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Clinical and Experimental Otorhinolaryngology Vol. 7, No. 4: 241-249, December 2014 http://dx.doi.org/10.3342/ceo.2014.7.4.241
Review
INTRODUCTION
Allergic rhinitis (AR) is a globally increasing health problem af-
fecting roughly about 500 million patients worldwide [1]. The
annual costs of AR nearly range from US$ 2–5 billion according
to 2003 values [2]. It affects the quality of life and represents a
major cause of morbidity [3]. AR is a chronic disease showing
symptoms of nasal congestion, nasal itching, rhinorrhea and
sneezing [4]. The management of the disease depends mainly on
the avoidance of exposure to antigens–which is not usually feasi-
ble–and symptomatic pharmacological treatment including anti-
histamines and topical corticosteroid.
One of the available causal treatments is allergen immunother-
apy which is effective after the end of the treatment course, un-
like symptomatic drugs. Specific immunotherapy (SIT) modifies
the basic allergic mechanism of the disease by inducing desensi-
tization through gradually increasing the dose of the specific al-
lergen over an optimum long period [3].
Over one hundred years, Leonard Noon in 1911 began to
study subcutaneous immunotherapy (SCIT) in the treatment of
AR [5]. In 1986, the British Committee for Safety of Medicines
reported 26 deaths connected with SCIT, so multiple methods
of delivery have been developed such as oral, nasal, bronchial
and sublingual routes [6].
The first randomized controlled trial (RCT) worked on sublin-
gual immunotherapy (SLIT) dates back to 1986 [4]. A panel of
experts from the World Health Organization (WHO) and vari-
ous allergy and immunology societies concluded in 1998 that
SLIT was a viable alternative to the injection route [1]. In 2010,
SLIT was included in the latest update of Allergic Rhinitis and
its Impact on Asthma (ARIA) guideline for both adults and chil-
dren [7].
ARIA 2008 suggested 4 main indications for SLIT: (1) patients
•Received April 15, 2013
Revision May 20, 2013
Accepted July 2, 2013
•Corresponding author: Omar Ali Aboshady
Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
Tel: +20-48-2282698, Fax: +20-48-2317502
E-mail: omr.ali@med.menofia.edu.eg
pISSN 1976-8710 eISSN 2005-0720
Sublingual Immunotherapy in Allergic Rhinitis:
Efficacy, Safety, Adherence and Guidelines
Omar Ali Aboshady ∙ Karim Mohamed Elghanam
Faculty of Medicine, Menoufia University, Menoufia, Egypt
Allergic rhinitis (AR) is a globally increasing health problem affecting the quality of life. Specific immunotherapy is an
available causal treatment changing the basic allergic mechanisms of the disease. Over one hundred years, subcutaneous
immunotherapy (SCIT) was developed and proved its efficacy but many adverse effects were recorded including anaphy-
laxis. In 1986, sublingual immunotherapy (SLIT) was introduced as an alternative solution to solve this problem. Our study
aims to discuss SLIT from the points of efficacy, safety, adherence and guidelines developed. A literature search was con-
ducted in Medline/PubMed and the Cochrane Library in January 2013 using the keywords “allergic rhinitis, sublingual im-
munotherapy, efficacy, safety, compliance, adherence, guidelines.” All types of publications were included. We augmented
our study by searching the reference lists of identified reviews. SLIT has been established in many guidelines as an evi-
dence-based effective treatment in AR with safer profile than SCIT. The meta-analyses confirmed its efficacy and showed a
significant reduction in both symptoms and medication scores. The most common recorded adverse effects were minor lo-
cal effects in the mouth, gastrointestinal reactions with few cases of anaphylaxis and no fatality. Adherence is more favor-
able for SLIT mainly because it is safe, noninvasive and easily taken at home. We support the call to conduct large multi-
centric studies to gain more statistical power and overcome the problem of heterogeneity observed in the meta-analyses.
Keywords.
