(Acta Paediatr Jpn 1990: 32: 192
-
196)
Immunological Aspects of Asthma (Prophylaxis) Setsuko Ito M.D. and Haruki Mikawa M.D. Department of Pediatrics, Kyoto University, Kyoto, Japan
A long follow-up study revealed that convalescent stage children still have the potency to have an immediate type hypersensitivity reaction on exposure to mite antigen, with a high titer of mite specific IgE in their sera, but they are free from asthmatic attacks because of the reduction in the amount of mite antigen in the body, as shown by the reduction in the amount of mite specific IgC. We also made a prospective study to see whether early elimination of the allergen has any beneficial effect on the cessation of the development of allergic diathesis thereafter. Our study suggested that early elimination of food allergen in infancy not only improved clinical manifestations but also had a protective effect on the progression of the allergic march so far as production of reaginic antibodies was concerned: production of total IgE and mite specific IgE was kept to a minimum. Key Words
Bronchial Asthma, Mite Allergy, Egg Allergy Allergen-specific IgE, Allergen+pecific IgG
Introduction The aim of the management of patients with bronchial asthma is to lead them to clinical convalescence. To clarify the immunological events essential in leading patients with bronchial asthma to clinical convalescence, we made two studies: a long follow-up study of patients with bronchial asthma and a prospective study of the development of mite allergy in patients with atopic dermatitis due to egg allergy, which seems to be one of the first manifestations of the allergic march. The follow-up study was made to see whether or not those who had been free from asthmatic attacks for several years had any immunological characteristics which were different from the Received June 30,1989 Correspondence address: Setsuko Ito, M.D., Department of Pediatrics, Ijinkai Takeda General Hospital, Ishidamori Minami-cho 28-1, Fushimi-ku, Kyoto, 601 -13, Japan
characteristics of those who were still suffering from asthmatic attacks. This study was made on the basis of the fact that allergen specific IgG is a good indicator of allergen invasion into the body as was shown in patients with atopic dermatitis due to egg allergY i l l . The latter prospective study [2] was based on the hypothesis that the period of antigen exposure is critical in the development of allergic diseases thereafter. In other words, early initiation of treatment to shorten the period of antigen exposure is essential in treating allergic diseases.
Materials and Methods Patients With Bronchial Asthma: 79 patients with bronchial asthma who had been followed up for more than 10 years were selected in the cooperative long follow-up study of four institutes (Kyoto University, Doai Fraternity Memorial Hospital, Kanagawa Children’s Medical
Immunological aspects of asthma (77) 193 Center and National Minami-Fukuoka Chest Hospital). Fifty-one patients were still suffering from asthmatic attacks when the study was made: 22 mild cases, 1 6 moderate cases and 13 severe cases. We randomly selected 28 patients who had been suffering from bronchial asthma before but had been free from asthmatic attacks for several years at that time. We refer to these latter patients as the convalescent group. The levels of mite specific IgE and mite specific IgG were measured in these patients. Patients With Atopic Dermatitis due to Egg Allergy: Breast-fed babies with eczema caused by egg allergy were followed up regularly after initiation of an elimination diet to see the development of IgE specific to mite, the most common allergen in bronchial asthma in Japan. The early elimination group consisted of 11 babies who were diagnosed as having egg allergy before the age of 6 months when they were fed solely by breast milk. Eggs and egg products had been eliminated from their and their mothers’ meals completely until the age of 2. The late elimination group consisted of 19 babies who were diagnosed as having egg allergy after initiation of weaning, and the elimination diet was begun thereafter. The titers of egg white specific IgE, mite specific IgE and total IgE were measured every 3 to 6 months until the age of 2 years.
Serum IgE: The level of serum IgE was measured by RIST. Mite Specific IgE and Egg White Specific IgE: The level of these allergen specific IgEs was measured by RAST. Mite Specific IgG: The level of mite specific IgG was evaluated by RAST using radiolabelled HG 2-25, which is an ideal second antibody to detect allergen-bound IgG as the second antibody [3].
