure and box pressure changes during panting through
the mouth against a closed shutter. Mouth pressure in
conditions of no flow is then considered to be equal to
alveolar pressure.
For the measurement of nasal resistance with whole
body plethysmography, the mouthpiece, connected to the
pneumotachometer, was replaced by a solid nasal mask
(nasal continuous positive airway pressure (CPAP) mask).
The mask was supported by both of the patient's hands,
ensuring that the mask was fixed on the face of the pati-
ents without leakage of air, and preventing the patient
from blowing out the cheeks. The patients were instructed
to breathe quietly through the nose, keeping the mouth
closed. Nasal flow through both nostrils was recorded.
When five reproducible measurements of nasal flow were
recorded, PA was determined by the manoeuvre descri-
bed above. Nasal resistance (Rn) in both nostrils was then
calculated from the nasal flow and the PA, according to
the formula Rn=PA/V'n.
In contrast to the pattern of the PA-V' curve during
measurement of airway resistance, the S-shape of the
Paw-V' diagram of the nose is most pronounced in the
inspiratory phase: during inspiration the patency of the
nose is less than during expiration and more sensitive for
detection of nasal obstruction due to allergen challenge.
Therefore, the inspiratory nasal resistance (Rn,insp) was
used for the monitoring of the allergic reaction. The ini-
tial value of Rn,insp on the control day and on the aller-
gen challenge day was considered as 0%. The other values
of Rn,insp were expressed as percentage changes com-
pared to the initial value.
Rhinomanometry
Active anterior rhinomanometry was performed with
a rhinomanometer, developed by Bachmann (Nasaltest
WB; NT-Vertrieb, Mannheim Germany). Nasal flow
(mL·s-1) measured at a pressure of 150 Pa is recorded.
Mean flow of both nostrils was used for the follow-up
of the allergic reaction.
Peak nasal inspiratory flow
Peak nasal inspiratory flow was measured with the peak
nasal inspiratory flow meter (Youlten, Clement Clarke,
London, UK). From three measurements the highest value
was recorded.
M.S. DE BRUIN-WELLER ET AL.
1702
Table 1. – Clinical data of the patients studied
Patient Age Sex Allergy Asthma Smokers Medication
No. yrs Rhinitis* Asthma**
µg
800
400
1
2
3
4
5
6
7
8
9
30
27
25
36
23
21
34
23
23
21
42
55
23
34
M
F
F
F
M
F
F
M
F
F
F
M
M
F
HDM
HDM
HDM
GP
GP
GP
GP
GP
GP
GP
GP
GP
GP
GP
+
+
+
-
-
+
+
+
+
+
-
+
+
+
-
-
-
-
-
-
-
-
-
-
-
-
-
-
S
-
S
-
-
-
-
-
S, A
-
-
-
S,A
S,A
-
S
-
800
100
1600
800
1000
200
1000
400
10
11
12
14
15
*: medication used for rhinitis; **: dose of inhaled steroids. M: male; F: female; HDM: house-dust mite; GP: grass
pollen; S: nasal steroids; A: antihistamines.
-

