Sub-lingual Immunotherapy: World Allergy Organization Position Paper 2009

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Sub-lingual Immunotherapy: World Allergy Organization Position
Paper 2009
Chair: G Walter Canonica
CoChairs:
Jean Bousquet, Thomas Casale, Richard F Lockey, Carlos E Baena-Cagnani, Ruby Pawankar,
Paul C Potter
Authors:
Philippe J Bousquet, Linda S Cox, Stephen R Durham, Harold S Nelson, Giovanni Passalacqua, Dermot P
Ryan, Jan L Brozek, Enrico Compalati, Ronald Dahl, Luis Delgado, Roy Gerth van Wijk, Richard G Gower,
Dennis K Ledford, Nelson Rosario Filho, Erkka J Valovirta, Osman M Yusuf, Torsten Zuberbier
Co-Authors:
Wahiduzzaman Akhanda, Raul Castro Almarales, Ignacio Ansotegui, Floriano Bonifazi, Jan Ceuppens,
Toma
´s Chivato, Darina Dimova, Diana Dumitrascu, Luigi Fontana, Constance H Katelaris, Ranbir Kaulsay,
Piotr Kuna, De
`sire
´e Larenas-Linnemann, Manolis Manoussakis, Kristof Nekam, Carlos Nunes, Robyn
O’Hehir, Jose
´M Olaguibel, Nerin Bahceciler Onder, Jung Won Park, Alfred Priftanji, Robert Puy, Luis Sar-
miento, Glenis Scadding, Peter Schmid-Grendelmeier, Ester Seberova, Revaz Sepiashvili, Dirceu Sole
´, Alkis
Togias, Carlo Tomino, Elina Toskala, Hugo Van Beever, Stefan Vieths*
Acknowledgement
World Allergy Organization acknowledges Ronald L
Rabin for reviewing this Position Paper. Ken Rainey,
Medical Writer, and Karen Henley, WAO Global Project
Director, are acknowledged for their assistance in editing
and co-ordinating the manuscript.
This supplement is co-published as an article: Canonica
GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE
et al. Sublingual Immunotherapy: World Allergy Organi-
zation Position Paper 2009. World Allergy Organization
Journal, 2009; 2(11):233-281. www.WAOJournal.org
Societies/Organisations Attending the Paris Meeting
Regional Member Societies
Asia Pacific Association of Allergology and Clinical
Immunology.
Commonwealth of Independent States (CIS).
European Academy of Allergy and Clinical Immunology
(EAACI).
Latin American Society of Allergy and Immunology.
Affiliate Member Societies
Interasma (International Association of Asthmology).
National Member Societies
Albanian Society of Allergology and Clinical Immunology.
Allergy Society of South Africa.
American Academy of Allergy, Asthma and Immunology.
American College of Allergy, Asthma and Immunology.
Argentine Association of Allergy and Immunology.
Australasian Society of Clinical Immunology and Allergy.
Bangladesh Society of Allergy and Immunology.
Belgian Society of Allergology and Immunology.
Brazilian Society of Allergy and Immunopathology.
British Society for Allergy and Clinical Immunology.
Allergy 2009: 64 (Suppl. 91): 1–59 2009 The Authors
Journal compilation 2009 World Allergy Organization
ALLERGY
1
Correspondence: G. Walter Canonica, MD, Allergy and Respiratory
Diseases, DIMI, Department of Internal Medicine, University of
Genoa, Largo Rosanna Benzilo, Genoa 1-16132, Italy
Email: canonica@unige.it
Bulgarian National Society of Allergology.
China Allergology Society and Chinese Allergists.
Cuban Society of Allergology.
Czech Society of Allergology and Clinical Immunology.
Finnish Society of Allergology and Clinical Immunology.
French Society of Allergology and Clinical Immunology.
GermanSocietyforAllergologyand Clinical Immunology.*
Hellenic Society of Allergology and Clinical Immunology.
HungarianSociety ofAllergologyand ClinicalImmunology.
Italian Association of Territorial and Hospital Allergists.
Italian Society for Allergology and Clinical Immunology.
Japanese Society of Allergology.
Korean Academy of Allergy, Asthma and Clinical
Immunology.
Malaysian Society of Allergy and Immunology.
Mexican College of Clinical Immunology and Allergy
(CMICA).
Mexican College of Clinical Immunology and Allergy
(CMICA).
Mexican College of Pediatricians Specialized in Allergy
and Clinical Immunology.
Portuguese Society of Allergology and Clinical Immunol-
ogy.
RomanianSocietyof Allergology and ClinicalImmunology.
Singapore Society of Immunology, Allergy and Rheuma-
tology.
Spanish Society of Allergology and Clinical Immunology.
Swiss Society of Allergology and Immunology.
Singapore Society of Immunology, Allergy & Rheumatol-
ogy.
Turkish National Society of Allergy and Clinical
Immunology.
Venezuelan Society of Allergy and Immunology.
Contributing Non-Member Society
Southern European Allergy Society.
Non-Governmental Organizations
Allergic Rhinitis and Its Impact on Asthma (ARIA).
European Federation of Allergy and Airway Diseases
Patients Association (EFA).
International Primary Care Respiratory Group (IPCRG).
Global Allergy and Asthma European Network
(GA
2
LEN).
National Institutes of Health (NIH).
Ratification by WAO Member Societies not attending the
Paris meeting
Approved by:
Colombian Allergy, Asthma, and Immunology Associa-
tion.
Egyptian Society of Allergy and Clinical Immunology.
Egyptian Society of Pediatric Allergy and Immunology.
Icelandic Society of Allergy and Immunology’’.
Indian College of Allergy, Asthma and Applied Immunology.
Mexican College of Allergy, Asthma and Clinical Immu-
nology.
Mongolian Society of Allergology.
Norwegian Society of Allergology and Immuno-
pathology.
Peruvian Society of Allergy and Immunology.
Russian Association of Allergology and Clinical Immunology.
Allergy and Immunology Society of Thailand.
Abbreviations
AAAAI: American Academy of Allergy and Clinical Immunology
ACAAI: American College of Allergy and Clinical Immunology
ADR: Adverse Drug Reaction
AE: Adverse Event
AMP: Adenosine Monophosphate
ARIA: Allergic Rhinitis and its Impact on Asthma
AUC: Area Under Curve
BHR: Bronchial Hyperresponsiveness
CHMP: Committee for Human Medicinal Products
CIS: Commonwealth of Independent States
CMD: Cumulative Monthly Dose
CONSORT: Consolidated Standards of Reporting Trials
DBPCFC: Double-blind placebo-controlled food challenge
DBPC-RCT: Double-blind, placebo-controlled – randomized clinical
trial
EAACI: European Academy of Allergy and Clinical Immunology
EBM: Evidence-Based Medicine
ECP: Eosinophil Cationic Protein
EFA: European Federation of Allergy and Airway Diseases
Patients Association
EMEA: European Medicines Agency
EU: European Union
FDA: (US) Food and Drug Administration
FeNO: Fraction of exhaled Nitric Oxide
FEV
1
: Forced Expiratory Volume in One Second
FVC: Forced Vital Capacity
GA
2
LEN: Global Allergy and Asthma European Network
GP: General Practitioner
GRADE: Grading Recommendations, Assessment, Development
and Evidence
HCP: Health Care Professional
HDM: House Dust Mite
ICAM-1: Intercellular Adhesion Molecule-1
ICER: Incremental Cost-Effectiveness Ratio
IDO: Indoleamine 2,3-dioxygenase
Ig: Immunoglobulin
IL: Interleukin
Interasma: International Association of Asthmology
IPCRG: International Primary Care Respiratory Group
IT: Immunotherapy
LLR: Large Local Reactions
MedDRA: Medical Dictionary for Regulatory Activities
MHC: Major Histocompatibility Complex
mRNA: Messenger Ribonucleic Acid
NIH: National Institutes of Health
PAT: Preventive Allergy Treatment (study)
PEF: Peak Expiratory Flow
22009 World Allergy Organization
G. Walter Canonica
QoL: Quality of Life
RCT: Randomised Controlled Trial
RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire
SAE: Serious Adverse Event
SCIT: Subcutaneous Immunotherapy
SCORAD: Score in Atopic Dermatitis
SCUAD: Severe Chronic Upper Airway Disease
sECP: Serum Eosinophil Cationic Protein
SIT: (allergen-) Specific Immunotherapy
SLIT: Sublingual Immunotherapy
SMD: Standardized Mean Differences
SPT: Skin Prick Test
SR: Systemic Reaction
T regs: Regulatory T Cells
TGF: Transforming Growth Factor
Th: T Helper cells
VAS: Visual Analogue Scale
WAO: World Allergy Organization
WHO: World Health Organisation
Preface
Sublingual immunotherapy (SLIT) has gained wide accep-
tance in many European countries and has raised the level
of interest in immunotherapy among practicing allergists
and primary care physicians. Large pivotal double-blind,
placebo-controlled, randomized clinical trials have con-
firmed the efficacy and safety of SLIT, although some
negative trials have also been published. In 2008, the World
Allergy Organization (WAO) Board of Directors decided
that it was important and timely to advise our global
constituents on the current State of the Art on SLIT, to offer
consensus on its use based on currently available evidence
and expert opinion, and to develop practice parameters.
Unmet needs would be identified by analysis of recent and
ongoing SLIT clinical trials, then recommendations for
further studies needed, and suggestions for the appropriate
methodology to conduct them, would be offered.
To ensure a truly global consensus on SLIT, a meeting
was held on 22 - 23 January 2009 in Paris, France. WAO
invited its Regional, National and Affiliate Member
Societies to participate actively by sending representatives
to the meeting. Non-Governmental Organizations work-
ing in the field of allergy were also invited to attend, and
ARIA, EFA, IPCRG, Interasma, GA
2
LEN et al were
represented.
The meeting and its outcomes remain totally independent
from the interest/influence/funding of the pharmaceutical
or the allergen extract/vaccine industry.
Regulatory Perspective
Historical perspective:
Before the 1980s there was no allergen standardization;
this resulted in marked variations in allergenic strength
among allergen vaccine batches produced in different
phases.
Until 1991 allergen vaccines were considered ‘‘Galenic’’
drugs, because they were prepared upon request of the
physician for a specific patient. Specific immunotherapy
was administered through the injective route only, and the
available allergen preparations were used both in diagnosis
and therapy. Most firms produced batches of ready-to-
prepare extracts and the final phase of production consisted
of matching the name of a patient with a specific pre-
prepared vaccine. Leading up to 1991, the companies active
in the allergen manufacturing sector noticed that physi-
cians had changed their prescribing patterns, and were now
requesting single specific allergens for immunotherapy,
rather than the allergen mixtures that had previously been
supplied.
In the 1990s, when sub-lingual immunotherapy first
appeared on the market, the available vaccines for SLIT
were only single allergen preparations, as required by the
first guideline in this field. It immediately became evident
to the regulatory authorities that documents pertaining to
the production of allergens and their standardization
method were needed; it is important not only to prepare
extracts that are always equivalent between different
batches, but also to prepare an initial reference extract
(the standard extract) which is allergenically/biologically
active, to provide a comparison with subsequent produc-
tion batches.
Current situation
According to Guideline 2001/83/EC, allergens are immu-
nological medicinal products and therefore, in general,
require a marketing authorization. However, in several
countries national regulations are implemented that still
allow marketing of allergen products as ‘‘named patient
preparations’’ (NPPs) without a marketing authorization.
For example, in Germany it has been estimated that
approximately 50% of the market for allergen products
are NPPs. This market segment includes the majority of
allergen products for SLIT.
From the regulatory point of view, there is no difference
between allergen products for SLIT and SCIT. By contrast
a clear difference exists between the requirements on natural
allergen extracts versus recombinant allergens, in particular
regarding acceptance criteria for product quality (1–3). In
Germany, four products for SLIT were authorized up to
mid-2009, while more than 200 allergen products for SCIT
had a marketing authorization. Of the SLIT products, one
grass pollen allergen tablet successfully passed a mutual
recognition procedure and is available in the majority of EU
countries.
Recent Phase III clinical trials performed with two grass
pollen tablets involved hundreds of patients in each trial
and were performed according to an adequate DBPC-
RCT design. These studies and others showed that
2009 World Allergy Organization 3
Sub-lingual immunotherapy
particularly for SLIT, parameters such as determination
of an adequate pre-treatment period in seasonal rhino-
conjunctivitis trials, and exploratory studies for determi-
nation of the dose resulting in the most favorable
risk:benefit ratio, are of major importance. A recent
WAO statement (4) and the EMEA Guideline (5) define
for the first time the regulatory requirements for clinical
trials in SIT, and will lead to improved harmonization of
assessments by regulatory agencies of data obtained from
clinical trials.
Increased availability of authorized allergen products
with proven quality, safety and efficacy will lead to an
improved benefit for allergic patients and may also
improve the general acceptance of SIT as an established
treatment by regulatory agencies.
Sub-lingual vaccines appear to have heralded a new
era in specific allergen desensitization; because of their
efficacy and safety, they have been considered eligible
for submission for registration by many regulatory
authorities. New products registered for respiratory
allergopathologies approach this pathology in an etio-
logic way; they may act as real biological modifiers, and
have long-lasting effects. This benefit is interesting not
only clinically, but also in terms of their pharmaco-
economic profile.
Why sub-lingual immunotherapy vaccines should be
licensed
For the physician
The prescription of non-authorized products weak-
ens the role of the allergy specialist, and may have
contributed to the current paucity of allergy spe-
cialists available to treat the estimated figure of 20%
of the world population that suffers from allergies.
The prescription of products not sold in pharmacies
creates difficulties for the global management of
vaccines (from the point of ordering, up to receipt
and storage).
For the patient
The use of products, which are not distributed
in pharmacies weakens, the credibility of the product
itself; it precludes any patient interaction with the
pharmacist (a traditional counselor of patients) and
weakens the image of the product, which has to be
used for years.
An authorized pharmaceutical product offers the
patient more guarantees, consequently increasing
compliance with treatment (at present only 30% of
vaccinated patients complete at least 3 years of
treatment in accordance with the recommended
guidelines for duration of therapy).
For the industry
A non-regulated sector makes possible the use of
‘‘low quality’’ products, and fails to give adequate
recognition to the ethical manufacturers who con-
duct scientific research and employ good manufac-
turing practices. A more regulated sector attracts the
increasing interest of ethical and qualified investors.
For the regulatory agencies
Marketing of non-regulated products precludes
correct pharmacovigilance and, in consequence,
precludes all the activities connected with an open
and transparent dialogue among the stakeholders,
eg, pre- and post-registration clinical trials, profes-
sional training, and congress activities.
References, Preface
1. Lorenz AR, Lu
¨ttkopf D, Seitz R, Vieths S. The regulatory system
in Europe with special emphasis on allergen products. Int Arch
Allergy Immunol. 2008;147:263–275.
2. Guideline on Allergen Products: Production and Quality Issues.
EMEA, CHMP/BWP/304831/2007 adopted by CHMP Novem-
ber 20, 2008.
3. European Pharmacopoeia 6.6, Allergen Products, 01/2010/1063.
4. Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ,
Lockey RF, Malling HJ, et al. Recommendations for standard-
ization of clinical trials with Allergen Specific Immunotherapy for
respiratory allergy. A statement of a World Allergy Organization
(WAO) taskforce. Allergy 2007;62:317–324.