ResuI ts Age Distribution of Patients with Bronchial Asthma Table 1 shows the age distribution of these 79 cases. The mean age was 22.0 years and the mean age of onset of the disease was 3.1 years. The convalescent stage group had been free from asthmatic attacks for 8.1 years in average. Mite Specific IgE in Patients with Bronchial Asthma Figure 1 shows the titer of mite specific IgE in these 79 patients. It clearly shows that the titer of mite specific IgE remained high even after the patient attained clinical convalescence.
Table 1. Age Distribution of 79 Patients. The mean age was 22.0 years when the study was made. There (was no significant difference in the present age, the age of the onset and years after onset between convalescent stage patients and active stage patients. Bronchial Asthma in a Long Follow-Up Study active
convalescent mild Present age (years) onset age (years) years after onset recovery age (years) years after recovery
moderate
total severe
3.7
19.8
f
2.6
2.3
3.2 f 1.9
3.8
f
3.0
2.2
f
2.1
19.3 f 3.2
17.8 f 4.4
16.0 f 4.0
23.6
f
10.7
22.2
f
3.0
2.9
f
14.1
f
f
25.8 f 10.3
22.0
f
5.3
3.1
f
2.3
18.9 f 5.9
3.7
8.1 f 4 . 5
Vol. 32 No. 2 April I990
21.0
(Mean f S.D.)
194 (78) It0 and Mikawa
Mite Specific IgC in Patients with Bronchial Asthma The distribution pattern of mite specific IgG is different from that of IgE. Figure 2 shows mite specific IgG measured by using radiolabelled HG 2-25 which is an ideal second antibody. The titer of specific IgG in the convalescent stage sera, shown in the left column, was significantly low compared with that in the active stage sera, especially in the sera obtained from moderate and severe cases, shown in the right two columns.
tion of the elimination diet. RAST scores became zero in 6 out of l l patients, became smaller in 3 patients, and remained at the same score only in two patients, at the age of 2 years. On the contrary, the level of egg white specific IgE remained high for years in the late elimination group (Fig, 4). RAST scores remained as high as those of the active stage in 11 out of 19 patients at the age of 2. RAST
mite specific IgG Egg White Specific IgE in Patients with Atopic Dermatitis due to Egg Allergy Figure 3 shows the level of egg white specific IgE in the early elimination group. RAST scores declined gradually with age after initia-
.
X
vy A
800 b
700
mite specific IgE
600
.. .
PRU/ml 500
20
15
0
..
X&
400 0
300
A
0
10 0
5
.
X
X
:
convalescent
200
100
f h€
i
:
-
A
A X
A
3
:I
I
t
I1 4
X
AA
r
A
x
m A 8
X
yc
mild moderate severe
.
.. -1
A
a
active
Fig. 1: The Titer of Mite Specific IgE in Bronchial Asthma. There is no significant difference between the titer of mite specific IgE in convalescent stage sera and that in active stage sera.
convaiescent
mild
moderate severe
\
active Fig. 2: The Titer of Mite Specific IgG in Bronchial Asthma. The titer of mite specific IgG in the convalescent stage sera was significantly low compared with that in the moderately and severely active stage sera.
AcfaPaediatr Jpn
Immunological aspects of asthma (79) 195 Egg White Specific IgE Antibody
Egg White Specific IgE Antibody RAST
(late elimination group)
(early elimination group)
RAST scorie
score
l\
4-
3-
3
2-
2
T
1
0
6
12
18
24
agehonths)
Fig. 3: The Level of Egg White Specific IgE in Early Elimination Group. RAST scores became 0 in 6 out of 11 patients (54.5%) at the age of 2.
scores became smaller in 7 patients and became zero only in one patient.