Allergic rhinitis, Sublingual immunotherapy, Guideline adherence
242 Clinical and Experimental Otorhinolaryngology Vol. 7, No. 4: 241-249, December 2014
with seasonal rhinitis “sensitive to pollens” or perennial rhinitis
“sensitive to house mite”; (2) patients uncontrolled by pharma-
cological treatment; (3) patients presented by systemic reactions
from the drugs; and (4) patients with poor compliance or refus-
ing injections [8].
Mechanisms of SIT are not well identified till now. The most
accepted theory is that SIT shifts the immune response from Th2
to Th1 through stimulation of the T-regulatory cell, which secretes
interleukin (IL) and transforming growth factor (TGF)-β [9].
These T-regulatory cells with its mediators help to shift the im-
mune response from the IgE to IgG. The IgG antibody especially
IgG4 is considered as a blocking antibody which is known to in-
terrupt the inflammatory cascade and stop the inflammatory
mechanism initiated by the IgE release [10].
Today, SLIT is widely used in clinical practice, especially in Eu-
ropean countries, since it is noninvasive, has minimal side-effects
and can be easily administered at home. There are still some risks
of adverse effects that range from mild local reactions like itching
and swelling of the oral mucosa to severe systemic manifestation
like anaphylaxis [11].
We aim to discuss SLIT in the treatment of AR, with a particu-
lar focus on efficacy, safety profile, patient adherence and the
guidelines developed.
EFFICACY OF SLIT
Evaluation of the clinical efficacy of SIT in AR depends mainly
on the assessment of reduction in symptoms severity and medi-
cation use [11]. There is an increasing number of RCTs done in
this field over the last decades. The results of those RCTs were
pooled on six meta-analyses for SLIT [3,12-16] and one meta-
analysis for SCIT [17]. Meta-analysis, which is the statistical
method pooling the results of different independent studies to
provide a quantitative estimate of treatment, is considered the
most robust proof of the efficacy of a treatment/intervention.
The higher grade “A” recommendations is usually derived from
meta-analyses [18,19].
SIT meta-analyses
The only available SCIT meta-analysis in AR was done by Calde-
ron et al. [17] in 2007 and was published under the frame of the
Cochrane Collaboration. It examined 51 RCTs published be-
tween 1984 and 2006 with a total number of 2,871 patients
(1,645 active, 1,226 placebo). None of these studies were done
exclusively in children, but nine studies included participants
younger than 18 years. A wide range of allergens was adminis-
tered in these studies: 12 trials ragweed, 16 trials mixed grass, 5
trials timothy, 6 trials Parietaria, 4 trials birch, 3 trials cedar, 2
trials orchard, one each for bermuda, Juniperusashei, and Cocos-
nucifera. There was an overall significant reduction in symptom
score from 15 trials with standardized mean difference (SMD)
corresponding to –0.73 and to –0.57 in medication score data
from 13 trials in immunotherapy treated group [17].
The SLIT meta-analyses started in 2005 when Wilson et al. [12]
published a Cochrane review by working on 22 RCTs with five
only in children and the total number was 979 patients (503 ac-
tive, 476 placebo). This review was updated in 2011 by Radulo-
vic et al. [3] who worked on 60 RCTs with 49 were suitable for
pooling in meta-analysis with a total number of 4,589 patients
(2,333 active and 2,256 placebo). There were 34 studies done in
adults and 15 in children using a wide range of allergens includ-
ing grass pollen in 23 trials, Parietaria in 5 trials, ragweed in 2
trials, trees in 9 trials, olive in 2 trials, cypress in 3 trials, birch
pollen in 2 trials, mixed trees in 2 trials, house dust mite in 8 tri-
als and cat in one trial. The overall results were significant in the
reduction of symptoms (SMD, –0.49; P<0.001) and medication
use (SMD, –0.32; P<0.001) compared with placebo. The sub-
group analyses showed that SLIT is highly effective in both sea-
sonal however perennial AR. Also, the study was not able to
identify a significant reduction in either symptoms or medication
scores in children [3].
There are two meta-analyses which worked only on children.
