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77]

original article

Inflammatory response to subcutaneous allergenspecific

immunotherapy in patients with bronchial asthma and
allergic rhinitis
Raj Kumar, Nitesh Gupta, Indu Bisht

Access this article online

ABSTRACT

Website: www.ijaai.in

DOI: 10.4103/0972-6691.162972
Quick Response Code:

Background: Bronchial asthma(BA) and allergic rhinitis(AR) are chronic

inflammatory disorders of the airways. The allergic response is driven by the
production of different immunological effector cells cytokines like interleukin5(IL5)
and IL6 among others. Subcutaneous allergenspecific immunotherapy(SCIT)
modifies basic immunological mechanisms, reducing IL5 production. The
effect of SCIT on levels of IL6 is undetermined. Objective: The aim is to
study the changes in immunological parameters that follow SCIT in patients
suffering from BA and/or AR. Materials and Methods: Twentynine patients
(1848years, mean 25.5years) diagnosed with BA and/or AR were evaluated
for allergic sensitivity using skin prick test(SPT). The patients were started on
standardized treatment for BA and AR as per global initiative for asthma and
AR and its impact on asthma guidelines, respectively. SCIT was initiated as per
the standard Indian guidelines. IL5 and IL6 levels were obtained at 0, 3 and
6months during the course of SCIT and the response was evaluated using
Friedman test. Results: Twentynine patients; 16males and 13females were
evaluated and initiated on SCIT. The decreasing order of antigen sensitivity on
SPT was mosquito(65.5%), housefly(58.6%), female cockroach(58.6%), male
cockroach(48.2%), moth(34.4%) and house dust mite(17.2%). The IL5 and
IL6 levels, for 0, 3 and 6months were compared, and it was noted that with an
increase in duration of treatment, the levels of inflammatory markers significantly
decreases(P=0.003). On comparison, the inflammatory response between
male and female, duration of symptoms and number of positive antigens was
not statistically significant. Conclusion: Immunologic changes associated with
immunotherapy are complex and allergic patients suffering from asthma, and/or
rhinitis showed a significant reduction in levels of inflammatory markers.
Key words: Allergic rhinitis, bronchial asthma, subcutaneous immunotherapy

Department of Respiratory Allergy and Applied

Immunology, Vallabhbhai Patel Chest Institute,
Universityof Delhi, NewDelhi, India

This is an open access article distributed under the terms of the Creative
Commons AttributionNonCommercialShareAlike 3.0 License, which allows
others to remix, tweak, and build upon the work noncommercially, as long as the
author is credited and the new creations are licensed under the identical terms.

Address for correspondence: Prof. Raj Kumar,

For reprints contact: reprints@medknow.com

Department of Respiratory Allergy and Applied Immunology,

NationalCentre of Respiratory Allergy Asthma and Immunology,
Vallabhbhai Patel Chest Institute, University of Delhi,
NewDelhi110007, India. Email:rajkumarvpci@gmail.com

How to cite this article: Kumar R, Gupta N, Bisht I. Inflammatory

response to subcutaneous allergen-specific immunotherapy in patients
with bronchial asthma and allergic rhinitis. Indian J Allergy Asthma
Immunol 2015;29:7-13.

2015 Indian Journal of Allergy, Asthma and Immunology | Published by Wolters Kluwer -Medknow

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Kumar, etal.: Immunotherapy in asthma and rhinitis

INTRODUCTION
The occurrence of allergic diseases such as bronchial
asthma(BA) and allergic rhinitis(AR) has been on increasing
trend all over the world including developing countries like
India. It has been reported that 2030% of world population
suffers from an allergy, pollonosis alone accounting for
1015% cases.[13]
Allergen immunotherapy(AIT) is defined as the repeated
administration of specific allergens to patients with
IgEmediated conditions for the purpose of providing protection
against the allergic symptoms and inflammatory reactions
associated with natural exposure to these allergens.[4] The two
most commonly prescribed routes for AIT are subcutaneous
immunotherapy(SCIT) and sublingual immunotherapy.
Different immunological effector cells are responsible for
allergic inflammation. [5] In humans, Th1cells produce
interleukin2(IL2), interferongamma(IFN) and
possibly small amounts of IL6, IL10, and IL13. On the
other hand, Th2cells produce IL4, IL5, IL6, IL9, and
IL13. Normally, Th1cells support cellmediated immune
response and suppress the proliferation of Th2cells, whereas
Th2cells support humoral and allergic responses.[6,7] AIT
acts by altering basic immunological mechanisms resulting
in the suppression of the seasonal increase in eosinophilia,
in the reduction of the latephase reactivity and a shift from
a Th2to Th1like response is initiated and maintained.[813]
Hence, this study was undertaken to study the immunological
changes that follow SCIT in patients suffering from
BA and/or AR.