5. Guideline on the Clinical Development of Products for Specific
Immunotherapy for the Treatment of Allergic Diseases. EMEA,
CHMP/EWP/18504/2006, adopted by CHMP November 20,
2008.
Chapter 1: Introduction and
historical background to
sublingual immunotherapy
Subcutaneous immunotherapy (SCIT) currently
represents the standard immunotherapy modality,
with well ascertained clinical efficacy.
The first SLIT randomized double-blind, placebo-
controlled trial (DBPC-RCT) was published in
1986. The rationale proposed for SLIT was to
improve the safety and to make the treatment more
convenient.
The first DBPC-RCT trial with tablets was published
in 1986.
SLIT was firstly accepted as a viable alternative to
SCIT in the WHO position paper, published in 1998,
and then included in the ARIA guidelines.
42009 World Allergy Organization
G. Walter Canonica
Since 1986, 60 DBPC-RCT trials have been pub-
lished.
The available meta-analyses are in favour of SLIT
(rhinitis in adults, asthma and rhinitis in children),
although the conclusions are limited by the great
heterogeneity of the studies.
Adequately powered, well-designed DBPC-RCTs
involving hundreds of patients, published in the last
3 years have clearly confirmed the efficacy and the
dose dependent effect of SLIT for grass allergens in
both adults and children.
Allergen-specific immunotherapy (SIT), or allergen vac-
cination is the practice of administering to allergic
subjects increasing amounts of allergen(s) (the allergenic
extract or vaccine) to achieve hyposensitization, that is
to reduce the symptoms occurring during the natural
exposure to the allergen(s) itself. The history of SIT
began in first years of the twentieth century, based on
the idea of the vaccination against infectious agents. In
fact, Leonard Noon (1) aimed at achieving a vaccina-
tion against Ôairborne toxinsÕ, and for this reason he
chose the subcutaneous route of administration.
Although the theoretical background was incorrect,
SIT was immediately found to be effective in reducing
symptoms of hay-fever, its use spread rapidly, and the
subcutaneous route (SCIT) remained therefore the
standard practice.
Indeed, the idea of administering the allergenic extracts
via non injection routes is not as recent as commonly
believed. The first descriptions of the ÔoralÕroute of
administration also appeared in the early 1900s (2) and
the first clinical attempts with this administration were
carried out only few years later (3, 4). Subsequently,
other routes of administration were proposed, that is,
local bronchial during the 1950s (5, 6) and local nasal (7,
8) during the 1970s. The overall rationale of these
attempts was of course that of finding a safer and more
convenient route of administration for SIT. Those routes
have been variously named, that is, alternative, non-
parenteral, non-injection or local routes. Presently, it is
agreed that the most proper terms are local and non-
injection, which are equivalent; whereas the word alter-
native has been abandoned since it might generate
confusion with other unconventional medicines. The oral
route was investigated in several clinical trials performed
during the 1980s (9–12), but the clinical results were
controversial and, in some cases, important gastrointesti-
nal adverse events were reported. For these reasons, oral
administration was gradually abandoned. In 1986, the
British Committee for the Safety of Medicines (13)
reported several deaths caused by SCIT, and raised
serious concerns about the safety and the risk/benefit
ratio of SIT, also because cheaper and effective drugs
(e.g. oral H1-antihistamines and topical corticosteroids)
had become available for the treatment of respiratory
allergy. In this scenario, the interest in non-injection
routes of IT increased again (14), and in 1986 the first
randomized controlled trial with the sublingual route
(SLIT) was published (15). This study was conducted
with very low doses of a mite extract. The original idea
supporting SLIT was to achieve a prompt absorption of
the vaccine through the sublingual mucosa as happens,
for instance with nitroglycerine or nifedipine. Indeed, ten
years later, biodistribution studies with radiolabelled
allergens in humans (16, 17), consistently showed that
the direct absorption of the extract through the oral
mucosa is absent or negligible, and that the clinical effect
should be rather ascribed to the interaction of the
allergen with the mucosal immune system. Nonetheless,
from a clinical point of view, SLIT was confirmed to be
effective in several controlled studies utilizing either drops
or tablets (18, 19), and the first paediatric study appeared
in 1990 (18).
In the subsequent years, the number of DBPC-RCTs
of SLIT rapidly increased, and SLIT began to be
mentioned in official documents. In 1993 the European
Academy of Allergy and Clinical Immunology (EAACI)
stated in its position paper that SLIT could be regarded
as a Ôpromising routeÕfor desensitization (14). Five years
later, the World Health Organization (WHO), based on
the results of 8 DBPC-RCTs, stated that SLIT Ômay be
considered as a viable alternative to the injection route
in adultsÕ(20). In the same year, EAACI produced a
position paper on non-injection routes, stating that
the use of SLIT in clinical practice is justified because of
the ascertained efficacy and the favourable safety profile
(21). In 2001, the ARIA position paper accepted the use
of SLIT in adults and children, as a valid alternative to
SCIT (22) and this was confirmed by the ARIA update
in 2008 (23). In SLIT, the allergen extract (prepared
as drops or tablets) is kept under the tongue for
1–2 minutes and then swallowed: thus this route is also
called sublingual-swallow. In some studies a different
method was adopted: the allergen was kept under
the tongue and then spat out (sublingual-spit) (24).
Presently, only the sublingual-swallow route is used,
therefore the acronym SLIT refers to the sublingual-
swallow modality.
Nowadays, more than 50 DBPC-RCTs are available
in the literature (25). Their results were also pooled and
evaluated in several meta-analyses, which concluded that
SLIT is significantly efficacious compared to placebo for
rhinitis and asthma in adults and children (26–29). In
the last 2 years, some adequately powered, well-designed
DBPC-RCTs with grass drops (30) or tablets (31–33)
including hundreds of patients, were published. These
studies have confirmed the efficacy of SLIT for these
allergens and, more importantly, have demonstrated a
dose-effect relationship. In parallel to the clinical trials,
post-marketing surveys (34), mechanistic investigations
(35, 36), prevention studies (37, 38) and pharmaco-
2009 World Allergy Organization 5
Sub-lingual immunotherapy
economic assessments (39) were also published in the
last 10 years, so that several aspects of SLIT were
gradually clarified. Concerning safety, all clinical trials
and post-marketing surveys have consistently agreed
that SLIT is safe, and the majority of side effects are
local and mild. In more than 20 years of clinical trials
and everyday use, only six cases of anaphylaxis with
SLIT have been reported, some of which were with
mixtures of multiple unrelated allergens using non-
standardized extracts, but two patients had a severe
reaction following the first dose of a grass tablet. It has
also been reported that use of multiple allergens for
SLIT does not increase the rate of side effects in
children (40). Furthermore, it has been suggested (41)
that the safety profile of SLIT does not differ in
children below the age of five years (a relative contra-
indication to SCIT).
SLIT is currently commercialized and used in most
European and South American countries, as well as in
Australia and Asian countries, but not in the USA. After
an initial scepticism, due to the paucity of data, the USA
scientific community also acknowledged the efficacy and
safety of SLIT (42). Nevertheless, because there is so far
no FDA-approved product for SLIT, this modality is not
currently recommended in clinical practice in the USA,
where the Practice Parameter states that Ôthere is no
US Food and Drug Administration (FDA)-approved
formulation for sublingual or oral immunotherapy in the
United States. Therefore sublingual and oral immuno-
therapy should be considered investigational at this time.Õ
(43) Clinical trials for FDA registration in the USA are
currently ongoing.
There are several aspects of SLIT still needing inves-
tigation and confirmation, including the optimal dose,
the long-lasting effect, the preventive action and the
exact mechanisms of action. This relative lack of
information is not surprising if we consider that the
history of SLIT is only 20 years in duration, and that
the majority of studies were aimed at demonstrating the
efficacy and safety of the treatment. Moreover, despite
the number of clinical trials available, the value of SLIT
in paediatric patients was a matter of debate (44), until
the new positive adequately powered, well-designed
DBPC-RCTs in children were reported (45, 46). The
most important concern that still remains is to determine
the optimal dose of allergen for SLIT, since the
treatment has been shown effective over a very large
range of doses (from 5 to 300 times the dose used for
SCIT). However, it is clear that the effective doses of
allergens for SLIT must be higher than for SCIT (in fact,
we commonly speak of high-dose SLIT). On the other
hand, the recently published large trials have indicated
the correct direction for research; that is, dose-finding
studies, standardization and uniformization of adminis-
tration schedules, and the use of no-updosing regimens,
which are more simple and patient-friendly. In the
meantime, new opportunities are being explored with
SLIT, including the possibility of using it in conditions
other than respiratory allergy, namely food allergy (47)
or Hymenoptera venom allergy (48) and the use of
adjuvants and mucoadhesive substances. Other issues
concern the indication of SLIT since there is no study
assessing its efficacy in patients uncontrolled despite
optimal pharmacotherapy (Slide 1).
Slide 1: History of sublingual immunotherapy.
62009 World Allergy Organization
G. Walter Canonica
References, Chapter 1
1. Noon L. Prophylactic inoculation against hay fever. Lancet
1911;i:1572–1573.
2. Curtis HH. The immunizing cure of hayfever. Med News (NY)
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3. Black JH. The oral administration of pollen. J Lab Clin Med
1927;12:1156.
4. Black JH. The oral administration of pollen: clinical report. J
Lab Clin Med 1928;13:709.
5. Herxeimer H. Bronchial hypersensitization and hyposensitiza-
tion in man. Int Arch Allergy Appl Immunol 1951;40:40–57.
6. Herxeimer H, Prior EN. Further observations in induced asth-
ma and bronchial hyposensitization. Int Arch Allergy Appl
Immunol 1952;3:159–161.
7. Metha SB, Smith JM. Nasal hyposensitization and hayfever.
Clin Allergy 1975;5:279–284.
8. Taylor G, Shivalkar PR. Local nasal desensitization in allergic
rhinitis. Clin Allergy 1972;2:125–126.
9. Rebien W, Wahn U, Puttonen E, Maasch HG. Comparative
study of immunological and clinical efficacy of oral and subcu-
taneous hyposensitization. Allergologie 1980;3:101–109.
10. Taudorf E, Weeke B. Orally administered grass pollen. Allergy
1983;38:561–564.
11. Urbanek R, Gehl R. Wirksaimkeit oral hiposensibilisierung bei
hausstabmilbenallergie. Monatssch Kinderheilkd 1982;130:150–
152.
12. Taudorf E, Laursen L, Lanner A, Bjorksten B, Dreborg S,
Weeke B. Specific IgG IgE and IgA antibody response to oral
immunotherapy in birch pollenosis. J Allergy Clin Immunol
1989;83:589–594.
13. Committee on the safety of medicines. CSM update. Desensi-
tizing vaccines. Br Med J 1986;293:948.
14. Malling H, Weeke B eds. Immunotherapy. Position Paper of the
European Academy of Allergy and Clinical Immunology. Al-
lergy 1993;48(Suppl 14):9–35.
15. Scadding GK, Brostoff J. Low dose sublingual therapy in pa-
tients with allergic rhinitis due to dust mite. Clin Allergy
1986;16:483–491.
16. Bagnasco M, Mariani G, Passalacqua G, Motta C, Bartolomei M,
Falagiani P, Mistrello G et al. Absorption and distribution
kinetics of the mayor Parietaria allergen administered by nonin-
jectable routes to healthy human beings. J Allergy Clin Immunol
1997;100:121–129.
17. Bagnasco M, Passalacqua G, Villa G. Pharmacokinetics of an
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therapy in allergic volunteers. Clin Exp Allergy 2001;31:54–60.
18. Tari MG, Mancino M, Monti G. Efficacy of sublingual immu-
notherapy in patients with rhinitis and asthma due to house dust
mite. A double-blind study. Allergol Immunopathol
1990;18:277–284.
19. Sabbah A, Hassoun S, Le Sellin J, Andre C, Sicard H. A double-
blind placebo-controlled trial by the sublingual route of immu-
notherapy with a standardized grass pollen extract. Allergy
1994;49:309–313.
20. Bousquet J, Lockey R, Malling HJ eds. World Health Organi-
zation Position Paper. Allergen immunotherapy: therapeutical
vaccines for allergic diseases. Allergy 1998;53:1–42.
21. Malling HJ, Abreu-Nogueira J, Alvarez-Cuesta E, Bjorksten B,
Bousquet J, Caillot D et al. EAACI Position Paper on local
immunotherapy. Allergy 1998;53:933–944.
22. Bousquet J, Van Cauwenberge P eds. Allergic Rhinitis and its
Impact on Asthma. J Allergy Clin Immunol 2001;108(Suppl
5):S147–S334.
23. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ,
Togias A et al. Allergic Rhinitis and its Impact on Asthma
(ARIA) 2008 update (in collaboration with the World Health
Organization, GA(2)LEN and AllerGen). Allergy 2008;86:8–
160.
24. Nelson H, Oppenheimer J, Vatsia G, Buchmeier A. A double-
blind, placebo-controlled evaluation of sublingual immuno-
therapy with standardized cat extract. J Allergy Clin Immunol
1993;92:229–236.
25. Passalacqua G, Durham SR. Allergic rhinitis and its impact on
asthma update: allergen immunotherapy. J Allergy Clin
Immunol 2007;119:881–891.
26. Wilson DR, Torres L, Durham SR. Sublingual immunotherapy
for allergic rhinitis. Allergy 2005;60:3–8.
27. Penagos M, Compalati E, Tarantini F et al. Efficacy of sublin-
gual immunotherapy in the treatment of allergic rhinitis in
children. Meta analysis of randomized controlled trials. Ann
Allergy Asthma Immunol 2006;97:141–148.
28. Calamita Z, Saconato H, Bronhara Pela
`A et al. Efficacy
of Sublingual immunotherapy in asthma. Systematic review
of randomized clinical trials. Allergy 2006;61:1162–
1172.
29. Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE,
Orozco S, Pedroza A et al. Metaanalysis of the efficacy of
sublingual immunotherapy in the treatment of allergic asthma
in pediatric patients, 3 to 18 years of age. Chest 2008;133:599–
609.
30. Pfaar O, Klimek L. Efficacy and safety of specific immuno-
therapy with a high-dose sublingual grass pollen preparation: a
double-blind, placebo-controlled trial. Ann Allergy Asthma
Immunol 2008;100:256–63.
31. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S.
Sublingual immunotherapy with once-daily grass-allergen
tablets: a randomised controlled trial in seasonal allergic
rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:
802–809.
32. Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S,
Emminger W et al. Efficacy and safety of sublingual
immunotherapy with grass allergen tablets for seasonal
allergic rhinoconjunctivitis. J Allergy Clin Immunol
2006;118:434–440.
33. Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut
A et al. Optimal dose, efficacy, and safety of once-daily
sublingual immunotherapy with a 5-grass pollen tablet for
seasonal allergic rhinitis. J Allergy Clin Immunol
2007;120:1338–1345.
34. Passalacqua G, Guerra L, Fumagalli F, Canonica GW. Safety
profile of sublingual immunotherapy. Treat Respir Med
2006;5:225–234.