The first was done in 2005 by Olaguibel et al. [13] who worked
on 7 RCTs with a total population of 256 (129 active, 127 place-
bo) including house dust mite in 3 trials, one trial each for grass
mixed, olive and Parietariain. The results showed that there was
no significant effect on nasal (SMD, –0.44; P=0.27) and eye
symptoms (SMD, –0.49; P=0.19) but there was a significantly
effective reduction of asthma symptoms (SMD, –1.42; P=0.01)
and drug consumption (SMD, –1.01; P=0.06) [13]. In 2006,
Penagos et al. [14] worked on 10 RCTs with 484 pediatric pa-
tients aged from 3 to 18 years (245 active, 239 placebo). Aller-
gens included were mites in 4 trials, grass mix in 3 trials, one trial
each for olive, Parietaria, and Phleumpoa. The study showed a
significant reduction of both symptoms (SMD, –0.56; P=0.02)
and medication score (SMD, –0.76; P=0.03). The subgroup anal-
yses showed that high efficacy was obtained in duration longer
than 18 months and for pollen allergens compared with house
dust mites [14].
According to allergen used, two meta-analyses limited their
inclusion to one type of allergen. The first one was in 2009 when
Compalati et al. [15] worked on 8 RCTs for house dust mite-in-
duced AR in adult and children, including 382 (194 active and
188 placebo) and the results showed significant reduction in
symptoms (SMD, –0.95; P=0.02). The medication score was
(SMD, –1.88; P=0.04) in 89 patients [15]. Another one by Di
Bona et al. [16] in 2010 worked on 22 SLIT RCTs conducted
with grass pollen extracts in adult and children with a total num-
ber of 2,971 (1,518 active and 1,453 placebo) and found a sig-
nificant reduction in both symptoms (SMD, –0.32) and medica-
tion use (SMD, –0.33). The authors concluded that adult treat-
ment seems to be more effective that children [16] (Table 1).
There is an obvious limitation of included meta-analyses
Aboshady OA et al. Sublingal Immunotherapy in Allergic Rhinitis 243
which is the heterogeneity in data. The results of meta-analyses
were affected with different dosages, types of pollen, standardiza-
tion methods, treatment schedules and patient populations [11].
Nieto et al. [20] concluded in his paper about the quality of SLIT
meta-analyses that the meta-analyses showed “discrepancies, in-
consistencies, and lack of robustness and do not provide enough
evidence” for the current routine use of SLIT. These heterogene-
ities make the interpretation of results difficult especially when
you extend the results to all patients, allergens, and AR vs. asth-
ma [21]. There is a possible solution to overcome the problem of
heterogeneity by making single multi-centric study of a large
number of patients. This will allow adequate statistical power [11].
Type of allergen and doses of SLIT
The type of allergen used and its relation to efficacy is still con-
troversial. In the United States, multi-allergen extracts are pre-
ferred to address all major sensitivities. In Europe, allergists are
against this practice as they think, it may lead to dilution effect
and degradation of proteolytic activity decreasing effective dose
given to patients [21]. The studies published on the option of us-
ing multi-allergen SLIT are few [22-24] and there aren’t enough
data available on both efficacy and induction of immunological
tolerance for either mixture or simultaneous application of vari-
ous allergens. So, large studies are needed to evaluate and vali-
date multi-allergen SLIT especially in polysensitized patients as
the majority of the patients are polysensitized [25].
SLIT efficacy is suggested to be dose-dependent. The ARIA
initially informed that doses–at least 50 to 100 times higher than
those administered with SCIT by the same extracts–are needed
for treatment success [8]. World Allergy Organization updated
that a dose of about 600 mg of the major allergens every month
was suggested as an optimal dose for patients with grass-induced
seasonal rhinitis [26]. Di Bona et al. [16] in his meta-analysis
concluded that a monthly dose of major allergens showed that
the SMD of symptom scores was –0.47 in patients receiving dos-
es from 276 to 600 mg compared with –0.16 in patients treated
with a monthly dose up to 275 mg. However, more studies are
still needed to determine the optimum doses and schedules.