MATERIALS AND METHODS

Study design and demographics
The diagnosed patients of BA, AR and BA with AR(BAAR)
were enrolled for the study from the outpatient clinics.
Atotal of 29 a topic subjects(16males and 13females) aged
between 18 and 48years were enrolled for immunotherapy,
based on skin prick test(SPT) results for the purpose of
analysis. The diagnosis of asthma and AR were based on
the global initiative for asthma(GINA)[14] and AR and its
impact on asthma(ARIA)[15] respectively. The exclusion
criterion were:(1) Smoker(Former and current smokers)
and (2) history of urticaria/eczema. All the 29 subjects
underwent a battery of investigations including baseline
spirometry and blood sampling. Written informed consent
was obtained from all subjects. The study protocol was
approved by Institutional Ethical Committee.
All 29 subjects were initiated on their BA and/or AR
treatment as per the GINA and ARIA guidelines. SCIT,
based on their SPT results was also initiated, and the subjects
8

were followedup. IL5 and IL6 levels were obtained from

sera prior to initiation of SCIT and subsequently, at 3rdand
6thmonth of followup during immunotherapy treatment
for the purpose of the study. The level of asthma control
and medication requirement was noted at subsequent visits.
Spirometry with reversibility
Spirometry was performed on a dry, rollingseal spirometer of
the Benchmark model lung function machine(P. K. Morgan,
Kent, UK). Maximal expiratory flowvolume curves were
obtained as per the ATS recommendations.[16]
Skin prick testing
Skin prick testing to 58 common aeroallergens was
performed in all the patients as per standard guidelines.[17]
58 different types of allergens, included five types of grass
pollens(Cenchrus, Cynodon, Imperata, Pennisetum, Sorghum),
16 types of weed pollens(Adhatoda, Ageratum, Amaranthus
spinosus, Argemone, Artemisia, Asphodelous, Brassica,
Cannabis, Cassia occidentalis, Chenopodium album,
Chenopodium M, Dodonaea, Gynandropsis, Parthenium,
Suaeda, Xanthium), 11 types of tree pollens (Cassia siamea,
Ehretia, Eucalyptus, Kigelia, Melia, Morus, Prosopis,
Putranjiva, Ricinus, Salvadora, Holoptelia), 4 types of
dusts(house dust, wheat dust, paper dust, cotton dust),
12 types of fungi(Alternaria, Aspergillus fumigatus,
Aspergillus tamari, Candida, Cladosporium, Curvularia,
Helminthosporium, Mucor, Phoma, Trichoderma, Rhizopus,
Epicoccum), 6 types of insects(cockroach(M), cockroach(F),
housefly, rice weevil, mosquito, moth) and others(house dust
mite, kapok cotton, wool, silk) antigens. Atopy was defined
as a positive SPT(wheal diameter of>3mm as compared
to buffer saline as control) for at least1 aeroallergen.[17]
Subcutaneous perennial immunotherapy
The prescription for SCIT vials containing causative
antigens was decided after correlating with history, evidence
of exposure, precipitation of symptoms after exposure and
skin test positivity. In cases where more than single antigen
correlated with history, amount of individual antigen was
decided depending upon their skin test positivity. More
was the positivity; more was the amount of that antigen
to be included in the vaccine. [17] In most of the cases,
immunotherapy was started with 1:5000 w/vdiluted antigen
and the injections were given 2times a week starting from
and increased by 0.1ml in every injections. The injections
were given subcutaneously or intradermally with a graduated
syringe or insulin syringe. The idea was to achieve the highest
maintenance dose, that is, 1:501time a month, 1.0ml.
Usually the maintenance dose is between 0.5 and 1.0ml of
1:50 dilution.[17] The complete schedule is labeled in Table1.
Measurement of serum interleukin5 and interleukin6
Serum levels of IL5 and IL6 were estimated by ELISA
method using GENPROBE France, Diaclone kit as per
manufacturers instructions.