Mite Specific IgE in Patients with Atopic Dermatitis due to Egg Allergy Figure 5 shows mite specific IgE in the early elimination group. Only 2 out of 11 patients showed a positive RAST score at the age of 2 and none of them had shown respiratory symptoms. The mean level of serum IgE was 137.1 U/ml at the age of 2. On the contrary, RAST scores remained zero only in one patient at the age of 2 (Fig. 6). The RAST scores of the remaining 18 patients were greater than 2. Two patients had experienced mild wheezing by the age of 2. We consider that the persistence of egg allergy led the patients to the development of mite allergy. The mean level of IgE at the age of 2 was 1,546.6 U/ml, more than ten times hgher than that of the early elimination group.
Vol. 32 No. 2 April 1990
Fig. 4: The level of Egg White Specific IgE in Late Elimination Group. Rast scores remained the same level as those of active stage in 11 out of 19 patients (57.9%) and became 0 only in 1 out of 19 patients (5.3%) at the age of 2.
Discussion The long follow-up study revealed that clinical convalescence of bronchial asthma led the patients to have a lower level of mite specific IgG than those who were still suffering from asthmatic attacks. The data shown in Fig. 1 and Fig. 2 suggest that convalescent stage children still have the potency to experience an immediate type hypersensitivity reaction on exposure to mite antigen with high titer of mite specific IgE in their sera but that they are free from asthmatic attacks because of the reduction in the amount of mite antigen in the body as shown by the reduction in the amount of mite specific IgG. Reduction of broncial hypersensitivity in patients with bronchial asthma obtained through pharmacotherapy reduces allergen invasion into the lung owing to the recovery of bronchial epithelial cells, an important barrier to allergen invasion,
196 (80) It0 andMikawa RAST SC( 4
Mite Specific IgE Antibody Mite Specific IgE Antibody RAST
(early elimination group)
(late elimination group)
SCC
4
3 3
2 2
1
1
age(monthr1
Fig. 5 : The Level of Mite Specific IgE in Early Elimination Group. The level of mite specific IgE remained 0 in 9 out of 11 patients (7 1.8%) at the age of 2 .
from damage caused by allergic reaction. This is reflected in the reduction of IgG specific to mite. The reduction of allergen invasion results in the reduction of asthmatic attacks and then in the reduction of allergen exposure and so on. Finally, the patients with bronchial asthma come to be free from asthmatic attacks. This led us to the conclusion that reduction of bronchial tissue damage by reducing bronchial hypersensitivity is the clue to conduce patients with bronchial asthma to clinical convalescence. Another important approach to the control of asthmatic children should start, we consider, in early infancy before the appearance of clinical manifestations of bronchial asthma. We, then, made a prospective study to see whether early elimination of allergen has any beneficial effect on the cessation of the development of allergic diathesis thereafter. Our study suggested that early elimination of food allergens in infancy not only improved clinical manifestations but also had a protective effect on the progression of their allergic
0
6
12
18
24
(months)
Fig. 6: The Level of Mite Specific 1gE in Late Elimination Group. The level of mite specific IgE remained 0 only in 1 out of 19 patients (5.3%) at the age of 2 and the remaining 18 patients (94.7%) showed positive RAST scores.
march so far as production of reaginic antibodies was concerned: production of total IgE and mite specific IgE was kept to a minimum. Clinical convalescence obtained by early elimination of allergen results in a reduction of antigen invasion, cessation of the progression of allergic march, and finally in full recovery from allergic diseases. References 1. Ito S, Shinomiya K , Mikawa H. Ovalbumin (OA) and Ovomucoid (OM)-specific IgG Antibodies in Patients with Atopic Dermatitis due to Egg Allergy. J Allergy 1987; 24: 227-228. 2. Ito S, Inoue Y, Mayumi M et al. Prophylaxis of the Development of Mite Allergy in Patients with Atopic Dermatitis Owing to Egg Allergy. New England and Regional Allergy 1988; 9: 279. 3. Hosoi S, Shinomiya K, Nakano H et al. Monoclonal Anti-human IgG Antibodies for Quantitation of Allergen-specific IgG in Human Sera. J Allergy Clin Immunol1985; 72: 320-327.