35. Cosmi L, Santarlasci V, Angeli R, Liotta F, Maggi L, Frosali
F et al. Sublingual immunotherapy with Dermatophagoides
monomeric allergoid down-regulates allergen-specific
immunoglobulin E and increases both interferon-gamma-
and interleukin-10-production. Clin Exp Allergy 2006;36:261–
272.
36. Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, Jahn-
Schmid B, Ebner C. Sublingual immunotherapy induces IL-10-
producing T regulatory cells, allergen-specific T-cell tolerance,
and immune deviation. J Allergy Clin Immunol 2007;120:707–
713.
37. Novembre E, Galli E, Landi F et al. Coseasonal sublingual
immunotherapy reduces the development of asthma in children
with allergic rhinoconjunctivitis. J Allergy Clin Immunol
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2009 World Allergy Organization 7
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38. Marogna M, Tomassetti D, Bernasconi A, Colombo F, Massolo
A, Businco AD et al. Preventive effects of sublingual immuno-
therapy in childhood: an open randomized controlled study.
Ann Allergy Asthma Immunol 2008;101:206–210.
39. Berto P, Frati F, Incorvaia C. Economic studies of immuno-
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590.
40. Agostinis F, Foglia C, Landi M, Cottini M, Lombardi C,
Canonica GW et al. The safety of sublingual immunotherapy
with one or multiple pollen allergens in children. Allergy
2008;63:1637–1639.
41. Di Rienzo V, Minelli M, Musarra A, Sambugaro R, Pecora S,
Canonica WG et al. Post-marketing survey on the safety of sub-
lingual immunotherapy in children below the age of 5 years. Clin
Exp Allergy 2005;35:560–564.
42. Cox L, Linneman D, Nolte H, Weldon D, Finegold I, Nelson
HS. Sublingual immunotherapy: a comprehensive review.
J Allergy Clin Immunol 2006;117:1021–1035.
43. Allergen immunotherapy: a practice parameter second update.
J Allergy Clin Immunol 2007;120(Suppl 3):S25–S85.
44. Ro
¨der E, Berger MY, de Groot H, van Wijk RG. Immunotherapy
in children and adolescents with allergic rhinoconjunctivitis: a
systematic review. Pediatr Allergy Immunol 2008;19:197–207.
45. Wahn U, Tabar A, Kuna P, Halken S, Montagut A, de Beau-
mont O et al. Efficacy and safety of 5-grass-pollen sublingual
immunotherapy tablets in pediatric allergic rhinoconjunctivitis.
J Allergy Clin Immunol 2009;123:160–166.
46. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M,
Klimek L et al. Safety and efficacy in children of an SQ-stan-
dardized grass allergen tablet for sublingual immunotherapy.
J Allergy Clin Immunol 2009;123:167–173.
47. Enrique E, Pineda F, Malek T, Bartra J, Basagan
˜a M, Tella R
et al. Sublingual immunotherapy for hazelnut food allergy: a
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standardized hazelnut extract. J Allergy Clin Immunol
2005;116:1073–1079.
48. Severino MG, Cortellini G, Bonadonna P, Francescato E,
Panzini I, Macchia D et al. Sublingual immunotherapy for large
local reactions caused by honeybee sting: a double-blind,
placebo-controlled trial. J Allergy Clin Immunol
2008;122:44–48.
Chapter 2: Allergen specific
immunotherapy
An update on subcutaneous immunotherapy, other
routes of immunotherapy administration, different
allergens and impact of immunotherapy on the natural
history of disease.
Many double-blind, placebo-controlled studies con-
firm the efficacy of subcutaneous immunotherapy for
treatment of allergic rhinitis, allergic asthma, and
Hymenoptera venom hypersensitivity.
Studies are lacking that support immunotherapy
with fungal extracts, other than for Alternaria and
Cladosporium, and with cockroach extracts.
Although limited in number, some controlled studies
have demonstrated efficacy of subcutaneous
immunotherapy with multiple allergen mixes. How-
ever, there have also been negative studies.
There appear to be two distinct and perhaps
sequential immunological responses to immuno-
therapy, generation of regulatory T-cells (T regs)
secreting (IL)-10 and (TGF)-band immune devia-
tion from T
H
2toT
H
1 responses.
Subcutaneous immunotherapy has reduced the
development of new sensitizations in monosensitized
patients and, in a few studies, has reduced the
development of asthma in children who only have
allergic rhinitis
The beneficial effects of subcutaneous immunother-
apy persist for years after discontinuation
The use of subcutaneous immunotherapy is limited
by the occurrence of local and systemic reactions
(SRs) and the prolonged period required for build-
up to maintenance dosing
Historical development
Subcutaneous administration of increasing doses of a
grass-pollen extract to treat allergic rhinitis was intro-
duced by Leonard Noon in 1911 (1), with completion of
his studies by John Freeman (2). Timothy grass was
administered preseasonally or seasonally. This treatment
was subsequently extended to other seasonal and peren-
nial allergens and to the treatment of allergic asthma as
well as rhinitis (3). Perennial administration largely
replaced preseasonal treatment. While immunotherapy
was initially used based on the clinical impression of
efficacy, in the 1960s, definitive double-blind studies using
ragweed pollen extract established that this was an
effective form of treatment (4, 5).
Clinical efficacy
Many double-blind, placebo-controlled studies confirm the
efficacy of subcutaneous injection allergen specific immu-
notherapy (SCIT) for treatment of both allergic rhinitis (6)
and allergic asthma (7). These studies showed efficacy with
extracts of various pollens, animal danders, house dust
mites and fungi. For most classes of allergens, results
support efficacy. However, although a few small size studies
report positive results treating patients with Cladosporium
(8) and Alternaria (9), studies supporting immunotherapy
with many of the other available fungal allergen extracts are
lacking (10).
Most controlled studies included in SCIT meta-analyses
that show clinical efficacy of SCIT for allergic rhinitis and
asthma include only a single allergen extract. Although
82009 World Allergy Organization
G. Walter Canonica
there are controlled studies that demonstrate efficacy for
multiple allergens mixes for treatment of both allergic
rhinitis (4) and allergic asthma (11), the studies are over
40 years old and there are no recent studies.
Mechanisms of action
Along with evidence of the efficacy has come an under-
standing of the probable mechanisms by which SCIT
alters the disease processes. The earliest objective evidence
of an immune response was the observation by Noon that
immunotherapy reduced conjunctival sensitivity to timo-
thy grass extract (1). Subsequent observations confirm a
reduction of sensitivity to the injected allergen in the skin,
or topical allergen on the conjunctivae, nasal mucosa and
lungs (12, 13). Humoral responses were also observed,
with first an increase and later a decline in specific IgE (14)
and the generation of a blocking IgG antibody (15).
However, studies failed to correlate these responses with
clinical improvement (16).
Research today is focused on changes in T-lymphocyte
responses and two distinct patterns of change, which may
occur sequentially. An event that occurs within 7 days at
high allergen doses (17) and 2–4 weeks at low allergen
doses (18, 19) is the generation of regulatory T-cells
secreting IL-10 and TGF-b(19) accompanied by suppres-
sion of allergen-induced late cutaneous responses (17, 18).
This is followed at 6–12 weeks after initiating therapy by
corresponding elevations in allergen-specific IgG4 and
IgA at that parallel a more delayed suppression of
allergen-induced early cutaneous responses (18, 19). A
second and probably later immunologic response is
immune deviation with a shift in the allergen specific T-
cell response from predominantly T
H
2toT
H
1 (20).
Impact on natural history
Considering the profound effect on the immune response
to the administered allergen, it is not surprising that SCIT
alters the natural course of allergic diseases. Several
studies have demonstrated that SCIT, when administered
to monosensitized patients, reduces the likelihood of
developing new sensitivities (21–23). Moreover, the reduc-
tion in new sensitivities persists for at least 3 years
following discontinuation of treatment (22, 23). A similar
inhibitory effect occurs for the progression to asthma in
children suffering from only allergic rhinitis (24). Timothy
or birch pollen SCIT reduced the development of new
onset asthma during the course of three years of treatment
(25) and reduced the incidence of asthma with little loss of
effect over 7 years of post-treatment observation. The
beneficial effects of SCIT on allergy symptoms persist for
years following its discontinuation. In a prospective,
placebo-controlled trial, subjects who discontinued timo-
thy grass SCIT after 3–4 years of treatment had the same
level of symptoms during the next three grass pollen
seasons as did the group who continued on monthly
maintenance injections (26).
Alternative approaches to immunotherapy
Despite its clinical and disease-modifying efficacy, SCIT
has some disadvantages: it is not Ôpatient friendlyÕbecause
of the regular injections, which may arouse fear amongst
children and some adults, and it has some indirect costs
e.g. travel to the doctorÕs office and lost work/school
hours. The use of SCIT is also limited by the prolonged
time for build-up required to reach maintenance levels of
treatment and by adverse reactions. Attempts to improve
the former have lead to trials with accelerated treatment
schedules, while the latter has been addressed by modi-
fying the allergen extracts or administering them by routes
other than injection. Alternatives to the weekly build-up
include administering clusters of 2 or 3 injections, usually
30 min apart, during a single clinic visit with visits spread
over several weeks (27). This cluster schedule is not
associated with an increased incidence of adverse reac-
tions (28). However, a more rapid build-up, in which
maintenance is achieved in just one or a few days, is
associated with an increased incidence of reactions even
when treatment subjects are premedicated (29). Extract
modification includes adsorption of the extract to alu-
minium to achieve a depot effect (30) and modifying the
extracts with formaldehyde (31) or glutaraldehyde (32) to
reduce reactivity with specific IgE. Recombinant technol-
ogy is currently being used to produce altered proteins
(33) or peptides (34, 35) that retain T-cell epitopes but are
no longer recognized by the specific IgE. Another
approach is to combine the allergen with products, most
extensively with monophosphoryl lipid A (36) or CpG
motifs (37), that stimulate the innate immune system
thereby favouring a T
H
1 response.
Another approach is to administer the extracts by an
alternative route, for example, orally (38) or sublingually
(39) slowing absorption and presenting the extract to a
different component of the immune system. Other alter-
native approaches are to administer the extract directly on
to the respiratory mucosa, either into the upper or lower
respiratory tracts (40, 41). This approach can induce
allergic respiratory symptoms, therefore, either modified
extracts with decreased allergenicity are utilized (42) or
cromolyn sodium is applied to the mucosa before the
allergen is administered to block the allergic reaction (43).
References, Chapter 2
1. Noon L. Prophylactic inoculation against hay fever. Lancet
1911;i:1572–1573.
2009 World Allergy Organization 9
Sub-lingual immunotherapy
2. Freeman J. Further observations on the treatment of hay fever
by hypodermic inoculations of pollen vaccine. Lancet
1911;ii:814–817.
3. Cohen SG, Evans R III. Allergen immunotherapy in historical
perspective. In: Lockey RF, Ledford DK, eds. Allergens and
allergen immunotherapy, 4th edn. New York: Informa Health-
care, 2008:1–29.
4. Lowell FC, Franklin W. A double-blind study of the effective-
ness and specificity of injection therapy in ragweed hay fever. N
Engl J Med 1965;273:675–679.
5. Norman PS, Winkenwerder WL, Lichtenstein LM. Immuno-
therapy of hay fever with antigen E: comparisons with whole
pollen extract and placebo. J Allergy 1968;42:93–108.
6. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A,
Durham S et al. Allergen injection immunotherapy for sea-
sonal allergic rhinitis. Cochrane Database Syst Rev
2007;1:CD001936.
7. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy
for asthma. Cochrane Database Syst Rev 2003;4:CD001186.
8. Malling H-J, Dreborg S, Weeke B. Diagnosis and immuno-
therapy of mould allergy. V. Clinical efficacy and side effects of
immunotherapy with Cladosporium herbarum. Allergy
1986;41:507–519.
9. Horst M, Hejjaoui A, Horst V et al. Double-blind, placebo-
controlled rush immunotherapy with a standardized Alternaria
extract. J Allergy Clin Immunol 1990;85:460–472.
10. Salvaggio JE, Burge HA, Chapman JA. Emerging concepts in
mold allergy: what is the role of immunotherapy. J Allergy Clin
Immunol 1993;92:217–222.
11. Johnstone DE, Crump L. Value of hyposensitization therapy for
perennial bronchial asthma in children. Pediatrics 1961;27:39–
44.
12. Bousquet J, Maasch H, Martinot B et al. Double-blind, pla-
cebo-controlled immunotherapy with mixed grass pollen al-
lergoids. II. Comparison between parameters assessing the
efficacy of immunotherapy. J Allergy Clin Immunol
1988;82:439–446.
13. Hedlin G, Graf-Lonnevig L, Heilbron H et al. Immunotherapy
with cat and dog dander extracts: V. Effects of three years of
treatment. J Allergy Clin Immunol 1991;87:955–964.
14. Sherman WB, Stull A, Cooke RA. Serologic changes in hay
fever cases treated over a period of years. J Allergy 1940;11:225–
244.
15. Cooke RA, Barnard JH, Hebald S, Stull A. Serological evidence
of immunity with coexisting sensitization in a type of human
allergy (hay fever). J Exp Med 1935;62:733–750.
16. Alexander HL, Johnson MC, Bukantz SC. Studies on correla-
tion between symptoms of ragweed hay fever and titer of ther-
mostable antibody. J Allergy 1948;19:1–8.
17. Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis
M. In vivo switch to IL-10-secreting T regulatory cells in high
dose allergen exposure. J Exp Med 2008;205:2887–2898.
18. Francis JN, James LK, Paraskevopoulos G, Wong C, Calderon
MA, Durham SR et al. Grass pollen immunotherapy: IL-10
induction and suppression of late responses precedes IgG4
inhibitory antibody activity. J Allergy Clin Immunol
2008;121:1120–1125.
19. Jutel M, Akdis M, Budak F et al. IL-10 and TGF-bcooperate in
the regulatory T cell response to mucosal allergens in normal
immunity and specific immunotherapy. Eur J Immunol
2003;33:1205–1214.
20. Hamid QA, Schotman E, Jacobson MR et al. Increases in IL-12
messenger RNA+ cells accompany inhibition of allergen-in-
duced late skin responses after successful grass pollen immu-
notherapy. J Allergy Clin Immunol 1997;99:254–260.
21. Des Roches A, Paradis L, Menardo J-L et al. Immunotherapy
with a standardized Dermatophagoides pteronyssinus extract.
VI. Specific immunotherapy prevents the onset of new
sensitizations in children. J Allergy Clin Immunol 1997;99:
450–453.
22. Pajno GB, Barberio G, De Luca F et al. Prevention of new sen-
sitizations in asthmatic children monosensitized to house dust
mite by specific immunotherapy. A Six-year follow-up study. Clin
Exp Allergy 2001;31:1392–1397.
23. Purello-DÕAmbrosio F, Gangemi S, Merendino RA et al. Pre-
vention of new sensitizations in monosensitized subjects submit-
ted to specific immunotherapy or not. A retrospective study. Clin
Exp Allergy 2001;31:1295–1302.
24. Jacobsen L, Niggemann B, Dreborg S et al. Specific immuno-
therapy has long-term preventive effect on seasonal and peren-
nial asthma: 10-year follow-up on the PAT study. Allergy
2007;62:943–948.
25. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, Jacobsen
L et al. Pollen immunotherapy reduces the development of
asthma in children with seasonal rhinoconjunctivitis (the PAT-
study). J Allergy Clin Immunol 2002;109:251–256.
26. Durham SR, Walker SM, Varga E-M et al. Long-term clinical
efficacy of grass-pollen immunotherapy. N Engl J Med
1999;341:468–475.
27. Nanda A, OÕConnor M, Anand M et al. Dose dependence and
time course of the immunologic response to administration of
standardized cat allergen extract. J Allergy Clin Immunol
2004;114:1339–1344.
28. Tabar AI, Echechipia S, Garcia BE et al. Double-blind com-
parative study of cluster and conventional immunotherapy
schedules and Dermatophagoides pteronyssinus. J Allergy Clin
Immunol 2005;116:109–118.
29. Portnoy J, Bagstad K, Kanarek H et al. Premedication reduces
the incidence of systemic reactions during inhalant rush immu-
notherapy with mixtures of allergenic extracts. Ann Allergy
1994;73:409–418.
30. Corrigan CJ, Kettner J, Doemer C, Cromwell O. Efficacy and
safety of preseasonally-specific immunotherapy with an alumi-
num-adsorbed six-grass pollen allergoid. Allergy 2005;60:801–
807.
31. Norman PS, Lichtenstein LM, Marsh DG. Studies on allergoids
from naturally occurring allergens. IV. Efficacy and safety of
long-term allergoid treatment of ragweed hay fever. J Allergy
Clin Immunol 1981;68:460–470.
32. Casanovas M, Martin R, Jimenez C et al. Safety of immuno-
therapy with therapeutic vaccines containing depigmented and
polymerized allergen extracts. Clin Exp Allergy 2007;37:434–
440.
33. Niederberger V, Horak F, Vrtala S et al. Vaccination with
genetically engineered allergens prevents progression of allergic
disease. Proc Natl Acad Sci U S A 2004;101:14677–14682.
34. Norman PS, Ohman JL Jr, Long AA et al. Treatment of cat
allergy with T-cell reactive peptides. Am J Respir Crit Care Med
1996;154:1623–1628.
35. Verhoef A, Alexander C, Kay AB, Larche M. T cell epitope
immunotherapy induces a CD 4+ T cell population with regu-
latory activity. PLoS Med 2005;2:253–261.
36. Drachenberg KJ, Wheeler AW, Stuebner P, Horak F. A well-
tolerated grass pollen-specific allergy vaccine containing a novel
adjuvant, monophosphoryl lipid A, reduces allergic symptoms
after only four preseasonal injections. Allergy 2001;56:498–
505.
37. Creticos PS, Schroeder JT, Hamilton RG et al. Immunotherapy
with a ragweed-Toll-like receptor 9 agonist vaccine for allergic
rhinitis. N Engl J Med 2006;355:1445–1455.
10 2009 World Allergy Organization
G. Walter Canonica
38. Taudorf E, Laursen C, Lanner A et al. Oral immunotherapy in
birch pollen hay fever. J Allergy Clin Immunol 1987;80:
153–161.
39. Wilson DR, Lima MT, Duuham SR. Sublingual immunother-
apy for allergic rhinitis. Allergy 2005;60:1–2.
40. Passalacqua G, Albano M, Ruffoni S et al. Nasal Immuno-
therapy to Parietaria: evidence of reduction of local allergic
inflammation. Am J Respir Crit Care Med 1995;152:461–
466.
41. Tari MG, Mancino M, Monti G. Immunotherapy by inhalation
of allergen in powder in house dust allergic asthma. A double-
blind study. J Invest Allergo Clin Immunol 1992;2:59–67.
42. Georgitis JW, Nickelsen JA, Wypych JI et al. Local intranasal
immunotherapy with high-dose polymerized ragweed extract.
Int Archs Allergy Appl Immunol 1986;81:170–173.
43. Andri L, Senna G, Bettel C et al. Local nasal Immunotherapy
for Dermatophagoides-induced rhinitis: efficacy of a powder
inhaler. J Allergy Clin Immunol 1993;91:987–996.
Chapter 3: Mechanisms of
sublingual immunotherapy
Allergen immunotherapy provides an opportunity to
study antigen-specific tolerance in man.
Subcutaneous immunotherapy suppresses allergic
ÔT
H
2-mediatedÕinflammation and increases antigen-
specific IgG probably by induction of T regs, im-
mune deviation (T
H
2T
H
1) and/or apoptosis of
T cells.
Oral mucosa is a natural site of immune tolerance
(Langerhans cells, FcR1, IL-10, IDO [indoleamine
2,3-dioxygenase]).
Sublingual immunotherapy in optimal doses is
effective and may induce remission after discontin-
uation and prevent new sensitizations, features
consistent with induction of tolerance.
Sublingual immunotherapy is associated with:
sretention of allergen in sublingual mucosa for
several hours.
smarked early increases in antigen-specific IgE,
blunting of seasonal IgE.
smodest increases in antigen-specific IgG4 and IgE-
blocking activity.
sinhibition of eosinophils, reduction of adhesion
molecules in target organ.
ssome evidence of increase in peripheral T cell
IL-10.
SLIT induces modest systemic changes consistent
with SCIT, but additional local mechanisms in oral
mucosa and/or regional lymph nodes are likely
important.
Immunotherapy provides a unique opportunity to study
the evolution of antigen-specific tolerance in man. Under-
standing the underlying mechanisms may lead to the
development of vaccines with greater efficacy and allow
the identification of biomarkers that may predict the
clinical response to treatment. Whereas there is consider-
able knowledge concerning mechanisms of SCIT,
information on the mechanisms of SLIT (1, 2) is less
well-advanced.
Subcutaneous immunotherapy
Subcutaneous immunotherapy in patients with pollen
rhinitis is associated with transient increases in allergen-
specific IgE, blunting of seasonal increases in IgE (3),
and increases in allergen-specific IgG, particularly IgG4
(3–5), and IgA (5, 6). Serum antibody concentrations
appear to relate more to the dose of allergen adminis-
tered rather than correlate with clinical improvement (7).
Immunoreactive IgG populations include antibodies with
a wide range of clonality and/or affinity. In contrast,
functional assays of IgG are more likely to represent
that proportion of circulating IgG that is biologically
(and therefore clinically) relevant. For example, serum
obtained following SCIT has been shown to inhibit
allergen-IgE binding to B-cells (8), an effect mediated
largely by IgG4. This system has provided an in vitro
assay of the ability of ÔblockingÕantibodies to inhibit
IgE-facilitated antigen presentation. Similarly, basophil
histamine release can be used to measure the functional
ability of IgG to inhibit IgE-dependent activation and
mediator release (9), either via competition with IgE for
allergen and/or by stimulation of surface IgG-inhibitory
receptors present on basophils and mast cells (10).
Whereas post-immunotherapy serum IgA is unable to
block allergen-IgE binding to B cells, by triggering
surface IgA receptors on monocytes, IgA releases the
inhibitory cytokine IL-10 (6). Subcutaneous immuno-
therapy has been shown to decrease the numbers of
effector cells at mucosal sites, both during seasonal
allergen exposure (11) and after allergen challenge (12),
as well as reducing effector cell reactivity in vitro (9).
It has been suggested that allergic disease may result
from a relative imbalance between the effects of regula-
tory T cells and Th2 cells (13). Regulatory T cells can be
divided into Ônaturally occurringÕ, thymus derived CD4+
CD25+ cells, which are positive for the transcription
factor Foxp3, and ÔadaptiveÕregulatory cells, either Tr1
IL-10 secreting cells, or T
H
3 TGF-bsecreting cells (14).
Subcutaneous immunotherapy in patients with grass
pollen (15) and mite (5) allergy results in increased IL-
10 in allergen-stimulated peripheral T cell cultures.
Additionally, subcutaneous immunotherapy has been
associated with immune deviation in favour of T
H
1
responses (16, 17). However, changes in T cell responses
to allergen have not been universally observed in cells
derived from peripheral blood (18, 19). Studies of local
nasal T cell responses have identified skewing of cytokine
profiles in favour of T
H
1 responses (20, 21) and local
2009 World Allergy Organization 11
Sub-lingual immunotherapy
increases in IL-10+ (3) and TGF-b+ T cells (6) and
Foxp3+ phenotypic T regs (22) within the nasal mucosa.
The oral mucosa as a tolerogenic organ
The local environment in the mouth is regarded as a site of
natural immune tolerance (2). Despite continued exposure
to micro-organisms and multiple foreign substances, the
oral mucosa remains non-inflamed with a relative paucity of
effector cells compared to other mucosal sites. The presence
of a sophisticated network of Langerhans cells epithelial
cells and monocytes capable of producing IL-10, TGF-band
activins (23–26) may play a role in the maintenance of oral
tolerance. Local secretory IgA may also have an anti-
inflammatory effect (6).
Human oral Langerhans cells constitutively express
FcR1, Major Histocompatibility Complex (MHC) class I
and II and co-stimulatory and co-inhibitory molecules (27),
properties consistent with highly efficient antigen presen-
tation to T cells. Cross-linking of FcR1 on monocytes
induces production of IL-10 (28) and indoleamine 2, 3-
dioxygenase (29), the latter associated with reduced tryp-
tophan levels and consequent impaired T-cell stimulatory
capacity. Human oral mucosal Langerhans cells produce
substantial IL-10. Ligation of Toll-like receptor 4 on
isolated human oral Langerhans cells enhanced IL-10
production (30) and in co-culture experiments decreased T-
cell proliferation (in mixed lymphocyte reactions) with a
parallel induction of T-cells with a regulatory phenotype.
One hypothesis is that innate receptors enhance the
tendency toward tolerance to antigens presented in the
microbe-rich oral environment. Interaction between den-
dritic cells, Langerhans cells and T cells may occur locally
within the oral mucosa (27, 30), whereas animal studies (26)
imply that the principle site for such interactions is within
the regional lymph nodes. It is possible that oral Langer-
hans cells interact with naı
¨ve T-cells, resulting in the
generation of allergen-specific regulatory T-cells. Alterna-
tively, interaction with allergen-specific memory T
H
2 cells
may result in down regulation of function or redirection to a
regulatory or T
H
1 phenotype. Downstream events, as in
subcutaneous immunotherapy, may include B-cell class-
switch to IgG4 and IgA rather than IgE, and down
regulation of mucosal effector cells. It remains to be
determined whether such mechanisms operate in vivo
during sublingual immunotherapy.
Immunological effects of sublingual immunotherapy in man
Clinical studies of sublingual immunotherapy are hetero-
geneous, involving different allergens, doses and durations
of therapy. A wide range of laboratory techniques has
been used to measure putative immunological mecha-
nisms: this may explain, at least in part, the variability of
results obtained. Tracer studies of radio-iodine labelled
allergen have shown that allergen may be retained within
the oral mucosa for at least 2 hours (31) and up to 18–
20 hours (32) following sublingual administration, afford-
ing opportunities for both local as well as systemic effects
on the immune system.
Specific antibody levels
During pollen SLIT, increases in allergen-specific IgE occur
within weeks although do not appear to be associated with
adverse events. These early increases are followed by
blunting of seasonal rises in IgE. There follows an increase
in allergen-specific IgG/IgG4. These elevations are both
time- and allergen-dose dependent (33) and progressive for
at least 2 years (34) although of lower magnitude than
observed during SCIT (3, 35). Some studies have shown
increases in specific IgG4 in the absence of demonstrable
efficacy (36), whereas others have shown no difference in
IgG levels, likely related to the lower allergen doses
employed (37), particularly in relation to mite SLIT (38–
41). These findings raise the issue of causality verses
bystander effects. In functional assays, sera obtained after
grass pollen SLIT was able to inhibit IgE-binding in vitro
(34).
Effector cells
Sublingual mite immunotherapy (42) was associated with
decreases in conjunctival eosinophils, neutrophils and
epithelial expression of intercellular adhesion molecule-1
(ICAM-1) and accompanied by a reduction in circulating
eosinophil cationic protein (ECP). Similarly, SLIT in
Parietaria-sensitive patients reduced eosinophils, neu-
trophils and ICAM-1 expression in the nasal mucosa (43).
Decreases in ECP (42, 44) and eosinophils have been
observed in several but not all (40) studies. One study
investigated the effects of high dose grass pollen SLIT on
immune cells within the sublingual mucosa (45). No
differences in total T-cells, CD1a+ dendritic cells or
macrophages were detectable and no differences in IL-12
messenger ribonucleic acid (mRNA)+ cells, whereas the T
reg phenotype was not assessed. Interestingly, mast cells
and eosinophils are present, albeit in low numbers, within
the buccal/sublingual mucosa (46, 47) and corresponding
activation markers such as tryptase and ECP are detectable
within salivary secretions (48), providing a plausible
explanation for local itching and swelling that may occur
after sublingual allergen administration.
T cells and cytokines
Studies of peripheral T cell responses to inhalant aller-
gens, before/after SLIT have been highly variable.
Decreased T cell proliferative responses in birch (49) and
grass-treated (50) patients have been observed in some but
not other studies (37, 51) and even less convincing trends
for house dust mite-treated patients (52, 53). Similarly
12 2009 World Allergy Organization
G. Walter Canonica
results for T cell cytokine production at both messenger
RNA and protein levels have been highly variable, with
some studies showing an increase in interferon gamma
and/or decreases in T
H
2 cytokines (49, 51, 53–55) whereas
others show no changes (37, 41, 50). A more consistent
finding (as in SCIT) has been increases in peripheral T cell
IL-10 production which have been observed at protein
(49, 56, 57) and mRNA levels (54) in several, but not all,
studies (37). An elegant study by Bohle (49) on small
numbers of birch-treated patients showed a reduction in
proliferative responses to Bet v1 that was accompanied by
increases in IL-10. This suppression was reversed by anti-
IL-10 or depletion of CD25+ cells from the cultures
which implied involvement of regulatory T cells. Further
immunological studies on larger numbers of subjects using
validated clinical protocols are needed. One such recently
published DBPC-RCT evaluated HDM SLIT in 30
HDM-allergic subjects for more than 12 months. The
study reported suppression of IL-5 production and
allergen specific CD4+ T cell proliferation via TGF-b,
transient increase in CD4+ CD25+ Foxp3+/CD127lo T
regs with functional suppressor activity and allergen
specific antibody isotype switching to IgG4 in clinically
effective HDM SLIT (58).
Conclusion
A consensus is emerging that SLIT may involve similar
mechanisms to SCIT with allergen-driven altered T cell
responses underlying suppression of allergic inflammation
and the modest changes observed in circulating antibody
levels, particularly allergen-specific IgG4. Although re-
sults vary, the underlying event is likely to involve
induction of a population of IL-10 producing regulatory
T cells. Alternative mechanisms include immune deviation
in favour of T
H
1 responses and apoptosis and/or anergy
of antigen-specific T cells. Studies of local T cell responses
in the allergic mucosa may yield more definitive informa-
tion. In contrast to murine studies, it is difficult to assess in
man the likely additional local mechanisms involving
T cell-dendritic cell interactions within the oral mucosa
and/or local lymph nodes.