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Kumar, etal.: Immunotherapy in asthma and rhinitis

Table1: Immunotherapy schedule of the patient*

Concentration of antigen
1:5000
1:500
1:50
1:50
1:50
1:50
1:50
1:50

Duration and dose

Two times a week, from 0.1 to 0.9 ml
Two times a week, from 0.1 to 0.9 ml
One time a week, from 0.1 to 0.5 ml
One time in 2weeks, 0.6 ml
One time in 3weeks, 0.7 ml
One time a month, 0.8 ml
One time a month, 0.9 ml
One time a month, 1.0 ml-highest maintenance dose

*Adapted from reference[16]

Statistical analysis
All data analysis was performed using SPSS statistical
package version16.0 for windows(SPSS, Chicago, Illinois,
USA). The data were examined for distribution and
homogeneity of variances was checked before applying
parametric tests. The data on IL5 and IL6 were
expressed as meanstandard deviation. For comparing
the inflammatory response markers(IL5, IL6) for 0, 3
and 6months Friedman test was applied for k related
samples. MannWhitney Utest and KruskalWallis test
were applied to compare response between the subgroups.
The conventional 5% level(P<0.05) was considered to
be statistically significant.

RESULTS
The demographic characteristics are shown in Table2.
Of the total 29 subjects, 16 were males and rests 13 were
females. Overall there were 16 BA patients and 13 BA with
AR patients in the study.
Atopic profile
The various antigens positive on SPT were mosquito(65.5%),
housefly(58.6%), female cockroach(58.6%), male
cockroach(48.2%), moth(34.4%), rice weevil(31%), house
dust mite(17.2%), cassia(3.4%) and prosis(3.4%). SCIT
was initiated against single antigen in three subjects, two
antigens in six subjects, three antigens in five subjects, four
antigens in eight subjects and maximum five antigens in
seven subjects[Table2].
Interleukin5 levels
The mean level of IL5 at the baseline was 12.8013.09pg/ml.
The mean level obtained at 3rdmonth was 9.647.51pg/ml
and at 6thmonth was 7.184.88pg/ml. The decrease in IL5
level was statistically significant(P=0.003)[Figure1]. On
analysis comparison of IL5 levels at baseline between male
and female, duration of symptoms(010, 1020, 2030,
3040years), number of positive antigens (2, >2) the
mean response for each classification were not statistically
significant[Table3]. The mean level of IL5 ingroup
classification according to number of antigen positive
against, which SCIT were observed at initiation and in
3rdand 6thmonth of followup[Table4].

Figure1: Significant reduction in interleukin5(IL5) and IL6

observed during the treatment

Interleukin6 levels
The mean level of IL6 at the baseline was 5.041.35pg/ml.
The mean level obtained at 3rdmonth was 4.321.04pg/ml
and at 6thmonth was 4.301.13pg/ml. The decrease in
IL6 level was statistically significant(P=0.002)[Figure1].
On comparative analysis of IL6 levels at baseline between
male and female, duration of symptoms(010,1020,
2030, 3040years), number of positive antigens(2, >2)
the mean response for each classification were statistically
insignificant[Table3]. The mean level of IL6 ingroup
classification according to number of antigen positive
against which SCIT were observed at initiation and in 3rdand
6thmonth of followup[Table4].
Asthma control and medication requirement
All BA and/or AR patients were evaluated for the compliance
during the followup visits. BA patients had controlled
asthma during the followup at 3rdand 6 thmonth, with
no requirement of additional oral corticosteroids for
exacerbations and subsequently maintenance therapy
at lowest controlling step was continued as per GINA
guidelines.[14] In the assessment of AR, reduction in the
requirement of oral antihistamines was observed during
the followup.

DISCUSSION
Allergy is one of the immune tolerancerelated diseases that
arise as a direct consequence of a dysregulated immune
response. Allergenspecific immunotherapy has been
used for more than 100years in the therapy of allergic
diseases. Currently, allergenspecific immunotherapy by
the administration of increasing doses of allergen extracts
remains the single curative approach to allergic diseases
with the potential to modify its course.[18,19] Subcutaneous
SIT is able to decrease not only early, but also late asthmatic
responses following allergenspecific bronchial challenge,

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14
20
36
22
32
37
3
34
23
36
22
21
36
26
30
46
15
34
36
47
20
27
52
18
20
21
21
21
42

Female
Male
Female
Male
Male
Female
Male
Female
Male
Female
Female
Male
Male
Male
Female
Male
Male
Female
Female
Male
Male
Male
Female
Male
Female
Female
Male
Female
Male

10
1
36
18
12
2.5
3
7
4
15
8
3
4
3
8
2
15
1
2
5
8
7
2
3
2
21
21
21
40

BA
BA
BAAR
BAAR
BAAR
BA
AR
BAAR
AR
BAAR
BAAR
AR
BAAR
BAAR
BAAR
BAAR
BAAR
BAAR
AR
AR
BAAR
BAAR
BAAR
BA
BAAR
AR
AR
BAAR
BAAR

116
96
73
100
108
57
87
92
102
74
119
107
45
85
81
97
88
87
78
60
86
76
53
78
76
53
70
70
65