Acta Paediatr Jpn
-
196)
Immunological Aspects of Asthma (Prophylaxis) Setsuko Ito M.D. and Haruki Mikawa M.D. Department of Pediatrics, Kyoto University, Kyoto, Japan
A long follow-up study revealed that convalescent stage children still have the potency to have an immediate type hypersensitivity reaction on exposure to mite antigen, with a high titer of mite specific IgE in their sera, but they are free from asthmatic attacks because of the reduction in the amount of mite antigen in the body, as shown by the reduction in the amount of mite specific IgC. We also made a prospective study to see whether early elimination of the allergen has any beneficial effect on the cessation of the development of allergic diathesis thereafter. Our study suggested that early elimination of food allergen in infancy not only improved clinical manifestations but also had a protective effect on the progression of the allergic march so far as production of reaginic antibodies was concerned: production of total IgE and mite specific IgE was kept to a minimum. Key Words
Bronchial Asthma, Mite Allergy, Egg Allergy Allergen-specific IgE, Allergen+pecific IgG
Introduction The aim of the management of patients with bronchial asthma is to lead them to clinical convalescence. To clarify the immunological events essential in leading patients with bronchial asthma to clinical convalescence, we made two studies: a long follow-up study of patients with bronchial asthma and a prospective study of the development of mite allergy in patients with atopic dermatitis due to egg allergy, which seems to be one of the first manifestations of the allergic march. The follow-up study was made to see whether or not those who had been free from asthmatic attacks for several years had any immunological characteristics which were different from the Received June 30,1989 Correspondence address: Setsuko Ito, M.D., Department of Pediatrics, Ijinkai Takeda General Hospital, Ishidamori Minami-cho 28-1, Fushimi-ku, Kyoto, 601 -13, Japan
characteristics of those who were still suffering from asthmatic attacks. This study was made on the basis of the fact that allergen specific IgG is a good indicator of allergen invasion into the body as was shown in patients with atopic dermatitis due to egg allergY i l l . The latter prospective study [2] was based on the hypothesis that the period of antigen exposure is critical in the development of allergic diseases thereafter. In other words, early initiation of treatment to shorten the period of antigen exposure is essential in treating allergic diseases.
Materials and Methods Patients With Bronchial Asthma: 79 patients with bronchial asthma who had been followed up for more than 10 years were selected in the cooperative long follow-up study of four institutes (Kyoto University, Doai Fraternity Memorial Hospital, Kanagawa Children’s Medical
Immunological aspects of asthma (77) 193 Center and National Minami-Fukuoka Chest Hospital). Fifty-one patients were still suffering from asthmatic attacks when the study was made: 22 mild cases, 1 6 moderate cases and 13 severe cases. We randomly selected 28 patients who had been suffering from bronchial asthma before but had been free from asthmatic attacks for several years at that time. We refer to these latter patients as the convalescent group. The levels of mite specific IgE and mite specific IgG were measured in these patients. Patients With Atopic Dermatitis due to Egg Allergy: Breast-fed babies with eczema caused by egg allergy were followed up regularly after initiation of an elimination diet to see the development of IgE specific to mite, the most common allergen in bronchial asthma in Japan. The early elimination group consisted of 11 babies who were diagnosed as having egg allergy before the age of 6 months when they were fed solely by breast milk. Eggs and egg products had been eliminated from their and their mothers’ meals completely until the age of 2. The late elimination group consisted of 19 babies who were diagnosed as having egg allergy after initiation of weaning, and the elimination diet was begun thereafter. The titers of egg white specific IgE, mite specific IgE and total IgE were measured every 3 to 6 months until the age of 2 years.
Serum IgE: The level of serum IgE was measured by RIST. Mite Specific IgE and Egg White Specific IgE: The level of these allergen specific IgEs was measured by RAST. Mite Specific IgG: The level of mite specific IgG was evaluated by RAST using radiolabelled HG 2-25, which is an ideal second antibody to detect allergen-bound IgG as the second antibody [3].