Page 3

Study design
Subjects visited the hospital for two separate days, with
at least 3 weeks interval. Medication for the treatment
of allergic rhinitis was stopped before the tests: nasal
steroids and cromoglycate were stopped 1 week before
the tests; antihistamines were stopped 48 h before the
tests. None of the patients received oral corticosteroids
or immunotherapy. Inhalation medication for the treat-
ment of asthma was continued.
During the first study day, nasal resistance was regis-
tered 15 min after the inhalation of control solution and
after that every hour until 10 h after the inhalation.
On the second study day, allergen challenge was per-
formed. In all 15 patients, nasal resistance was measured
15 min after challenge and then every hour until 10 h
after challenge. Measurements were performed at the
same time of the day as on the control day. In 11 patients,
resistance in the lower airways was also recorded. In
10 patients nasal flow and peak nasal inspiratory flow
were also measured.
Data analysis
The mean percentage change in inspiratory nasal resis-
tance during early and late reaction was compared with
the mean percentage change in inspiratory nasal resis-
tance during the same period on the control day, using
the Wilcoxon test. Spearman's rank correlation was used
for correlation studies. Values are given as mean±SD in
text and ±SD/SEM as stated in figures. P-values less than
0.05 were considered significant.
Results
Whole body plethysmography, definition of early and late
responses
Figure 1 shows the follow-up of inspiratory nasal res-
istance (Rn,insp) of 15 patients, measured with whole body
plethysmography, both after allergen challenge and dur-
ing the control day. The initial value of Rn,insp on con-
trol day (0.63 kPa·L-1·s) and on allergen challenge day
(0.61 kPa·L-1·s) were defined as 0%. The mean percen-
tage change in Rn,insp ±SD in the period 0.25–2 h after
allergen challenge (early reaction) was 165±85%; and
in the period 4–10 h after challenge (late reaction) 46±50%
(fig. 2).
On the control day, the Rn,insp showed minor varia-
tion; no effect of challenge with control solution on Rn,insp
was found. The mean percentage change in Rn,insp ±SD
in the period 0.25–2 h was -6±14%; and in the period 4–10
h 1±14%. When the mean percentage change in Rn,insp
in the period 0.25–2 h on the challenge day was com-
pared with the mean percentage change in Rn,insp in the
same period on the control day a significant difference
was found (p=0.0007). This was also true, although to
a lesser extent, during the late phase response (4–10 h)
(p=0.007).
In order to define the cut-off point for early and late
nasal responses, the mean percentage changes in Rn,insp
on the control day in the above-mentioned periods plus
2SD were calculated (early phase 23%; late phase 29%).
For practical purposes, an early reaction was defined as
a mean percentage increase in Rn,insp >30% in the period
0.25–2 h after challenge, when the Rn,insp before chal-
lenge was defined as 0%; a late reaction was defined as
a mean percentage increase in Rn,insp >30% in the period
4–10 hours after challenge. When the above-mentioned
criteria were used, all 15 patients had early reactions, while
seven patients also showed late responses (table 2). We
also calculated the number of late responders based on
the maximal percentage change in Rn,insp in the period
4–10 h after challenge. On the control day, the mean
percentage change in nasal resistance of the 15 patients
for each individual time-point during the late phase peri-
od (4–10 h) plus 2SD was calculated. A cut-off point of
43% was then found. Ten of the 15 patients had a max-
imal increase in nasal resistance >43% during the late
phase period (table 2).
Figure 3 shows the follow-up of airway resistance in
the nose and in the lower airways after nasal allergen
challenge. No effect of nasal challenge was seen on the
airway resistance in the lower airways (inhalation medi-
cation was continued).
BODY PLETHYSMOGRAPHY AND ALLERGEN NOSE REACTION
1703
500
●
●
●
●
●
●
●
●
●
●
●
●
▲
▲
▲
▲
▲
▲
▲
▲
▲▲
400
300
200
100
-100
0
100
1
23476589
Time h
Change in Rn,insp %
Fig. 1. – Follow-up of inspiratory nasal resistance (Rn,insp) after aller-
gen challenge and on control day in 15 patients. Values are presen-
ted as mean±SEM. ●
: allergen challenge; ---▲--- : control.
400
300
200
100
0
-100
Early reactionLate reaction
p=0.007
p=0.0007
Change in Rn,insp %
Fig. 2. – Percentage change in inspiratory nasal resistance (Rn,insp)
during early and late phase period on allergen challenge day ( )
and on control day ( ) in 15 patients. Values are presented as
mean±SD. : cut-off point.

Page 4

In order to study whether the use of inhaled steroids
in the asthmatic patients could have influenced the inten-
sity of the allergic reaction in the nose, the relationship
between the dose of inhaled steroids and the intensity of
early and late allergic reaction was studied, calculated as
mean percentage increase in Rn,insp, in the nose. However,
no significant (inverse) correlation could be found (early
reaction: r=0.05, p=0.92; late reaction: r= -0.20, p=0.39).
Comparison with rhinomanometry and peak nasal inspi-
ratory flow
In 10 patients, the nasal reaction to allergen challenge
was registered using three methods: whole body plethys-
mography (Rn,insp); active anterior rhinomanometry
(mean flow); and peak nasal inspiratory flow (peak flow).
Figure 4 shows the results. The early reaction was regi-
stered with all three methods. When the nasal early res-
ponse was defined as the percentage change in nasal
resistance, flow and peak flow in the period 0.25–2 h
after challenge, a significant correlation was found bet-
ween the intensity of nasal early response measured with
whole body plethysmography and active anterior rhino-
manometry (r=-0.68; p=0.04). This was not true when
whole body plethysmography was compared with peak
nasal inspiratory flow (r=-0.08; p=0.81).
In the period 4–10 h after challenge, a slight increase
in nasal resistance was seen from 7 h after challenge.
This was not paralleled by a decrease in flow or in peak
flow (fig. 4). When the late nasal response was defined
as the percentage change in resistance, flow and peak
flow in the period 4–10 h after challenge, no significant
correlation was found between the intensity of the late
nasal response measured with whole body plethysmo-
graphy and active anterior rhinomanometry (r=-0.58;
p=0.08), or between whole body plethysmography and
peak nasal inspiratory flow (r=-0.26; p=0.44).
Discussion
In contrast to the lower airways, physiological chan-
ges during late nasal responses after allergen challenge
are difficult to establish. Furthermore, different criteria
are used to define late responses in the nose. In order to
detect minor physiological changes in the nose during
the late phase period, we used whole body plethysmo-
graphy, a very sensitive method for the measurement of
airway resistance. This method has been used for the fol-
low-up of nasal surgery [19, 20], but no other data are
available about its use for the follow-up of the allergic
reaction in the nose. This technique has the advantage
that no mechanical irritation or deformation of the upper
M.S. DE BRUIN-WELLER ET AL.
1704
Table 2. – Change in Rn,insp during early and late phase period on control day and on allergen challenge day
Control day Allergen challenge day
Mean ∆Rn,insp Mean ∆Rn,insp Mean ∆Rn,insp Mean ∆Rn,insp Max ∆Rn,insp Max ∆Rn,insp
Pt early response late response early response late response early response late response
No. % % % % % %
1
2
3
4
5
6
7
8
9
-26
-8
-9
5
23
-25
283
72
110
209
86
44
116
119
181
215
206
378
183
100
175
57*
10
180*
17
1
23
47*
17
103*
70*
71*
78*
-2
-16
28
531
106
195
454
227
120
160
323
233
410
440
900
504
251
256
157#
19
424#
39
20
61#
88#
68#
176#
110#
169#
321#
38
3
-24
-5
-11
0
12
7
18
-1
-4
-7
5
12
-2
-26
0
15
0
-3310
11
12
13
14
15
2
0
18
-1
-14
2
54#
Mean
SD
-6
14
1165
88
46
50
341
207
116
11914
*: late responder, defined as mean increase in Rn,insp (4–10 h) >30%; #: late responder, defined as maximum increase in Rn,insp
(4–10 h) at an individual time-point >43%. Pt: patient; Rn,insp: inspiratory nasal resistance.
●
●
●
●
●
●
●
■
●
●
●
●
●
■
■
■
■
■
■
■
■
■
■
500
400
300
200
100
0
-100
70
1
234568910
Time h
Change in Rinsp %
Fig. 3. – Follow-up of inspiratory airways resistance (Rinsp) measured
in the nose (n=11) and in the lower airways (n=11) after allergen chal-
lenge in the nose. Values are presented as mean±SEM.
■
: lower airways.
●
: nose;
Change in Rinsp %