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14 2009 World Allergy Organization
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Chapter 4: Clinical efficacy of
sublingual immunotherapy
Up to June 2009, there were 60 DBPC-RCTs of
SLIT, of which 41 conducted with grass or HDM
extracts. The majority of these studies is heteroge-
neous for allergen dose, duration and patientsÕ
selection.
48 trials provided overall positive results and 12 were
totally or almost totally negative.
The literature suggests that overall, SLIT is effective,
although differences exist among allergens.
The available meta-analyses are in favour of SLIT
(rhinitis in adults, asthma and rhinitis in children),
although the conclusions are limited by the great
heterogeneity of the studies.
The clinical efficacy and dose dependency have been
demonstrated, in adequately powered, well-designed
DBPC-RCTs, for rhinoconjuntivitis due to grass
pollen.
Dose finding trials and large studies with properly
defined outcomes and sample size are needed for the
other relevant individual allergens.
General aspects
As in the case of SCIT, the evaluation of the clinical
efficacy of SLIT relies on the assessment of symptom
severity and rescue medication use during the natural
exposure to allergens. This requires the adoption of a
rigorous methodological design, which is the DBPC-RCT.
Moreover, as suggested by WAO (1), an ideal study
should include:
only monosensitized patients
a baseline assessment (i.e. a run-in pollen season)
adequate pollen counts in trials on pollen-allergic
subjects
a sample size calculation for adequate power of the
study
a balanced symptom/medication score evaluation
an adequate duration and allergen dose
For practical (time consumption, budget, and rarity of
monosensitized subjects) and historical reasons (the ear-
liest studies were performed more than 10 years ago), only
few recent trials fulfil the above mentioned criteria.
Therefore, the majority of the published RCTs can be
considered as suggestive, rather than demonstrative.
Nonetheless, the RCTs taken together provide relevant
and reliable information.
DBPC-RCTs (Table 4-1)
The number of DBPC-RCTs is increasing: as shown in
Table 4-1, there were 60 DBPC-RCTs performed since
1986 (2–61), when the first controlled trial appeared (2).
Of these, 26 were performed with grass extracts, 15 with
mite, five with Parietaria, three with cat and the remaining
11 trials with other pollen extracts. The duration of the
trials ranged between 4 months and 4 years, 19 of them
being of 6 months duration or less. The majority of
studies was conducted in patients with rhinitis or rhinitis
plus asthma. Only a few studies (15, 21, 31, 38, 44, 46, 61)
were specifically designed to evaluate the efficacy in
asthma, and one study dealt with allergic conjunctivitis
(28). When stated, the dose used in the clinical trials
ranged between five and 375 times that used in an
equivalent SCIT course, but the monthly and cumulative
doses of major allergen(s) was largely variable from trial
2009 World Allergy Organization 15
Sub-lingual immunotherapy
Table 4-1 Placebo-controlled studies
Author (ref), year Age range
Patients
A/P* Dropout A/P* Allergen Duration
Dose
preparation Dose vs SCIT Disease
Manufac-
turer
Main positive
results No change
Scadding and
Brostoff (2), 1986
20/20 0/0 HDM NA R Reduction in
symptoms in 72%
patients
Tari et al. (3), 1990 5–12 30/28 HDM 18 months 15.4 mg Der p
1/month
Aqueous/
phenol
5 RA ALK Symptom score 12 months:
(P< 0.05); 18 months:
(P< 0.001). Drug score
20%
Nelson et al. (4),
1993
20–55 20/21 Cat 3.5 months 1.2 mg Fel d 1/
month
40 RA HS Drugs/symptoms
not evaluated
Symptoms on
challenge
Sabbah et al. (5),
1994
13–51 29/29 Grass 4 months 210 lg
Dac g 5 glyc-
erosaline
50 R STA Rhinitis (P< 0.05)
Ocular (P< 0.01)
Drugs (P< 0.01)
PatientÕs
assessment
P= 0.16
Feliziani et al. (6),
1995
14–48 18/16 0/0 Grass 4 months 19 lg
grass/month
Glycerol-phe-
nol
6 RA ALK Symptoms: Asthma
(P= 0.026); rhinitis
(P= 0.01)
Overall (P= 0.008)
Medications: overall
(P¼0.002) asthma
(P¼0.049) rhinitis
(P¼0.002)
Troise et al. (7),
1995
17–60 15/16 0/0 Parietaria 10 months 1 lg Par j 1/
month
20 R ALK P< 0.05 vs placebo
in pollen season
Monthly clinical
score
Hirsch et al. (8),
1997
6–16 13/14 HDM 1 year 48 lg Der
p 1/month
Cumulat:
570 lg Glyc-
erol
5 RA ALP P= 0.05 vs placebo for
asthma only
Medication score,
Rhinitis score,
Self assessment
Passalacqua et al.
(13), 1998
15–46 10/10 0/1 HDM
(monoid)
2 year 18.000
AU/month
Tablets
20 R LOF Rhinitis symptoms in winter
(P< 0.05). Meds not
assessed
Vourdas et al. (11),
1998
7–17 34/32 1/2 Olive 2 season 1215 lg Ole e
1/month Glyc-
erophenol
300 RA STA Dyspnea score (0.04 first
year and 0.03 second year).
Conjunctivitis P< 0.05
second season
Medication score,
PEF,
Rhinitis score,
Global
assessment
Clavel et al. (9),
1998
8–55 62/58 Grass 6 months 288 lg Phl p 5/
month Aque-
ous
100 R STA Medication score
(P< 0.01)
Oral steroids (P< 0.05)
Asthma symptoms (P0.02)
Rhinitis score,
Conjunctivitis
score
16 2009 World Allergy Organization
G. Walter Canonica
Table 4-1 (Continued)
Author (ref), year Age range
Patients
A/P* Dropout A/P* Allergen Duration
Dose
preparation Dose vs SCIT Disease
Manufac-
turer
Main positive
results No change
Horak et al. (10),
1998
16–48 18/16 Birch 4 months 62 lg Bet v
1/month
Glycerophenol
NS R ALK Anterior rhinomanom.
Vienna Challenge
Chamber. Symptom-medi-
cation not evaluated
Hordijk et al. (12),
1998
18–45 27/30 Grasses 6 months 4250 BU/month
Glycerinated
NS R ART Symptom decreased
29% at peak season
(0.03)
Medication score,
Symptom score
whole season
Bousquet et al. (15),
1999
15–37 32/33 17/18 HDM 2 years 300 lg Der p
1/month
Glycerosaline
200 A STA At 24 months asthma
symptoms (0.02), FEV
1
(0.01), PEF (0.01), QoL
Mean daily drug
score; asthma
symptom score;
patients evalua-
tion
Passalacqua et al.
(14), 1999
15–42 15/15 1/2 Parietaria 8 months 3.6 lg Par j
1/month.
Cumulat:
16 lg
Glycerophenol
7 R ALK vs baseline: symptoms
(P= 0.16) drug intake
(P= 0.08)
Pradalier et al. (17),
1999
6–25 60/59 2/4 Grass 5 months 255 lg Phl
p5/months
Cumulat:
935 lg
Glycerophenol
150 RA STA Asthma
symptomatic days (0.02);
% patients with asthma
(0.05); ocular symptoms
(0.05); albuterol (0.01).
Total
medication
score; oral steroids
(P0.059); patientsÕ
assessment
La Rosa et al. (18),
1999
6–14 20/21 4/4 Parietaria 6 months
2 seasons
2730 lg
Par j 1/month
Cumulat:
52.5 mg
Glycerophenol
375 RA STA Rhinitis score
2 years (0.02)
Medication scores,
Rhinitis score first
year
Purello et al. (16),
1999
14–50 14/16 0/0 Parietaria 8 months 1.5 lg Par
j 1/month
Cumulat:
12 lg
3 RA ALK Rhinitis and asthma scores
(P= 0.01); medication
score (P= 0.05)
Pajno et al. (21),
2000
8–15 12/12 0/3 HDM 2 years 10.4 lg
Der p 1/month
Cumulat:
360 lg
Aqueous
4 A ALK Asthma symptom score
second year (P< 0.01)
night symptom (0.01)
medication score
first and second year
(<0.01) VAS second year
(<0.01)
Asthma symptoms
first year; VAS first
year
2009 World Allergy Organization 17
Sub-lingual immunotherapy
Table 4-1 (Continued)
Author (ref), year Age range
Patients
A/P* Dropout A/P* Allergen Duration
Dose
preparation Dose vs SCIT Disease
Manufac-
turer
Main positive
results No change
Guez et al. (20),
2000
6–51 38/37 8/15 HDM 2 years 91 lg Der p 1/
month
Cumulat:
2.2 mg Aque-
ous
2 R STA Higher dropout
rate in placebo
Total symptom
score,
Medication score,
VAS score
Caffarelli
et al. (22), 2000
4–14 24/20 0/4 Grass (monoid) 3 months 12 000
AU/month
37 000 AU
5 RA LOF Total symptom
score (<0.05),
Asthma score (<0.05),
Symptom-med
scores for high
pollen count.
Medication score,
Ocular score
Yuksel et al. (19),
1999
5–15 21/18 NS Grass 4 months Cumulat 210 lg
Dac g 5 Glyc-
erosaline
NS RA STA Antihistamine (<0.05),
Rhinitis score (<0.01),
Overall efficacy by physi-
cian (P= 0.04)
Beta2 use,
Asthma scores,
PEF
Ariano et al. (23),
2001
19–50 10/10 0/0 Cypress 8 months 30 000
RU/month,
Cumulat
300 000,
Glycero-Aqua
5 RA ANA Symptoms and medications
score (<0.05)
Bahceciler et al.
(24), 2001
7–15 8/7 0/0 HDM 6 months 72 lg Der
p 1/month;
Cumul:
0.56 mg
Aqueous
NS RA STA Asthma score (P= 0.05),
Beta2 (P= 0.028),
PEF (P= 0.049),
Exacerbation(P= 0.007)
Nasal symptom
score,
ICS (P= 0.06),
NCS vs placebo
Voltolini
et al. (25), 2001
(second year open)
15–52 15/15 first,
24/10 second
0/1 Birch 24 months 90 lg Bet
v 1/month
Glycerophenol
5 RA ALK Symptoms vs
baseline (P=
0.001); drugs vs
baseline (P=
0.007). second
year: combined scores vs
baseline and
placebo
Symptoms
and drugs scores
vs placebo
Sanchez
et al. (26), 2001
18–50 20/20 0/0 Cat 1 year 0.3 lg Fel d 1/
day
Glycero-saline
NS RA CBF Symptom score (<0.01) Medication not
assessed
18 2009 World Allergy Organization
G. Walter Canonica
Table 4-1 (Continued)
Author (ref), year Age range
Patients
A/P* Dropout A/P* Allergen Duration
Dose
preparation Dose vs SCIT Disease
Manufac-
turer
Main positive
results No change
Lima et al. (27),
2002
16–48 26/23 2/1 Grass 18 months 0.9 mg Phl p 5/
month
Glycerinate
50 R ALK Patient
assessment (P= 0.02)
Rescue meds,
Symptom score
Mortemo-
usque et al. (28),
2003
6–60 26/19 4/11 HDM 24 months Cumulat:
2.2 mg Der p
1,
Glycero-aque-
ous
NS C STA Conjunctival provocation,
Conjunctival
score,
Nasal score
Andre et al. (29),
2003
6–55 48/51 7/4 Ragweed
3 doses
7 months 1.4–4.0 mg
Amb a 1/
month
Solution/tab-
lets
NS R STA Only highest dose:
Rhinitis score (P= 0.05),
Ocular score (P= 0.04),
Oral steroids (P= 0.05)
In all dose groups:
symptoms and
drugs combined
Ippoliti et al. (30),
2003
5–12 47/39 0/0 HDM 6 months 10.4 lg Der p
1/month
Cumulat:
57 lg Glycer-
ophenol
5 AR ALK Asthma score (<0.01),
Rhinitis score (<0.01),
FEV
1
(<0.01),
Drugs not
assessed
Pajno et al. (31),
2003 (vs placebo
and control)
8–14 15/15 1/2 Parietaria
Add on to
ICS
13 months 1.56 lg Par j 1/
month
Cumulat:
23 lg
Glycerosaline
NS RAC ALK Ocular score
0.025 vs controls; VAS
(P= 0.037)
vs placebo
Bronchial, nasal
scores
Wuthrich
et al. (32),
2003
6–13 10/12 4/2 Grass 2 years 6 lg/month
Glycerophenol
NS RA ALK Drug score second year
(0.05)
Drug score first
year, Symptom
score
Tonnel et al. (33),
2004
7–45 15/17 5/9 HDM 2 years 53 lg Der
p 1/month
Cumulat:
57 lg
Solution-tab-
lets
NS R STA Rhinitis score first year
(<0.03): second year
(<0.02)
Drug score
Bufe et al.
(34), 2004
6–13 68/74 0/10 Grass 1 year +
2 years open
273 lg Phl p 5/
month
Cumulat:
9.6 mg
Solution
10 RA HAL Symptom + drug score
P= 0.046 vs placebo:
only third year and only
most severe group
Symptom + drug
scores
Smith et al. (35),
2004
18–60 49 1 year, 46
2 years,
46 placebo
35 Grass 1 year
2 years
329 lg Dac g 5/
month
Solution-
tablets
300 R STA Second year: sneezing
(0.05) and rhinorrhea
(0.001)
Nasal score first
year: Drug scores
all study
2009 World Allergy Organization 19
Sub-lingual immunotherapy
Table 4-1 (Continued)
Author (ref), year Age range
Patients
A/P* Dropout A/P* Allergen Duration
Dose
preparation Dose vs SCIT Disease
Manufac-
turer
Main positive
results No change
Rolinck-
Werninghaus
et al. (36),
2004
3–14 39/38 1/1 Grass 3 years 6 lg major/
month
Glycerophenol
NS RA ALK Drug score (0.025)
Symptom + drug score
(0.049)
Ocular, nasal, bron-
chial symptom
score
Bowen et al. (37),
2004
6–52 36/40 8/11 Ragweed
3 doses
4 months 3.1–9.4 mg
Amb a 1/
month
Solution
NS R STA Sneezing and itching
(0.04); investigatorÕs
evaluation
Drug score,
Conjunctivitis
score
Durham et al. (41),
2006
18–66 569/286 39/26 Grass
3 doses
6 months 15 lg (136 pts)
150 lg (139
pts)
450 lg (294
pts) Phl
p 5/months
Tablets
NS R ALK Drug score – 28% (0.012):
Symptoms – 21% (0.002):
QoL, Only highest dose
Symptoms and drug
scores for the 2
low doses
Passalacqua
et al. (40),
2006
14–56 34/34 6/6 HDM
(monoid)
2 years 8.000 AU/
month
Tablets
10 R LOF First year: total
symptoms (0.03),
obstruction (0.05),
medication (0.03).
Second year: medications
(0.03);
General wellbeing
Symptom score and
obstruction at
second year. Sat-
isfaction profile.
Niu et al.
(38), 2006
6–12 56/54 7/6 HDM 6 months 320 lg Der p 1/
month
Cumulat,
1.7 mg
Glycerosaline
100 A STA Nighttime (0.002),
daytime (0.009),
total (0.01) asthma
score; FEV
1
, FVC
vs baseline (<0.05).