ResuI ts Age Distribution of Patients with Bronchial Asthma Table 1 shows the age distribution of these 79 cases. The mean age was 22.0 years and the mean age of onset of the disease was 3.1 years. The convalescent stage group had been free from asthmatic attacks for 8.1 years in average. Mite Specific IgE in Patients with Bronchial Asthma Figure 1 shows the titer of mite specific IgE in these 79 patients. It clearly shows that the titer of mite specific IgE remained high even after the patient attained clinical convalescence.
Table 1. Age Distribution of 79 Patients. The mean age was 22.0 years when the study was made. There (was no significant difference in the present age, the age of the onset and years after onset between convalescent stage patients and active stage patients. Bronchial Asthma in a Long Follow-Up Study active
convalescent mild Present age (years) onset age (years) years after onset recovery age (years) years after recovery
moderate
total severe
3.7
19.8
f
2.6
2.3
3.2 f 1.9
3.8
f
3.0
2.2
f
2.1
19.3 f 3.2
17.8 f 4.4
16.0 f 4.0
23.6
f
10.7
22.2
f
3.0
2.9
f
14.1
f
f
25.8 f 10.3
22.0
f
5.3
3.1
f
2.3
18.9 f 5.9
3.7
8.1 f 4 . 5
Vol. 32 No. 2 April I990
21.0
(Mean f S.D.)
194 (78) It0 and Mikawa
Mite Specific IgC in Patients with Bronchial Asthma The distribution pattern of mite specific IgG is different from that of IgE. Figure 2 shows mite specific IgG measured by using radiolabelled HG 2-25 which is an ideal second antibody. The titer of specific IgG in the convalescent stage sera, shown in the left column, was significantly low compared with that in the active stage sera, especially in the sera obtained from moderate and severe cases, shown in the right two columns.
tion of the elimination diet. RAST scores became zero in 6 out of l l patients, became smaller in 3 patients, and remained at the same score only in two patients, at the age of 2 years. On the contrary, the level of egg white specific IgE remained high for years in the late elimination group (Fig, 4). RAST scores remained as high as those of the active stage in 11 out of 19 patients at the age of 2. RAST
mite specific IgG Egg White Specific IgE in Patients with Atopic Dermatitis due to Egg Allergy Figure 3 shows the level of egg white specific IgE in the early elimination group. RAST scores declined gradually with age after initia-
.
X
vy A
800 b
700
mite specific IgE
600
.. .
PRU/ml 500
20
15
0
..
X&
400 0
300
A
0
10 0
5
.
X
X
:
convalescent
200
100
f h€
i
:
-
A
A X
A
3
:I
I
t
I1 4
X
AA
r
A
x
m A 8
X
yc
mild moderate severe
.
.. -1
A
a
active
Fig. 1: The Titer of Mite Specific IgE in Bronchial Asthma. There is no significant difference between the titer of mite specific IgE in convalescent stage sera and that in active stage sera.
convaiescent
mild
moderate severe
\
active Fig. 2: The Titer of Mite Specific IgG in Bronchial Asthma. The titer of mite specific IgG in the convalescent stage sera was significantly low compared with that in the moderately and severely active stage sera.
AcfaPaediatr Jpn
Immunological aspects of asthma (79) 195 Egg White Specific IgE Antibody
Egg White Specific IgE Antibody RAST
(late elimination group)
(early elimination group)
RAST scorie
score
l\
4-
3-
3
2-
2
T
1
0
6
12
18
24
agehonths)
Fig. 3: The Level of Egg White Specific IgE in Early Elimination Group. RAST scores became 0 in 6 out of 11 patients (54.5%) at the age of 2.
scores became smaller in 7 patients and became zero only in one patient.