Long-lasting and the preventive actions
The long-lasting effect and the preventive actions after discon-
tinuation of SIT are other unique advantages beside its efficacy.
These effects are due to complex, profound and persistent modi-
fications in the immune response to allergens [27]. There is a
study showed greater improvement in 70 patients with dust
mites AR treated with SLIT in 3 years compared with 67 pa-
tients treated for 2 years [28]. In another prospective open con-
trolled study, 4 groups of mono-sensitized patients to mites re-
ceived drug treatment only and another 3 groups received SLIT
for 3, 4, or 5 years and all groups were observed for 15 years.
The clinical scores showed that the clinical benefit continued for
7 years in patients treated for 3 years, while it continued for 8
years in those treated for 4–5 years [29].
Concerning the preventive action, Marogna et al. [30], in their
open randomized control study in children working with 144
patients showed that SLIT has the potential to decrease the inci-
dence of new sensitizations. The results of the study were 3.1%
in SLIT-treated patients versus 34.8% (P=0.01) in the control
for 3 years follow-up.
SAFETY OF SLIT
Most of the systematic reviews and meta-analyses met on that
SLIT is safer than SCIT. Although SCIT has proved its efficacy in
AR, the risk of systemic adverse effects and anaphylaxis–which
may occur with all types of allergen preparations either stan-
dardized extracts, allergoids, or recombinant allergens–make it
less favorable [31]. In the only available meta-analyses on SCIT
for seasonal AR, 8% and 7% of patients in the treated groups
experienced grades II and III systemic reactions respectively by
using the European Academy of Allergy and Clinical Immunolo-
gy classification for adverse events. Anaphylaxis (grade IV) was
reported in 3 cases in the SCIT group (0.72%) versus 1 case in
the placebo group (0.33%). This meta-analysis showed that epi-
nephrine was used in 3.4% of treated group versus 0.25% in
the placebo group but no fatalities were reported [17].
Table 1. Specific immunotherapy meta-analyses in allergic rhinitis
Year Author Population No. of patients Allergen used Symptom score
(SMD)
Medication
score (SMD)
Subcutaneous immunotherapy
2007 Calderon et al. [17] Adult 2,871 (1,645 active, 1,226 placebo) Various –0.73 –0.57
Sublingual immunotherapy
2005 Wilson et al. [12] Adults and children 979 (503 active, 476 placebo) Various –0.42 –0.43
2005 Olaguibel et al. [13] Children 256 (129 active, 127 placebo) Various –0.44 Not reported
2006 Penagos et al. [14] Children 484 (245 active, 239 placebo) Various –0.56 –0.76
2009 Compalati et al. [15] Adults and children 382 (194 active, 188 placebo) House dust mite –0.95 –1.88
2010 Di Bona et al. [16] Adults and children 2,971 (1,518 active, 1,453 placebo) Grass pollen –0.32 –0.33
2011 Radulovic et al. [3] Adults and children 4,589 (2,333 active, 2,256 placebo) Various –0.49 –0.32
SMD, standardized mean difference.
244 Clinical and Experimental Otorhinolaryngology Vol. 7, No. 4: 241-249, December 2014
Concerning SLIT safety, there is some heterogeneity in the re-
sults recorded but the adverse effects ranged from minor local ef-
fects in the mouth and gastrointestinal reactions (diarrhea and
vomiting) to systemic reactions like anaphylaxis with no deaths.
In the first meta-analysis by Wilson et al. [12] in 2005 who
worked on 22 RCTs and found that “there is no systemic reac-
tion but some minor local reaction like itching and swelling of
the oral mucosa were reported almost universally but were rarely
of significance.” Olaguibel et al. [13] worked on 7 RCTs with a
total population of 256 and found that there were no severe or
systemic reactions, but oral and gastrointestinal symptoms were
the most common adverse effects. In the most recent meta-anal-
ysis in 2011, Radulovic et al. [3] suggested a remarkably safe
profile without any severe systemic reactions, anaphylaxis or use
of adrenaline in 49 studies. Also, Radulovic et al. [3] found that
local reactions are common, unavoidable, have less distress, have
no lasting effect and don’t need the withdrawal of treatment. To
our knowledge, there are only 11 cases of SLIT anaphylaxis. In
some of them, the allergen used was mixture of multiple unrelat-
ed non-standardized extracts. But also, there were patients who
expressed a severe reaction after the first dose of a grass tablet
[32-37].