Global assessment
Oral steroids
PEF (0.07),
FEV1 and FVC
between groups
Dahl et al.
(39), 2006
18–64 74/40 13/8 Grass 5 months 450 lg Phl p 5/
month,
Cumulat.
2.7 mg,
Tablets
NS RCA ALK RC symptom
–37% (0.004),
RC drugs –41% (0.03),
Well days
–52% (0.004)
Asthma symptoms
and medications
Valovirta
et al. (42), 2006
6–14 65/33 8/6 Hazelnut, birch,
elm (two do-
ses)
18 months Weekly dose of
major
allergens,
Group 1
3.6 lg,
Group 2:
30 lg
NS RC ALK With higher dose:
total symptoms
(0.001), nose, lung,
eye symptoms
during birch season
(<0.05)
Total drug score,
Methacholine,
Skin test
20 2009 World Allergy Organization
G. Walter Canonica
Table 4-1 (Continued)
Author (ref), year Age range
Patients
A/P* Dropout A/P* Allergen Duration
Dose
preparation Dose vs SCIT Disease
Manufac-
turer
Main positive
results No change
Dahl et al. (43),
2006
23–35 316/318 42/46 Grass 6 months 450 lg Phl p 5/
months,
Cumulat:
2.7 mg,
Tablets
NS RC ALK RC symptom
–30% (0.001), RC drugs
)38% (0.001), Well days
–52% (0.004),
VAS
Lue et al.
(44), 2006
6–12 10/10 0/0 HDM 8 months Cumulat:
1.7 mg
Der p 1,
Glycerosaline
NS A STA Night symp (0.04)
vs pl Day symp (0.04),
FEV
1
,
drugs (0.01) vs
b/line
Day symptoms,
drugs, FEV
1
, PEF vs
placebo
Palma-Carlos
et al. (45),
2006
19–43 17/16 4/9 Grass
(monoid)
2 year 8000 AU/month
Tablets
NS RC LOF Conjunctivitis,
rhinorrhea,
sneezing (<0.05)
at the second year;
nasal reactivity
(0.03) at the
second year
Symptoms and na-
sal reactivity at
the first year
Pham-Ti
et al. (46),
2007
5–11 55/56 11/8 HDM 18 months 810 lg Der p 1/
month
Cumulat
6.9 mg,
Glycerosaline
NS A STA SPT (P= 0.01),
QoL (P< 0.01)
Asthma symptoms,
Asthma
medication,
Asthma free days,
(low: both groups)
Vervloet
et al. (48),
2007
19–60 38/38 2/4 Juniper 4 months,
2 seasons
6 mg Jun
a 1/month,
Glycero-aque-
ous
NS A STA First and second
season:
Nasal steroids
(0.01),
Total medications
(0.04), IgE and
IgG4
Both seasons:
Total and single
symptom scores.
Single medication
Roeder
et al. (47),
2007
6–18 108/96 26/24 Grass 2 years 168 lg Lol p 5/
month
Cumulat:
4.5 mg
Solution
NS RC ARTU Mean daily score,
Symptom-free
days,
Medication free
days,
QoL
Alvarez-
Cuesta et al. (49),
2007
16–51 25/25 8/9 Cat 1 year Cumulat:
17.1 lg Fel d
1,
Glycerosaline
2 RC CBF Bronchial, nasal, conjuncti-
val symptoms and PEF vs
baseline (<0.05) at room
challenge
2009 World Allergy Organization 21
Sub-lingual immunotherapy
Table 4-1 (Continued)
Author (ref), year Age range
Patients
A/P* Dropout A/P* Allergen Duration
Dose
preparation Dose vs SCIT Disease
Manufac-
turer
Main positive
results No change
Didier et al. (50),
2007
25–47 472/156 59/10 Grass,
3 doses
6 months 240 lg
(157 pt)/
month,
750 lg (155
pt)/month,
1.2 mg (160
pt)/month
Tablets
NS RC STA For 300 & 500 IR,
Total/individual symptom/
drug scores (<0.001);
RQLQ; medication-free
days
Horiguchi et al. (51),
2007
18–50 43/24 2/2 Jap cedar 7 months 6 lg Cry
j 1/month
Solution. Spit
100 RC TORI Symptoms + drugs (<0.05);
sneezing, obstruction,
rhinorrhea (P< 0.05). IgG4
De Blay et al. (52),
2007
12–41 61/57 8/8 Grass 10 months 250 lg group 5/
month
Cumulat:
2.5 mg,
Solution
NS RC ALB Medications (0.02); symp-
toms in pats without
asthma (0.01): QoL; IgG4
Global symp score,
Global medication
score
Moreno et al. (53),
2007
14–55 51/49 11/9 Olive + Grass 10 months 60 lg
group 5
90 lg Ole
e 1/month,
Solution
NS RC ALK vs first season: eye, nose,
lung and total symptom
(<0.01); symptom + drugs
(0.02) VAS (0.01); QoL
(0.01)
Symptom and drug
active vs placebo
Mosges et al. (54),
2007
18–50 48/53 6/5 Grass 9 months Cumulative
3.5 mg Phl p 5
NS RC STA Nasal + ocular
symptoms –37% (0.03)
Eye symptoms –47%
(0.003)
Nasal symptoms
(0.08),
IgE, IgG4
Panzer
et al. (55), 2008
15–50 45/30 4/0 Grass
SLIT or
supraling
1 year 38 lg Lol
p 5/month
Cumulat:
456 lg
Solution
NS RC SEVA Symptoms –38%
(supralingual);
–67% SLIT; drugs
–67%
IgE; SPT
Okubo
et al. (56),
2008
25–55 38/23 1/1 Cedar 5 months 2000 JAU NS RC TORI Symptoms and med
better in SLIT in
4 days of season; QoL
Overall season
symptoms and
medications
Pfaar and
Klimek (57), 2008
17–59 94/91 17/9 Grass 2 years 1.2 mg/month
Solution
NS RCA ALP Symptoms + med scores
AUC (<0.01), VAS
Wahn et al. (58),
2008
4–17 139/139 4/8 Grass 8 months 600 lg major
allergen/
month,
Tablets
NS RC STA Rhinitis score
–28% (0.01); Meds
–24% (0.006); Med. free
days (0.01)
22 2009 World Allergy Organization
G. Walter Canonica
to trial. The majority of the clinical trials used the
traditional symptom score assessment (graded from 0 to
3) plus recording of doses of rescue medications. In some
trials, other evaluation parameters were applied, including
visual analogue scale (VAS), combined score, symptom-
free days and medication-free days. Out of 60 DBPC-
RCTs, 18 enrolled more than 100 patients (9, 17, 34, 35,
38, 39, 41, 43, 46, 47, 50, 52, 57–60). Of these, ten had a
formal sample size calculation (41, 43, 46, 47, 50, 52, 57–
60). Twenty DBPC-RCTs involved only paediatric sub-
jects (<18 years of age). As shown in Table 4-1, in the
majority of the trials, the results were overall positive for
one or more of the parameters investigated. On the other
hand, there were four totally negative studies (4, 20, 47,
56) and eight trials reported only partial or negligible
clinically efficacy (8, 9, 11, 27, 34, 36, 46, 52).
During the last three years, adequately powered, well-
designed DBPC-RCTs involving several hundreds of
patients and using standardized grass pollen tablets, were
published (39, 41, 43, 50, 58–60). In those studies the
magnitude of the effect, defined as the reduction in diary
symptoms and rescue medication scores compared to
placebo was reported as 16% and 28% (41), 30% and
38% (43), 35% and 46% (50), 28% and 24% (58), 24%
and 34% (60) respectively. All these trials followed the
established methodological criteria, had a power calcula-
tion and clearly defined outcomes and statistical analyses.
So far, these large trials represent the best evidence
available on the efficacy of SLIT. According to these
trials, a dose-dependency of the efficacy of SLIT was
observed, and the optimal monthly maintenance dose for
grasses was identified as about 600 lg of the major
allergen(s). One large DBPC-RCT (47) of grass extract,
with 164 patients from general practice, screened and
selected by researchers and specialists from a university
allergy department, failed to demonstrate any difference
between active and placebo. In another large trial with
grass extract (52), a significant difference in rhinitis scores
could be seen only for those patients without asthma. The
vast majority of the DBPC-RCTs were designed to assess
the efficacy of SLIT in rhinoconjunctivitis, and asthma
was sometimes evaluated as a secondary outcome. Only
eight studies were specifically designed to assess the effect
of SLIT in asthma (15, 21, 31, 38, 39, 44, 46, 61), and the
majority confirmed a significant effect on symptoms and/
or medication intake. In the three asthma studies that
reported negative results (39, 44, 46), the patients were
almost completely free of asthma symptoms at enrolment
and remained so during the trial, so that the absence of
efficacy is not substantiated. Only two DBPC-RCTs
assessed the efficacy of multiple non cross-reacting aller-
gens (53, 62). The first one used grass and olive extracts,
and confirmed the efficacy of SLIT in rhinitis. The second
one compared the efficacy of SLIT with grass alone or
with grass plus nine other pollens and found that the
treatment with a single allergen had more effect on
immunological parameters than that with multiple aller-
Table 4-1 (Continued)
Author (ref), year Age range
Patients
A/P* Dropout A/P* Allergen Duration
Dose
preparation Dose vs SCIT Disease
Manufac-
turer
Main positive
results No change
Ott et al.
(59), 2009
20–50 142/67 3/1 Grass 5 years,
4 seasons
Cumulative
1.5 mg major
allergen/
season
NS RC STA Combined and symptoms
score sig. reduced from
first season. Symptoms
decrease from
–33% to 47%
(third season)
Medication score all
seasons
Bufe et al. (60),
2009
5–16 126/127 12/7 Grass 6 months 450 lg Phl p 5/
month
NS RC ALK Sig reduction in RC symp-
toms score ()24%), asth-
ma score ()64%), RC meds
()34%), well days (+28%).
All P< 0.03
Stelmach
et al. (61),
2009
6–17 25/25 5/10 Grass 6 months,
2 seasons
3.65 mg
Phl p 5 cumu-
lat.
NS A STA Sig reduction in asthma
score ()40%), asthma
med ()10%)
Eye symptoms
2009 World Allergy Organization 23
Sub-lingual immunotherapy
gens. Because of the low pollen count, no clinical
difference between the two groups and placebo was seen
in this study.
Meta-analyses
The first meta-analysis of SLIT for allergic rhinitis
included 22 trials and 979 patients up to September
2002. It concluded that SLIT was significantly more
effective than placebo (63), but the studies in allergic
asthma were too few to perform a meta-analysis. A meta-
analysis in asthma was recently repeated, including 25
trials (either open or blinded) and involving more than
1000 adults and children (64). This meta-analysis demon-
strated a significant effect of SLIT for most of the
considered outcomes (symptoms + medications, pulmo-
nary function, overall improvement), with the exception
of asthma symptoms alone. Another meta-analysis (65) of
SLIT for allergic rhinitis in paediatric patients (aged 4–
18 years) involved 10 trials and 484 subjects. It showed
that SLIT was significantly more effective than placebo, as
assessed by the reduction in both symptom scores and
rescue medications usage. Although all the studies were of
high methodological quality, there was a relevant heter-
ogeneity (I
2
> 80%), because of the large variability in
study design, duration, outcome measures and inclusion
criteria. Finally, a meta-analysis was also performed for
asthma in paediatric patients (66). This review included
nine DBPC trials and 441 patients, and found a significant
effect of SLIT on both asthma symptoms and rescue
medication usage. Also in this case, the heterogeneity of
the trials was very large (I
2
> 90%). The meta-analyses
mentioned pooled together all the allergens, whereas a
systematic evaluation of the efficacy of one specific
allergen is available only for house dust mite (67), with
positive results. In summary, the available meta-analyses
involve very heterogeneous trials, often without a proper
sample size calculation: publication biases and discrepan-
cies in data collection are additional concerns (68). Thus,
meta-analyses provide only suggestive evidence.
Other controlled studies (Table 4-2)
There are eight randomised open controlled trials (69–76)
assessing the clinical efficacy of SLIT, mostly compared
with control groups receiving drugs only. All these studies
provided positive results for clinical scores and/or med-
ication intake, and two of them (71, 74) also demonstrated
a significant reduction in non-specific bronchial hyperre-
sponsiveness. One trial (75) was specifically designed to
evaluate the safety of a no-updosing regimen, rather than
the efficacy, and another (76) demonstrated that SLIT
with two non cross-reacting allergens (birch and grass) is
overall more effective than SLIT with the single allergens
in both pollen seasons.
24 2009 World Allergy Organization
Table 4-2 Randomised controlled not double-blind
Author
(ref), year Description
Age
range Patients Allergen Duration
Dose
Preparation Disease
Manu-
facturer Main results
DÕAmbrosio
et al. (69),
1996
Randomised open.
Controls
with drugs only
18–56 20 SLIT
20 Control
Parietaria 6 months NS R ALK Lower symptom
score (P= 0.032)
and drug + symptom
score (P= 0.037)
Gozalo
et al. (70),
1997
Randomised open.
Controls
with drugs only
18–50 35 SLIT
19 Control
Grass 2 years NS R ALK Lees medications in
SLIT group in first
(0.05) and second
(0.01) pollen season
Lombardi
et al. (71),
2001
Randomised open.
Controls
with drugs only
18–55 26 SLIT
25 Control
Grass 6 months
3 seasons
8000 AU/month
Allergoid
RA LOF Decreased rhinitis/
asthma medication
(0.01), rhinitis/asthma
scores (0.01), non-specific
bronchial reactivity (0.01)
G. Walter Canonica
2009 World Allergy Organization 25
Table 4-2 (Continued)
Author
(ref), year Description Age range Patients Allergen Duration
Dose
Preparation Disease Manufacturer Main results
Marogna
et al. (72),
2004
Randomised, open
controlled
18–62 390 SLIT
192 Control
HDM
Grass
Parietaria
Birch
3 years 32 lg Der p 1/month
5.8 lg Phl p1/month
5.8 lg Par j1/month
8.3 lg Bet v1/month
RC ANA Clinical scores improvement
at 1, 2 and 3 years vs
baseline and
controls (<0.01).
New sensitizations at
3 years in 5.9% SLIT
and 38% controls (<0.01)
Marcucci
et al. (73),
2005
Randomised, open,
two different doses
6–14 100IR = 32
300IR = 42
Grass 6 months 100 IR
300 IR
Glycerosaline
RC STA Higher dose better
for overall score
(P= 0.024),
symptoms (0.03),
and medications
(0.04) during peak
pollen. No change in IgE
Marogna
et al. (74),
2005
Randomised open.
Controls
with drugs only
18–65 39 SLIT
40 Control
Birch 5 years
5 seasons
8.5 lg Bet v 1
glycerinated
RA ANA From second season:
reduction asthma/
rhinitis symptoms
(0.01), salbutamol
intake (0.001), methacholine
reactivity (0.01). No change
in the first season.
Guerra
et al. (75), 2006
Randomised, open.
Comparison
traditional vs
no updosing
18–45 10 tradition
10 no updosing
Parietaria 3 months 90 lg Par j 1
cumulative
Solution
R ALK No difference
in side effects
between the two
regimens
Marogna
et al. (76), 2007
Randomised open.