83
79
64
75
76
70
81
66
88
66
87
74
56
83
62
77
91
75
52
39
69
66
68
88
80
51
57
57
68

Duration Diagnosis FEV1% FEV1/

(years)
FVC %

SPT
Number of
IL5(pg/ml)
IL6(pg/ml)
Male
Female Housefly Moth Rice Mosquito House Cassia Propis antigens 0 month 3 months 6 months 0 month 3 months 6 months
positive
cockroach cockroach
weevil
dust mite
2+
3+
4+ 2+
4+
5
7
6
5.4
4.6
4.8
5.6
3+
3+
2
7
6.3
7.9
7.90
6.9
4.6
3+
3+
3+
3+
4
5.9
4.9
4.8
4.3
3.3
3.1
3+
3+
3+
3+
4
15
12
13
4.5
2.9
3.5
3+
2+
3+
3
7.8
7.6
7.0
3.4
8.5
3.3
4+
4+
4+
4+
4
10.9
10.9
11.7
3.9
3.3
2.9
2+
3+
2
4.1
7
4.0
5.0
3
3.4
4+
2+
4+
3+
4
8
11.6
3.9
3.4
3.6
3.2
3+
1
30
10.9
4.2
4.9
5.3
5.1
3+
3+
4+
3+
4
3.6
10.8
6.4
5.0
4.4
4.6
4+
1
62
17
19
2.4
2.9
2.8
4+
3+
4+
3+
4
3.5
2.9
3.2
7.2
3.9
5.9
2+
3+
2
7
15
6.5
4.2
23.5
4.5
3+
3+
4+
3+
4
15
6.9
7.0
3.3
4.1
4.0
4+
3+
4+
3
3.9
5.7
12
3.5
5.6
4.2
3+
3+
3+
4+
4
6.5
2.8
2.8
4.3
4.1
4
2+
2+
3+
3
2.7
3.6
5.8
5
6.1
5.1
2+
2+
3+
3
6.5
7.9
7.6
5.1
4.6
7.5
3+
3+
2
2.9
3.7
2.8
4
2.5
1.9
3+
3+
4+
3+
4+
5
18
12
11
5
4.8
4.9
4+
4+
4+
4+
4+
5
7.1
6.7
4
4.1
4.8
6.1
3+
3+
3+
3+
3+
5
14.8
4.0
4.2
4.8
4.7
4.4
4+
1
18
15
7.0
6
5.8
6
4+
4+
4+
4+
4+
5
8
4.3
4.0
6
4.8
4.6
3+
3+
2
4
3.6
3.8
5.5
5.5
5.1
3+
3+
2
6.8
7.0
6.0
5.0
4.3
4.5
4+
4+
4+
3+
3+
5
40
33
25
7
4.8
4.4
4+
4+
4+
3+
4+
5
30
32
1.4
2.9
2.8
2.1
3+
4+
4+
3
15.3
12.4
10.0
4.2
3.5
3.8

SCITSubcutaneous immunotherapy, BABronchial asthma, ARAllergic rhinitis, BAARBronchial asthma concomitant with allergic rhinitis, FEV1Forced expiratory volume in 1st s, FVCForced vital capacity, IL5Interleukin5, IL6Interleukin6, SPTSkin prick test

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29

Serial
Age Sex
number (years)

Table2: Clinical profile of 29patients undergoing SCIT

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Kumar, etal.: Immunotherapy in asthma and rhinitis

thus confirming the antiinflammatory effect of the

treatment in the lung.[20]
Through previous two decades in India, a remarkable
headway in research regarding characterization of various
aeroallergens and the effectiveness of immunotherapy of
significant value has occurred.[21,22]
According to the GINA report, AIT should be considered
only after strict environmental avoidance and pharmacologic
intervention, including ICS.[14] The evidence for SCIT efficacy
has been analyzed in the Cochrane review, which reported
an overall clinical efficacy; that is, reductions in asthma
symptom scores, medication usage, and allergenspecific
bronchial hyperreactivity(BHR), and limited reduction
in nonspecific BHR. [23] A recent metaanalysis of the
effectiveness of SCIT in the treatment of AR and asthma
concluded that SCIT reduces asthma symptoms and asthma
medication usage.[24]
Epidemiological studies show that polysensitization is more
prevalent in the general population.[25,26] In a study by Kumar
etal.,[27] on pattern of skin sensitivity to various aeroallergens
in patients of BA and/or AR in India, insects(43.90%) were
the most common offending allergen, and among insects,
the study reported moth(33%) as the most common cause.
In the current study, the insects were the commonest
causative allergen, with mosquito(65.5%) being a most
frequent allergen.
In a review of the literature, studies have been performed
with single allergens or crossreactive allergen extracts
in monosensitized patients and has been shown to be
Table3: Levels of IL5 and IL6 observed in various subgroups of
the study before initiation of SCIT
Parameters
IL5(meanSD) pg/ml IL6(meanSD) pg/ml
Male
12.6110.11
5.531.34
Female
13.0316.49
4.391.01
Duration of symptoms
<10years
12.4813.7
4.951.3
10-20years
7.224.8
5.521.6
20-30years
25.617.3
5.500.07
30-40years
10.66.6
4.250.07
Number of antigens positive
2
15.7519.42
5.111.5
>2
11.479.3
5.011.30
SCITSubcutaneous immunotherapy, IL5Interleukin5, IL6Interleukin6, SDStandard deviation