Page 5

airways occurs. Both nostrils are considered as a physio-
logical unit.
On the control day, the variation in nasal resistance
measured with whole body plethysmography was small,
indicating no interference of disturbing factors. The sta-
ble control day and the minor variations in values after
repeated measurements at the same time-point indicate
a good reproducibility of the method. On the allergen
challenge day, the large changes in nasal patency during
the early phase period were detected by whole body
plethysmography, active anterior rhinomanometry and
peak nasal inspiratory flow. The severity of the early
nasal response measured with whole body plethysmo-
graphy showed only a positive correlation with the sev-
erity measured with active anterior rhinomanometry.
During the quiet period between 4–7 h after challenge,
the standard error of the mean of the Rn,insp was rela-
tively small compared to the flow and inspiratory peak
flow. During the late phase period, the changes in nasal
resistance were relatively small compared to the changes
measured during the early phase period, but a significant
difference was found between the allergen challenge day
and the control day.
The order of challenge (control challenge and allergen
challenge) was not randomized in this study, because
when an allergen challenge is followed by a control chal-
lenge the interval between the two tests should be more
than 3 weeks to avoid interference of the allergen chal-
lenge on the control challenge. This large interval has
the disadvantage that differences in test conditions, espe-
cially patients' conditions, could occur between the two
test days. To exclude a learning effect, all patients had
to be able to produce reproducible values using whole
body plethysmography before the tests were started.
In order to define individual early and late responders,
the mean percentage changes in Rn,insp were calculated
in the period 0.25–2 h and 4–10 h, respectively, on the
control day and these value were enlarged by 2SD. When
the mean percentage increase in Rn,insp on the allergen
challenge day during the early or late phase period was
above this value (30%), patients were defined as early
or late responders, respectively. Using this definition, all
patients were classified as early responders, and 7 of the
15 patients (47%) as late responders.
The number of late responders largely depends on the
definition of the late response. In the literature, the maxi-
mal percentage change during early and late phase period
is often used to define a response. In order to define the
number of late responders in the present study based
on the maximal percentage increase in nasal resistance
BODY PLETHYSMOGRAPHY AND ALLERGEN NOSE REACTION
1705
3.6
3.2
2.4
2.8
2.0
1.6
1.2
0.8
0.4
0.0
0.30
0.25
0.20
0.15
0.10
0.05
0.00
a)
4
0
12356789 10
Time postchallenge h
Resistance kPa·L-1·s
Flow mL·s-1
●
●
●
●
●
●
●
●
●
●
●
●
3.6
3.2
2.4
2.8
2.0
1.6
1.2
0.8
0.4
0.0
280
250
220
190
160
130
100
b)
4
0
12356789 10
Time postchallenge h
Resistance kPa·L-1·s
Peak flow L·min-1
●
●
●
●
●
●
●●
●
●
●
●
Fig. 4. – a) Follow-up of early and late allergic reaction in the nose using whole body plethysmography and rhinomanometry in 10 patients. b)
Follow-up of early and late allergic reactions in the nose using whole body plethysmography and inspiratory nasal peak flow in 10 patients. Values
are presented as mean±SEM. ●
: resistance; ❍
: flow.