Four groups:
birch, grass,
birch + grass,
controls
19–43 11 birch,12
grass,
13 birch
+ grass
12 Control
Birch
Grass
2 seasons
Second and
Fourth year
100 lg Bet v1
80 lg Phl p1
RA ANA Single allergens
effective on symptoms
and medication scores
in the specific season
and other season.
Combined SLIT
significantly more
effective in both seasons.
Sub-lingual immunotherapy
26 2009 World Allergy Organization
Table 4-3 Comparisons between SLIT and SCIT
Author (ref),
year Design Patients Allergen Duration Dose Manufacturer Main results
Quirino et al.
(77), 1996
Randomised
DB double-dummy
without placebo arm
10 SLIT
10 SCIT
Grass 12 months 6.4 lg major
allergen/
month for
SCIT.
SLIT = 3 X
SCIT
ALK Significant reduction in symptom
and drug intake score
(P< 0.01) in both groups ver-
sus baseline. No change in IgE.
Increase in IgG and reduction
of skin reactivity only in SCIT
group
Bernardis et al.
(79) 1996
Randomised, open,
without placebo
SCIT
SLIT
Altern ALK
Piazza and
Bizzarro (80),
1993
Randomised,
open, SLIT and SCIT vs
nasal IT and controls
17 SCIT
14 SLIT
12 LNIT
14 Controls
HDM 2 years SCIT: 4.8 lg/
month
SLIT: 12 lg/
month
LNIT: 32 ng/
month
ALK SLIT: decrease in symptoms at
3 months (0.01) but not
12–24 months.
SCIT: decrease in symptoms at
3, 12, 24 months (<0.01).
IgE, IgG and IgG4 changed only
in SCIT.
No change at all in LNIT
Mungan et al.
(81), 1999
Randomised open, pla-
cebo- SLIT controlled
15 SLIT
10 SCIT
11 Placebo
HDM 1 year Der p 1
SLIT: 21.6 lg/
month
SCIT: 0.6 lg/
month
STA Reduction in rhinitis score for
SLIT (<0.01) and SCIT (<0.05).
Asthma score reduction only
SCIT (<0.05). Reduction drug
score for both SLIT and SCIT.
Reduction SPT diameter only in
SCIT.
Khinchi et al.
(78), 2002
Randomised
DB double-dummy
placebo contr.
21 SCIT
18 SLIT
19 Placebo
Birch 2 seasons Bet v 1/month
SCIT: 3.28 lg
SLIT: 738 lg
STA Reduction of rhinitis score in
SLIT (0.36) and SCIT (0.75). No
significant difference between
treatments, both superior to
placebo (P= 0.002). Medica-
tion scores SLIT and SCIT vs
placebo (P= 0.02). No change
in QoL.
Mauro et al.
(82), 2007
Randomised open
SLIT vs SCIT
19 SCIT
15 SLIT
Birch 4 months Cumulative
50.65 IR SCIT
4653.1 IR SLIT
STA During pollen season, no differ-
ence SLIT-SCIT in symp-
toms + drug scores. Specific
IgG4 significantly increases
with SCIT only
G. Walter Canonica
2009 World Allergy Organization 27
Table 4-4 DBPC-RCTs in Diseases other than Respiratory Allergy
Author (ref),
year Age range
Patients
A/P* Dropout A/P* Allergen Duration Dose Disease Manufacturer Main results
Enrique
et al. (83),
2005
19–53 12/11 1/0 Hazelnut 6 months 188 lg Cor
a1/day
Food
allergy
Significant increase in the food
challenge provocation dose
(P= 0.02). 50% active subjects
tolerated maximum dose. No
change IgG4 and skin test.
Fernandez Rivas
et al. (84),
2009
20–40 37/19 4/3 Peach 6 months 300 lg Pru
p 3/month
Food allergy ALK Significant increase (3–5 times)
of the provocation dose at
DBPCFC
Bernardini (85),
2006
5–14 12/14 0/0 Latex 1 year Skin, respiratory
and oral allergy
due to latex
ALK Active group:
Improvement glove test at
3 months and 1 year
(P< 0.01).
Reduction oral allergy syn-
drome
Pajno et al. (87),
2007
5–16 28/28 2/6 Mite 18 months 3.3 lg Der
p 1/week
Atopic
dermatitis
ANA Only in mild-moderate subjects:
Reduction SCORAD starting
from month 9 (P= 0.025).
Reduction rescue medications
(P0.02)
Nettis et al.
(86), 2007
18–47 20/20 2/3 Latex 12 months 1200 lg/month Latex allergy,
urticaria, asthma
ALK Active group:
Decreased reactivity glove test
(P< 0.05),
Decreased bronchial reactivity
to latex (<0.05),
Symptoms and rescue medica-
tion scores at 6 and 12 months
Severino et al.
(88), 2008
18–65 15/15 1/3 Honey bee 6 months 525 lg venom/
month
Hymenoptera
allergy,
Large local reactions
ANA Reduction peak diameter LLR
(P= 0.014) at sting challenge.
Increase specific IgG4 (0.03)
*Active/Placebo; Rhinitis, Asthma, Conjunctivitis.
ALK, Alk-Abell; ANA, Anallergo; ALB, AllerBio; AL P, Allergopharma; ART, Artu Biologicals; CBF, CBF Leti; HS, Hollister-Stier; LOF, Lofarma; STA, Stallergenes; SEVA, Seva Pharma; TORI, Torii Pharmaceuticals.
Sub-lingual immunotherapy
Comparison with SCIT (Table 4-3)
When comparing two different routes of administration,
the gold standard methodology is the use of a double-
blind, double-dummy design. One double-dummy study,
although without a placebo group, conducted in grass
pollen allergic patients, showed that the clinical efficacy
of SLIT (symptoms and medication use) was equivalent
to that of SCIT (77). Another rigorous double-blind,
double-dummy, placebo-controlled trial with birch pol-
len extract, compared SLIT and SCIT. Symptoms and
medication use were reduced by about one-third in the
SLIT group and by one-half in the SCIT group, with
no significant difference evident between treatments.
However, there were six grade 3 and 4 adverse reactions
in the SCIT group and none in the SLIT group (78).
Four other comparative studies have been published,
but they were all conducted in an open fashion.
Bernardis et al. (79) performed an open comparative
12 months study in Alternaria tenuis allergic patients
and found a clinical improvement in symptoms (mainly
rhinitis) and medication use in both groups with a
statistically significant difference in favour of SLIT. In
another study (80), the clinical efficacy of SLIT, SCIT
and nasal immunotherapy was assessed in 43 patients
with rhinitis due to mites. This study considered only
the immunological changes, which were significant only
for SCIT. An open comparison (81), again in mite-
allergic patients, showed that the clinical improvement
was more prompt with SCIT, especially for asthma
symptoms, although SLIT controlled rhinitis symptoms
well. Finally, Mauro et al. (82), compared SCIT and
SLIT in 47 patients with birch allergy and found no
difference between the two treatments in seasonal
symptom score, although specific IgG4 significantly
increased only with SCIT.
DBPC-RCTs of SLIT in other diseases (Table 4-4)
The efficacy of SLIT was investigated, as proof of
concept, in DBPC-RCTs in diseases other than respira-
tory allergy, namely food allergy (83, 84), latex allergy
(85, 86), atopic dermatitis (87), and Hymenoptera
venom allergy (88). The results of all these trials were
clearly in favour of SLIT. Enrique (83) found that SLIT
was able to significantly increase the oral provocation
threshold in patients with hazelnut allergy and the same
was shown by Fernandez et al. with peach (84). Pajno
et al. (87) showed that in patients allergic to mites and
with mild-moderate atopic dermatitis SLIT after
9 months significantly reduced the SCORAD score.
Severino et al., in 30 patients with honeybee allergy,
demonstrated that a 6-month course of SLIT with a
maintenance dose of 525 lg venom significantly reduced
the severity of large local reactions to sting challenge
(88).
Unmet needs
Recent large trials with grass extracts have identified the
optimal dose for this allergen: similar studies (dose-
finding, DBPC-RCT) are mandatory for the other rel-
evant allergens, that is, house dust mite (HDM),
Parietaria, ragweed and cat dander, but should take
into account the variability of potency of extracts
among manufacturers (89).
According to press releases and one abstract (90), some
US clinical trials failed to reach the primary outcome,
thus, FDA approval is still pending. Possible reasons
for those results, including inappropriate patient selec-
tion and low pollen counts, have been extensively
analysed by a WAO task force (91), who also provided
recommendations for future trials.
Current data on the clinical efficacy of SLIT in asthma
are controversial: it is essential that RCTs with appro-
priate sample sizes are conducted in patients symp-
tomatic for asthma under natural allergen exposure.
Symptom and rescue medication intake scores are a
reasonable outcome measure, but objective parameters
(FEV
1
, PEF) should be included as co-primary end-
points.
Experimental data on mixtures of unrelated allergens
are very scarce, thus properly conducted clinical trials
evaluating this are needed (the safety aspect is of pri-
mary relevance). Since the European Agency for Med-
ications (EMEA) recommends against mixing different
allergens in a single preparation (92), there may be
problems with the feasibility of clinical studies with such
mixtures.
Other relevant questions are the optimal duration of a
SLIT course, the duration of the preseasonal induction
and the efficacy/safety of the no-build up regimens.
Oral allergy symptoms are commonly reported in many
studies and it is not possible to control for this side-
effect. This fact could influence results.
Although positive results on the use of SLIT in latex
allergy, food allergy, atopic dermatitis and Hymenop-
tera venom allergy have been reported, these should be
considered as investigational: further data on efficacy
and safety are needed.
No clinical data are available for nickel-induced sys-
temic reactions (SRs).
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78. Khinchi S, Poulsen LK, Carat F, Andre
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80. Piazza I, Bizzarro N. Humoral response to subcutaneous, oral
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81. Mungan D, Misirligil Z, Gurbuz L. Comparison of the
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85. Bernardini R. Sublingual immunotherapy with a latex extract in
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674–681.
87. Pajno GB, Caminiti L, Vita D, Barberio G, Salzano G, Lom-
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2009 World Allergy Organization 31
Sub-lingual immunotherapy
Chapter 5: Safety of sublingual
immunotherapy
SLIT appears to be better tolerated than SCIT.
SLIT should only be prescribed by allergy-trained
physicians.
Specific instructions should be provided to patients
regarding the management of adverse reactions,
unplanned interruptions in treatment and situations
when SLIT should be withheld.
The majority of SLIT adverse events appears to oc-
cur during the beginning of treatment.
A few cases of SLIT-related anaphylaxis have been
reported but no fatalities.
Risk factors for the occurrence of SLIT severe ad-
verse events have not yet been established.
There is a need for a generally accepted system of
reporting adverse reactions/anaphylaxis.
Classification and frequency of SLIT adverse events
One of the purported advantages of SLIT over SCIT is
greater safety, which may allow for administration of
this treatment outside of the medical setting. In a
comprehensive review of 104 articles on SLIT, there
were 66 studies that provided some information on
safety and tolerance, representing 4378 patients who
received approximately 1 181 000 SLIT doses (1). The
amount of information on the adverse events (AE) in
these studies varied greatly, ranging from general
summary statements, such as Ôno relevant side effects,Õ
to a detailed analysis of the AEs. One consideration
with SLIT is that the majority of doses are administered
outside of the clinic setting with no direct medical
supervision, and the accuracy of the AE reporting is
dependent on the patient and/or familyÕs interpretation
of the event and recall. The vast heterogeneity in
classifying and reporting immunotherapy (SCIT and
SLIT) AEs in the published clinical trials makes
comparisons and analysis of safety difficult. Recognizing
the need for a more uniform classification of immuno-
therapy AEs, a Joint Task Force (representing members
of the American College of Allergy and Clinical
Immunology [ACAAI], American Academy of Allergy
and Clinical Immunology [AAAAI], EAACI, and WAO
immunotherapy committees) was formed with the
purpose of developing a uniform classification system
for anaphylaxis. This grading system is referred to as
the World Allergy Organization Subcutaneous Immu-
notherapy Systemic Reaction Grading System, and a
paper is in press in the Journal of Allergy and Clinical
Immunology.
Only ten studies in this review classified the severity of the
AE according to varying criteria. Three studies classified the
reactions according to the recommendations of EAACI,
which have subsequently been modified and were originally
intended as a classification system for SCIT reactions (2).
Oral-mucosal reactions, considered a SLIT local reaction,
were relatively common, affecting up to 75% of patients,
and seen most frequently in the build-up phase. In the
studies that specified the type of reaction, 169 of 314 959
(0.056% of doses administered) were classified as systemic
reactions (SR). There were 244 moderate AEs requiring
dose adjustment or causing withdrawal from the study in
2939 patients treated for 4586 treatment years with 810 693
doses of SLIT (50 studies). The majority of these reactions
were gastrointestinal symptoms, rhinoconjunctivitis, urti-
caria or some combination of these symptoms.
In the 38 placebo-controlled studies, there were approx-
imately 282 894 SLIT doses administered to 1688 patients,
which resulted in 353 (21%) patients reporting 823 AEs
(2.9 per 1000 doses) and 226 261 placebo doses adminis-
tered to 1302 patients, resulting in 152 (11.7%) patients
reporting 207 AEs (0.9 per 1000 doses). AEs accounted for
withdrawal in 3% of the SLIT patients compared with
1.4% of the placebo-treated patients. To provide some
perspective, in one review of 38 SCIT studies, the systemic
reaction rate with non-accelerated schedules (single dose
increase per visit) ranged between 0.05–3.2% of injections
and 0.8–46.7% of patients (mean, 12.92%) (3).
SLIT serious adverse events
In the SLIT comprehensive review, there were no fatalities
or events described as anaphylaxis, although there were 14
probable SLIT-related serious adverse events (SAE) in 3984
patients treated with a total of 1 019 826 doses in 58 studies.
This represents 1.4 SAEs per 100 000 SLIT doses and one
SLIT-related SAE per 384 treatment years or 285 patients.
The most common SLIT-related SAEs were asthmatic
reactions (7), one of which required hospitalization: the
others were abdominal pain/vomiting (3), uvula oedema
(1), and urticaria lasting 48 hours. Subsequent to this
review, there have been four case reports of SLIT-associ-
ated anaphylaxis:
One occurred on the third day of build-up with a multi-
allergen SLIT extract in a 31-year-old woman with
allergic rhinitis and asthma (4).
One occurred in a 11-year-old girl with allergic rhinitis
and asthma shortly after administration of mixed pollen
SLIT at the height of pollen season, 1 month after
beginning maintenance (5).
One occurred on the fourth day of a latex rush protocol
(6).
32 2009 World Allergy Organization
G. Walter Canonica
One occurred after a 3-week gap in maintenance treat-
ment after taking a dose six times higher than pre-
scribed HDM SLIT (60 drops of 100 IR instead of 10
drops) in a 16-year-old girl with allergic rhinitis and
asthma. She had two previous episodes of wheezing
related to SLIT within the first 3 months of mainte-
nance. This reaction resulted in loss of consciousness
and admission to the intensive care unit (7).