effective.[28,29] However, the efficacy of multiallergen IT

in polysensitized patients has been debated. Nelson[30] in
his review of 13 studies on multiAIT for AR and asthma
concluded the simultaneous administration of more
than 1 allergen extract is clinically effective. However,
more studieSs are needed, particularly with more than 2
allergen extracts and with the sublingual administration.
In the current study, the reduction in inflammatory markers
(IL5 and IL6) was significant in both groups having number
of positive antigens2 and>2. Thus showing the efficacy
of immunotherapy in subjects with more than 2 allergen
extracts.
Wilson etal., [31] reported grass pollen immunotherapy
leads to symptomatic improvement which correlates with
reductions in eosinophils and IL5 mRNA expression in the
nasal mucosa during the pollen season. Immunotherapy
induces transforming growth factorbeta, which is also
a Tregulatory cell mediator [32] and is responsible for
the downregulation of the Th2 responsereducing IL5
production[13] and preventing allergenexposureinduced
eosinophilia and inflammation.[31] In the present study, a
statistically significant reduction in IL5 and IL6 levels
was reported both at 3 and 6months following initiation
of allergenspecific immunotherapy. Karmakar etal. [33]
in a placebocontrolled study on IT for 612months
with Cocos nucifera pollen extract showed significant
clinical improvement(symptommedication score),
reduction in IgE and elevation of specific IgG in
posttherapeutic patients sera than placebo. Gaur and
Gupta[34] similarly reported>50% improvement in clinical
parameters(symptoms) after immunotherapy for 1year in
cases of asthma and/or rhinitis.
A doubleblind placebocontrolled study[35] on IT with
mosquito extract in asthma and AR patients demonstrated
significant clinical improvement, supported with changes in
airway reactivity and immunologic parameters(IgE, IgG1,
IgG4 and IFN) from the baseline and placebo. Similarly,
a doubleblind, placebocontrolled trial of cockroach IT[36]
reported improved clinical and immunological status of
asthma and rhinitis patients. AClinicoimmunologic
study[37] on immunotherapy with mixed and single insect
allergens concluded IT with two to three mix extract from
the same allergen group is effective for insect hypersensitivity.
Rasool etal.[38] reported a significant reduction in severity

Table4: Levels of IL5 and IL6 observed in various subgroups before and after 3 and 6 months following SCIT
Number of
antigens positive
1
2
3
4
5

0 month
36.6622.74
5.31.83
7.244.93
8.554.63
17.8412.76

IL5(meanSD) pg/ml
3 months
14.33.10
7.14.16
7.443.26
7.853.94
14.0012.91

6 months
10.067.86
5.161.93
8.482.59
6.603.84
7.858.10

0 month
4.331.84
5.261.40
4.260.82
4.481.23
4.911.31

IL6(meanSD) pg/ml
3 months
4.661.55
7.667.94
5.661.87
3.700.50
4.500.75

6 months
4.631.65
4.001.16
4.801.63
3.900.98
4.581.26

SCITSubcutaneous immunotherapy, IL5Interleukin5, IL6Interleukin6, SDStandard deviation

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Kumar, etal.: Immunotherapy in asthma and rhinitis

and medication requirements in cases of AR and BA

following initiation of immunotherapy.

13.

CONCLUSION
Immunologic changes associated with immunotherapy
are complex, and the exact mechanism or mechanisms
responsible for its clinical efficacy are continually being
elucidated.

14.

15.

In the current study of BA and AR patients, a significant

reduction of inflammatory markers was observed during
6month followup. However, a longterm study is required
to elucidate clearly the response and effectiveness of
immunotherapy.

16.

Financial support and sponsorship

Nil.

18.

Conflicts of interest
There are no conflicts of interest.

19.
20.

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