Mite Specific IgE in Patients with Atopic Dermatitis due to Egg Allergy Figure 5 shows mite specific IgE in the early elimination group. Only 2 out of 11 patients showed a positive RAST score at the age of 2 and none of them had shown respiratory symptoms. The mean level of serum IgE was 137.1 U/ml at the age of 2. On the contrary, RAST scores remained zero only in one patient at the age of 2 (Fig. 6). The RAST scores of the remaining 18 patients were greater than 2. Two patients had experienced mild wheezing by the age of 2. We consider that the persistence of egg allergy led the patients to the development of mite allergy. The mean level of IgE at the age of 2 was 1,546.6 U/ml, more than ten times hgher than that of the early elimination group.
Vol. 32 No. 2 April 1990
Fig. 4: The level of Egg White Specific IgE in Late Elimination Group. Rast scores remained the same level as those of active stage in 11 out of 19 patients (57.9%) and became 0 only in 1 out of 19 patients (5.3%) at the age of 2.
Discussion The long follow-up study revealed that clinical convalescence of bronchial asthma led the patients to have a lower level of mite specific IgG than those who were still suffering from asthmatic attacks. The data shown in Fig. 1 and Fig. 2 suggest that convalescent stage children still have the potency to experience an immediate type hypersensitivity reaction on exposure to mite antigen with high titer of mite specific IgE in their sera but that they are free from asthmatic attacks because of the reduction in the amount of mite antigen in the body as shown by the reduction in the amount of mite specific IgG. Reduction of broncial hypersensitivity in patients with bronchial asthma obtained through pharmacotherapy reduces allergen invasion into the lung owing to the recovery of bronchial epithelial cells, an important barrier to allergen invasion,
196 (80) It0 andMikawa RAST SC( 4
Mite Specific IgE Antibody Mite Specific IgE Antibody RAST
(early elimination group)
(late elimination group)
SCC
4
3 3
2 2
1
1
age(monthr1
Fig. 5 : The Level of Mite Specific IgE in Early Elimination Group. The level of mite specific IgE remained 0 in 9 out of 11 patients (7 1.8%) at the age of 2 .
from damage caused by allergic reaction. This is reflected in the reduction of IgG specific to mite. The reduction of allergen invasion results in the reduction of asthmatic attacks and then in the reduction of allergen exposure and so on. Finally, the patients with bronchial asthma come to be free from asthmatic attacks. This led us to the conclusion that reduction of bronchial tissue damage by reducing bronchial hypersensitivity is the clue to conduce patients with bronchial asthma to clinical convalescence. Another important approach to the control of asthmatic children should start, we consider, in early infancy before the appearance of clinical manifestations of bronchial asthma. We, then, made a prospective study to see whether early elimination of allergen has any beneficial effect on the cessation of the development of allergic diathesis thereafter. Our study suggested that early elimination of food allergens in infancy not only improved clinical manifestations but also had a protective effect on the progression of their allergic
0
6
12
18
24
(months)
Fig. 6: The Level of Mite Specific 1gE in Late Elimination Group. The level of mite specific IgE remained 0 only in 1 out of 19 patients (5.3%) at the age of 2 and the remaining 18 patients (94.7%) showed positive RAST scores.
march so far as production of reaginic antibodies was concerned: production of total IgE and mite specific IgE was kept to a minimum. Clinical convalescence obtained by early elimination of allergen results in a reduction of antigen invasion, cessation of the progression of allergic march, and finally in full recovery from allergic diseases. References 1. Ito S, Shinomiya K , Mikawa H. Ovalbumin (OA) and Ovomucoid (OM)-specific IgG Antibodies in Patients with Atopic Dermatitis due to Egg Allergy. J Allergy 1987; 24: 227-228. 2. Ito S, Inoue Y, Mayumi M et al. Prophylaxis of the Development of Mite Allergy in Patients with Atopic Dermatitis Owing to Egg Allergy. New England and Regional Allergy 1988; 9: 279. 3. Hosoi S, Shinomiya K, Nakano H et al. Monoclonal Anti-human IgG Antibodies for Quantitation of Allergen-specific IgG in Human Sera. J Allergy Clin Immunol1985; 72: 320-327.
Acta Paediatr Jpn