The safety of SLIT in children was evaluated in some studies
suggesting that it is safe in children younger than 5 years. One
study worked with 65 children aged from 3 to 7 years old and
showed that high dose immunotherapy didn’t increase the ad-
verse effects including urticaria, gastrointestinal problem and oral
pruritus in children less than 5 years in comparison with children
aged from 5 to 7 [38]. Another study confirmed the safety of
SLIT in children less than 5 years by working with 126 children
aged from 3 to 5 years. The study showed that only nine adverse
effects were reported in seven patients, corresponding to 5.6% of
patients. Two of the nine were local oral itching which were mild
and transient and did require neither dose adjustment nor medi-
cal intervention. The other seven adverse effects involved the gas-
trointestinal tract in the form of abdominal pain which was mild.
In six cases, the pain was associated with diarrhea [39].
In the aspect of the relation between types of allergen used and
safety, a study showed the same risk of adverse effect in multiple
allergens compared with mono-allergen SLIT. It worked with 433
pediatric patients and concluded that the use of multiple allergens
for SLIT does not increase the rate of adverse effects in children
[40]. We think that more studies are needed to assess the safety
according to standardized classification and reporting methods of
adverse events associated with SLIT around the world.
ADHERENCE
It is common that the term adherence and compliance are used
interchangeably but actually there is some difference. Adherence
is defined as “the extent to which a person’s behavior, taking
medication, following a diet and/or executing lifestyle changes
corresponds to the recommendations agreed with a healthcare
provider” [41]. This term became more globally used and more
specified than compliance which is defined as “the extent to
which a person corresponds to the physician’s prescription” [42].
Non-adherence to the therapy or lifestyle modification is the
greatest problem of medical practice in chronic diseases. This
point derived WHO–in its report in 2003 on the importance of
medication adherence–to use Haynes’s quotation; “Increasing
the effectiveness of adherence to interventions may have a far
greater impact on the health of the population than any improve-
ment in specific medical treatments” [43].
In general, the causes of non-adherence may be related to the
patient himself, the disease, treatment or the health care system
(Table 2) [44].
Although, SIT changes the immunological basis of the disease
and decreases the times of use of symptomatic treatment, but
the patient will need to adhere to the treatment for a few years.
So, SIT adherence is considered one of the most critical prob-
lems affecting completion of therapy.
There are nearly few studies which assessed the adherence of
the immunotherapy, so it wasn’t discussed in details in the meta-
analyses. In comparison of adherence to SLIT with SCIT, the
adherence rate in SLIT ranged from 75% to more than 95% in
6 RCTs [45-50]. It was favorable than that of SCIT which ranged
from 33% to 89% in 8 RCTs [47,51-57]. This is mainly due to
the inconvenience of SCIT; as patients need to go for the injec-
tion in the physician’s office in contrast to SLIT doses which are
taken at home [58]. Despite that, SLIT still has moderate results
in adherence because patients take drugs by themselves or par-
Table 2. Causes of non-adherence to treatment
· Factors related to the patient
Cognitive difficulties
Psychiatric co-morbidities
Age (children, adolescents and elderly present high risk of non-adherence)
Knowledge
Expectations
Social and family support
Coping style
· Factors related to the disease
Chronicity
Symptom stability
Absence of symptoms
· Factors related to the treatment
High number of daily doses taken
Presence of side effects
Ease of use
· Factors related to the healthcare system
Difficulty of the patients to access health services
Poor treatment by clinic staff
High medication costs
Reprinted from Passalacqua et al. [44] with permission of John Wiley and
Sons.
Aboshady OA et al. Sublingal Immunotherapy in Allergic Rhinitis 245
ents [59] (Table 3).
In a recent Italian study by Senna et al. [60] in 2010 conduct-
ed on sales data provided by two major manufacturers, more
than 50% of patients discontinued SLIT during the first year. In
the second year, only 28% remained on the treatment which be-
came 13% in the third year. Senna et al. [60] referred this high
drop-out rate mainly to the costs and modality of reimburse-
ment. He informed that the regimen of administration or doses
didn’t seem to play a relevant role in the discontinuation rate.
The solutions to improve the adherence and reduce drop-out
rates are to develop more convenient allergen formula and sched-
ules [59]. Also, receiving detailed information on special educa-
tional programs to the patient seems to be helpful in increasing
adherence. The not well-trained patient will lead to trivial side-ef-
fects to SLIT such as oral and gastrointestinal local reactions, and
this will lead to sudden withdrawal of the treatment [61].
In a trial to know the causes of non-adherence, a survey con-
ducted between the specialists who routinely prescribed SLIT,
reported that the absence of the perceived efficacy is the most
frequent causes for withdrawing followed by cost and tolerability.
The side effects, patient education and ease of use were judged
to be of low importance [62]. What makes this study of a low im-
portance is that the data were obtained from the doctors not
from the patient, who are the main protagonists of the compli-
ance scenario [44]. We suggest that more studies discussing ad-
herence are needed to assess and determine the main limitations
in patient adherence to treatment.
SLIT GUIDELINES
Clinical practice guidelines for the management of AR had been
developed over the past 15 years and proved its efficacy in im-
proving the medical care [63]. SIT was firstly introduced and
discussed in January 1997–in Geneva, Switzerland–in a meeting
between experts from WHO and many other allergic societies in
a trial to produce guidelines for allergen immunotherapy [1]. Af-
ter one year in 1998, the editors and participating members
reached a consensus about the information to be published un-
der the title “Allergen immunotherapy: therapeutic vaccines for
allergic diseases. WHO position paper.” They informed that SCIT
is effective in alleviating symptoms and modifying the basic al-
lergic mechanisms of the disease but there were sever adverse
effects reported like anaphylaxis and other systemic reactions.
That derived the experts to search for other safe routs like sub-
lingual swallow, oral immunotherapy or bronchial routs. They
suggested that SLIT is a good available alternative route to SCIT
but it is not recommended and well-designed studies were need-
ed to prove its efficacy [1].
In 1999, during the ARIA WHO workshop, a panel of experts
provided suggestions that were published in 2001 [64] under the
title of “Allergic Rhinitis and its Impact on Asthma (ARIA)
guideline.” This was considered the first in the field of guidelines
for AR. The ARIA guideline was innovative in many items like
proposing a new AR classification into “intermittent” or “persis-
tent” according to persistence and severity of symptoms and the
co-morbidities between upper and lower airways disease. Re-
garding SIT, the ARIA recommended the use of SLIT for adult
and children complaining from seasonal AR and for adult with
perennial AR. But, there was no recommendation for children
with perennial AR [64]. After 7 years, in 2008, the ARIA group
made a major revision to cover the growing up knowledge in AR
in collaboration with Global Allergy and Asthma European Net-
work (GA
2
LEN) and AllerGen NCE. This update recommended
SLIT in the treatment of pollen allergy in adult and not recom-
mended but “may be used” in patients with mite allergy [8].
In the World Allergy Organization position paper in 2009, SLIT
was recommended as an effective treatment for AR. The paper in-
Table 3. Adherence studies of SIT
Year Author Patient Duration (month) Compliance (%)
Results of SLIT adherence studies
2004 Lombardi et al. [45] 86 A 4–12 75–97
2004 Marogna et al. [46] 319 A 36 80
2005 Pajno et al. [47] 806 C 36 79
2006 Passalacqua et al. [48] 443 A 676
2007 Passalacqua et al. [49] 71 C 685
2008 Roder et al. [50] 154 A 24 77
2010 Senna et al. [60] Not stated 24 1st year, 44; 2nd year, 28; 3rd year, 13
Results of SCIT adherence studies
1993 Lower et al. [51] 315 C 48 44
1993 Cohn and Pizzi [52] 217 A 48 48
1995 Tinkelman et al. [53] 3,349 A 18 65
1997 Ruiz et al. [54] 247 A 18 62
1999 Rhodes [55] 1,033 A 36 88
2002 More and Hagan [56] 361 A 36 77
2005 Pajno et al. [47] 1,886 C 36 89
2008 Hankin et al. [57] 3,048 C >36 2 years, 18; 3 years, 13; >3 years, 16
SIT, specific immunotherapy; SLIT, sublingual immunotherapy; A, adult; C, children; SCIT, subcutaneous immunotherapy.
246 Clinical and Experimental Otorhinolaryngology Vol. 7, No. 4: 241-249, December 2014
formed that SLIT is effective in children ≥5 years of age and it
may be safe in children ≥3 years of age. It also informed that
SLIT can be used for AR in children with asthma. In this paper,
comparison between SLIT and SCIT was made. It concluded that
SLIT is well tolerated and safer than SCIT. All adverse effects of
SLIT occur during the first dose and the majority of them are lo-
cal. Only few cases of SLIT-related anaphylaxis have been report-
ed with no fatalities. The experts confirmed at the point that the
patient must be well informed about adverse effects, how to deal
with them and when to seek medical advice especially as the
doses will be administered at home [26].
On July 2010, GA
2
LEN/European Academy of Allergology
and Clinical Immunology (EAACI) pocket guide for SIT for AR
and asthma answered the question “which route of administra-
tion is preferable SLIT or SCIT?” by informing that there are
many independent studies comparing SLIT with SCIT conclud-
ed that there was no difference in efficacy. No fatality and only
few severe adverse events have been reported with SLIT but
many local adverse effects were recorded. Regarding the final
choice between SLIT and SCIT, the guide suggested making the
decision individually with each patient after many consider-
ations such as home based treatment vs. doctor visit, fear of in-
jection, costs and compliance. Concerning the point of age, the
guide concluded that many studies suggested the age to be more
than 5 years to be safer and more effective and for old age there
is no upper limit [65].
In December 2010, American Academy of Allergy, Asthma &
Immunology (AAAAI), American College of Allergy, Asthma &
Immunology (ACAAI) and Joint Council of Allergy, Asthma &
Immunology (JCAAI) concluded that SLIT reduces symptoms
but require higher doses than that of subcutaneous route with
frequent local and gastrointestinal adverse effects. But, currently
there is no Food and Drug Administration (FDA)-approved for-
mulation for a non-injection immunotherapy extracts [66].
All these guidelines and recommendations used evidence-
based approaches but none of them used Grading of Recommen-
dation, Assessment, Development and Evaluation (GRADE) sys-
tem [67-69]. This system grades recommendations on two levels:
strong and weak (alternative term is conditional) and quantifies
evidence into four categories: high (in symbolic language four
plus), moderate (three plus), low (two plus), and very low (one
plus) [67].
In 2010, a panel of ARIA and GA
2
LEN experts formulated 42
questions about prevention, management of AR and the relation
between AR and asthma in the same patient. Then, methodolo-
gists developed 48 questions based on patient-intervention-com-
parison-outcome (PICO) style and evidence based answer was
prepared for each question using the GRADE approach. This
Table 4. Chronological presentation of SLIT recommendations
Paper Year Recommendation for SLIT
Allergen immunotherapy: therapeutic vaccines
for allergic diseases. WHO position paper
1998 SLIT is a good available alternative route to SCIT but it’s not recommended.
ARIA 2001 SLIT is accepted in adult and children as an alternative route to SCIT.
ARIA update 2008 SLIT is recommended in pollen allergy in adult.
SLIT is not recommended but “may be used” in patients with mite allergy.
World Allergy Organization 2009 SLIT is recommended as an effective treatment for AR.
SLIT is effective in AR in children ≥5 years of age.
SLIT may be safe in AR in children ≥3 years of age.
ARIA update (using GRADE system) 2010 Jun Adult:
∙ SLIT is recommended for adult with AR due to pollen (with weak recommendation
and moderate quality of evidence).
∙ SLIT is recommended for adult with AR due to house dust mites (weak recommen-
dation and low quality of evidence).
Children:
∙ SLIT is recommended in children with AR due to pollen (with weak recommendation
and moderate quality of evidence).
∙ In children sensitive to HDM, it suggested not to administer SLIT outside highly
prepared clinics (weak recommendation and low quality of evidence).
GA
2
LEN/EAACI pocket guide 2010 Jul SLIT is effective like SCIT.
SLIT is safer than SCIT with no systemic reaction.
SLIT in children is preferred to be ≥5 years old, and no upper limit age.
Allergen immunotherapy: a practice parameter
third update by AAAAI, JCAAI and ACAAI
2010 Dec SLIT is effective in reducing symptoms but require higher doses than that of SCIT.
Frequent local and gastrointestinal adverse effects were recorded.
Currently there is no FDA-approved formulation for a non-injection immunotherapy
extracts.
SLIT, sublingual immunotherapy; WHO, World Health Organization; SCIT, subcutaneous immunotherapy; ARIA, Allergic Rhinitis and its Impact on Asthma;
AR, allergic rhinitis; GRADE, Grading of Recommendation, Assessment, Development and Evaluation; GA
2
LEN, Global Allergy and Asthma European Net-
work; EAACI, European Academy of Allergology and Clinical Immunology; AAAAI, American Academy of Allergy, Asthma & Immunology; JCAAI, Joint
Council of Allergy, Asthma & Immunology; ACAAI, American College of Allergy, Asthma & Immunology; FDA, Food and Drug Administration.
Aboshady OA et al. Sublingal Immunotherapy in Allergic Rhinitis 247
made ARIA 2010 update more understood and accepted from
the health care provider [69]. SLIT in ARIA 2010 update was
recommended for adult with AR due to pollen (with weak rec-
ommendation and moderate quality of evidence) or house dust
mites (weak recommendation and low quality of evidence). This
recommendation is due to the high value in alleviating the symp-
toms and relatively low value on avoiding adverse effects and
costs. In children with AR due to pollen, SLIT is recommended
with weak recommendation and moderate quality of evidence.
But, in children sensitive to mites, it suggested not to administer
SLIT outside highly prepared clinics (weak recommendation and
low quality of evidence) [7] (Table 4).
Implementation of these guidelines and re-evaluation is very
important. Derivative of guidelines such as pocket guides, web-
based activities, questionnaires and web-based documents must
be disseminated internationally. The 2008 ARIA update was trans-
lated into more than 50 languages, and there was a plan to dis-
seminate 2010 update internationally [69]. Specialists and prima-
ry care physicians should be encouraged to use these guidelines
and its derivatives and should be involved in their production.
CONCLUSION
SLIT has been established as evidence-based treatment for AR.
SLIT was introduced in latest update of ARIA guidelines in 2010
with weak recommendation and moderate quality of evidence
for patient sensitive to pollen and low quality of evidence for
house dust mite according to the GRADE system. Beside its effi-
cacy in reducing the symptoms and medication scores recorded
in meta-analyses, the unique advantages of long-lasting and pre-
ventive actions are due to profound and persistent modifications
in the immune system. Also, the safety of SLIT was found to be
more favorable than SCIT. The most common recorded adverse
effects were minor local effects in the mouth, gastrointestinal re-
actions and rare anaphylaxis with no fatality. In children, many
of guidelines and recommendations suggested not to start SLIT
in children ≤5 years due to lack of safety evidence. Adherence
to treatment was found to be more better for SLIT with less
drop-out rates than SCIT mainly due to its safety, noninvasive-
ness and easy administration at home. We support the call to
conduct large multi-centric studies to gain more statistical power
and overcome the problem of heterogeneity observed in the me-
ta-analyses. Also, retrospective studies are needed to record
causes of drop-out rates in the real life.
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was re-
ported.
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