Two cases of anaphylaxis occurring with the first dose
of a sublingual grass tablet have recently been reported
(8). Both of these individuals had previously discon-
tinued grass-pollen SCIT because of systemic reactions.
One reaction was urticaria in a 13-year-old boy with
allergic rhinitis, who developed periorbital angioedema
and urticaria within 15 min of administering the grass
tablet. The other case involved a 27-year-old woman
with allergic rhinitis and asthma, who began to experi-
ence asthma symptoms, generalized itching, faintness
and abdominal cramps immediately after the first grass
tablet dose. She was wheezing and hypotensive (blood
pressure 90/50) when she arrived in her general practi-
tionerÕs (GP’s) office, where she was treated with sub-
cutaneous epinephrine.
In comparision, SCIT fatalities, although rare, have
been reported at a rate of one in 2–2.5 million injections
in three surveys of AAAAI members that date from
1945 to 2001 (9–11). The most recent survey also as-
sessed the frequency of SCIT near-fatal reactions, de-
fined as severe respiratory compromise and/or fall in
blood pressure requiring emergency treatment with
epinephrine (12). The incidence of unconfirmed near-
fatal reactions during the period of 1990–2001 was 23
per year or 5.4 events per one million injections.
Risk factors for SLIT adverse events
No clear predictors for SLIT AEs have been identified
although some of the factors in the SLIT anaphylaxis case
reports are recognized as risk factors for SCIT: i.e. height
of season (12), history of previous SRs (13), dose (14) and
accelerated schedules (15). In addition, most of the
patients with SLIT-related SAEs or anaphylaxis had
asthma, which has been identified as a risk factor (16).
Dose and adverse reaction rate
There does not appear to be a consistent correlation
between the adverse reaction rate or severity and the
administered SLIT dose. In an 18-month study of 58
asthmatic children with dust mite allergy treated with
relatively low-dose SLIT (1.2 mg of Der p 1 three times a
week or 15.4 mg of Der p 1 cumulative monthly dose
[CMD]), there were 32 SRs in approximately 6933
administered doses (0.46% per dose) (17). Seventeen of
these reactions were classified as severe and because of
exceeding Ômaximum tolerated doseÕ. In contrast, a
multicentre study of 97 dust-mite allergic children with
mild-to-moderate asthma who received high-dose SLIT
(20 drops of 300 IR/ml = approximately 783 mg CMD
of mixed mites), there were no incidences of serious SLIT-
related AEs or a significant difference in the incidence of
AEs between the SLIT and placebo groups (18). The
CMD dose in this study was about 50 times the dose used
in the study that reported 17 severe dose-related reactions,
and the daily dose appeared to be equal to the amount
taken by the16-year-old, who developed anaphylaxis after
taking six times her usual dose after a 3-week gap in
treatment. However, in some large dose response studies,
a relationship between dose and frequency and severity of
AE has been demonstrated (19, 20).
Induction schedule
Unlike SCIT, which appears to be associated with a
greater incidence of AEs during some accelerated induc-
tion schedules such as rush, there does not appear to be a
relationship between the type of induction schedule and
AEs with SLIT. Rush, ultra-rush and no-induction
schedules appear to be equally well tolerated with SLIT.
In a study of 679 patients with allergic rhinitis, asthma, or
both, who underwent a 20- to 25-minutes ultra-rush SLIT
induction, during which increasing doses of allergen were
administered every 5 minutes, the cumulative allergen
doses achieved after half an hour were in the range of 4.7–
525 lg of major allergens (21). All patients were reported
to have tolerated the treatment well, with 17.96% of
patients reporting mild local symptoms, primarily oral
pruritis. Two patients experienced urticaria 2 and 3 hours
after the ultra-rush induction and one patient had
urticaria and rhinitis 3 hours later.
In two large multi-centre dose response studies of 855
and 628 patients with grass-pollen allergic rhinitis, treated
with grass tablets containing up to 15 lg of Phl p 5 (22) or
41 lg of the group 5 major allergens (20), respectively,
administered with no induction phase, there was only one
serious SLIT-related AE. One patient in the middle-dose
treatment group (5lg Phl p 5) was hospitalized for
observation with Ômild uvula edemaÕ(22): the patient
continued the study without any further complications.
Although the induction phase does not appear to
influence the SLIT AE rate, many studies reported that
the majority of AEs occurred during the induction phase
as compared with the maintenance phase.
SLIT in young children
SCIT is not generally prescribed to young children,
primarily because of safety concerns (23). It has been
2009 World Allergy Organization 33
Sub-lingual immunotherapy
suggested that children under 5 years of age may have
difficulty cooperating in an immunotherapy program,
particularly, in communicating symptoms of systemic
reactions (24). It has also been suggested that injections
can be traumatic to very young children.
Three studies, two observational and one post-mar-
keting survey, specifically designed to assess the safety
of SLIT in young children, included a total of 231
children younger than 5-years-old, who were treated
with various pollen and mite allergens (33 patients
received allergoid) (25–27). AEs were reported in 5–15%
of patients in a total of 68 975 doses with rates of
0.268, 0.0766, and 1.767 AEs per 1000 doses in the
three studies. Most reactions appeared to be mild or
moderate and resolved without treatment. Dose reduc-
tion by changing from a sublingual-swallow to a
sublingual-spit method controlled gastrointestinal reac-
tions in one study (27). One further RCT with HDM
SLIT in 138 children aged 2–5 years with asthma
or rhinitis showed only mild to moderate local AEs
(28).
Multi-allergen SLIT
Two of the case reports of SLIT anaphylaxis involved
multi-allergen SLIT and the vast majority of SLIT studies
employed single allergens. Two studies have investigated
the safety of multi-allergen SLIT in adults and children
(29, 30). There was no significant difference in AEs in a
study of 159 adult patients with allergic rhinitis ± asthma
(age 16–59 years), who were treated with either a single
allergen (n= 76) or multiple allergens (n= 83), with 45
AEs occurring in 42 patients who received 7296 single
allergen doses and 51 AEs reported in 47 patients, who
received 8051 multi-allergen doses (29). Similar results
were found in a study of 355 children (age 3–18 years)
who received either single allergen SLIT (n= 179) or
multi-allergen SLIT (n= 254) with 76 AEs reported in
the single allergen group (42.46% patients, 4.43/1000
doses) and 102 AEs in the multi-allergen group (40.3%
patients, 4.42/1000 doses) (P= NS) (29).
SLIT safety: special considerations
Because this treatment is administered at home without
direct medical supervision, patients should be provided
with specific instructions regarding: how to manage
adverse reactions, unplanned treatment interruptions,
when and what to report to the prescribing physician,
situations when SLIT should be withheld (e.g. oropha-
ryngeal infection, oral abrasion, acute gastroenteritis,
asthma exacerbation, etc.) (2). Careful consideration
should also be given to the ability of the patient and/or
their family to adhere to these instructions and the
treatment regimen.
SLIT safety summary
In general, SLIT appears to be associated with fewer
and less severe AEs than SCIT. Oropharyngeal reac-
tions are the most common AEs but other reactions,
such as asthma, urticaria and abdominal pain have been
reported with SLIT. There have been a few case reports
of anaphylaxis with SLIT, including two reports of
anaphylaxis with the first dose. Risk factors for SLIT
AEs have not been clearly established. Some studies
suggest a greater frequency of AEs during the induction
phase compared to the maintenance phase, but there
does not appear to be a relationship between induction
schedule and SLIT AEs, with ultra-rush and no-induc-
tion schedules reported as being well tolerated in several
studies.
Further studies are needed to identify and characterize
SLIT risk factors and patients who should initially receive
this treatment in a medically supervised setting.
Unmet needs
The safety of SLIT in moderate to severe asthmatics.
The safety of SLIT in patients who have had systemic
reactions with SCIT.
The safety of SLIT with multiple allergens.
Interruptions in treatment: how long between doses is it
safe to administer usual dose?
- This might also include treatments with no induction
phase: once treatment has begun and there is a gap in
treatment, the response to reintroduction is not known.
- Can someone stop e.g. daily grass tablets for a few
weeks then restart and stop periodically as patients
often do in real life?
- If so would it be safe to start mid-season if they are most
symptomatic in season?
Is it safe to administer SLIT with no induction with all
formulations? Or do some require an updosing phase?
Are oropharyngeal infections or lesions (e.g. ulcers, gin-
givitis, paradentosis) risk factors for SLIT systemic
reactions?
Under which clinical situations should an SLIT dose be
withheld (e.g. recent respiratory tract infection, recent
exacerbation of asthma, gastroenteritis)?
The safety of SLIT in pregnant or breast or feeding wo-
men.
The safety of SLIT in patients on beta-blockers.
Are there any risk factors that identify which patients
may experience a systemic reaction with SLIT?
References, Chapter 5
1. Cox LS, Larenas-Linnemann D, Nolte H, Weldon D, Finegold
I, Nelson HS. Sublingual immunotherapy: a comprehensive re-
view. J Allergy Clin Immunol 2006;117:1021–1035.
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2. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR,
Malling HJ, Valovirta E. Standards for practical allergen-spe-
cific immunotherapy. Allergy 2006;61(Suppl. 82):1–20.
3. Stewart GE 2nd, Lockey RF. Systemic reactions from allergen
immunotherapy. J Allergy Clin Immunol 1992;90:567–578.
4. Dunsky EH, Goldstein MF, Dvorin DJ, Belecanech GA. Ana-
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5. Eifan AO, Keles S, Bahceciler NN, Barlan IB. Anaphylaxis to
multiple pollen allergen sublingual immunotherapy. Allergy
2007;62:567–568.
6. Antico A, Pagani M, Crema A. Anaphylaxis by latex sublingual
immunotherapy. Allergy 2006;61:1236–1237.
7. Blazowski L. Anaphylactic shock because of sublingual immu-
notherapy overdose during third year of maintenance dose.
Allergy 2008;63:374.
8. de Groot H, Bijl A. Anaphylactic reaction after the first dose of
sublingual immunotherapy with grass pollen tablet. Allergy
2009;64:963–964.
9. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TA. Survey
of fatalities from skin testing and immunotherapy 1985-1989. J
Allergy Clin Immunol 1993;92:6–15.
10. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatal-
ities from immunotherapy (IT) and skin testing (ST). J Allergy
Clin Immunol, 1987;79:660–677.
11. Bernstein DI, Wanner M, Borish L, Liss GM. Twelve-year
survey of fatal reactions to allergen injections and skin testing:
1990-2001. J Allergy Clin Immunol 2004;113:1129–1136.
12. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal
reactions to allergen immunotherapy injections. J Allergy Clin
Immunol 2006;117:169–175.
13. Moreno C, Cuesta-Herranz J, Fernandez-Tavora L, Alvarez-
Cuesta E. Immunotherapy safety: a prospective multi-centric
monitoring study of biologically standardized therapeutic vac-
cines for allergic diseases. Clin Exp Allergy 2004;34:527–531.
14. Dolz I, Martinez-Cocera C, Bartolome JM, Cimarra M. A
double-blind, placebo-controlled study of immunotherapy with
grass-pollen extract Alutard SQ during a 3-year period with
initial rush immunotherapy. Allergy 1996;51:489–500.
15. Cox L. Advantages and disadvantages of accelerated
immunotherapy schedules. J Allergy Clin Immunol 2008;
122:432–434.
16. Simons FER, Anthony JF, Ignacio JA, Bruce SB, David BKG,
Fred DF et al. Risk assessment in anaphylaxis: current and fu-
ture approaches. J Allergy Clin Immunol 2007;120:S2–S24.
17. Tari MG, Mancino M, Monti G. Efficacy of sublingual immu-
notherapy in patients with rhinitis and asthma due to house dust
mite. A double-blind study. Allergol Immunopathol (Madr)
1990;18:277–284.
18. Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. Efficacy of
sublingual immunotherapy with high-dose mite extracts in
asthma: a multi-center, double-blind, randomized, and placebo-
controlled study in Taiwan. Respir Med 2006;100:1374–1383.
19. Kleine-Tebbe J, Ribel M, Herold DA. Safety of a SQ-standar-
dised grass allergen tablet for sublingual immunotherapy: a
randomized, placebo-controlled trial. Allergy 2006;61:181–184.
20. Larsen TH, Poulsen LK, Melac M, Combebias A, Andre C,
Malling HJ. Safety and tolerability of grass pollen tablets in
sublingual immunotherapy–a phase-1 study. Allergy
2006;61:1173–1176.
21. Rossi RE, Monasterolo G. A pilot study of feasibility of ultra-
rush (20–25 minutes) sublingual-swallow immunotherapy in 679
patients (699 sessions) with allergic rhinitis and/or asthma. Int J
Immunopathol Pharmacol 2005;18:277–285.
22. Durham S, Yang W, Pedersen M, Johansen N, Rak S. Sublin-
gual immunotherapy with once-daily grass allergen tablets: a
randomized controlled trial in seasonal allergic rhinoconjuncti-
vitis. J Allergy Clin Immunol 2006;117:802–809.
23. Bousquet J, Lockey R, Malling HJ, Alvarez-Cuesta E, Can-
onica GW, Chapman MD et al. Allergen immunotherapy:
therapeutic vaccines for allergic diseases. World Health
Organization. American academy of Allergy, Asthma and
Immunology. Ann Allergy Asthma Immunol 1998;81(5
Pt 1):401–405.
24. Joint Task Force on Practice Parameters; American Academy of
Allergy, Asthma and Immunology; American College of Al-
lergy, Asthma and Immunology; Joint Council of Allergy,
Asthma and Immunology. A practice parameter second update.
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25. Agostinis F, Tellarini L, Canonica GW, Falagiani P, Passa-
lacqua G. Safety of sublingual immunotherapy with a
monomeric allergoid in very young children. Allergy
2005;60:133–134.
26. Fiocchi A, Pajno G, La Grutta S, Pezzuto F, Incorvaia C, Sensi
L et al. Safety of sublingual-swallow immunotherapy in children
aged 3 to 7 years. Ann Allergy Asthma Immunol 2005;95:254–
258.
27. Rienzo VD, Minelli M, Musarra A, Sambugaro R, Pecora S,
Canonica WG et al. Post-marketing survey on the safety of sub-
lingual immunotherapy in children below the age of 5 years. Clin
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28. Rodriguez-Santos O. Sublingual immunotherapy for Allergic
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29. Agostinis F, Foglia C, Landi M, Cottini M, Lombardi C,
Canonica GW et al. The safety of sublingual immunotherapy
with one or multiple pollen allergens in children. Allergy
2008;63:1637–1639.
30. Lombardi C, Gargioni S, Cottini M, Canonica GW, Passalac-
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more allergens in adults. Allergy 2008;63:375–376.
Chapter 6: Impact of sublingual
immunotherapy on the natural
history of respiratory allergy
Allergen specific immunotherapy may alter the nat-
ural history of respiratory allergy by preventing the
onset of new skin sensitizations and/or reducing the
risk of asthma onset.
There are two randomised open controlled studies
suggesting that SLIT reduces the risk of asthma
onset in children with rhinitis.
Two open randomised studies show that SLIT
reduces the onset of new allergen sensitizations.
One DBPC-RCT and one nonrandomised prospec-
tive study suggest the persistence of the clinical
effects for 3–5 years after discontinuation.
2009 World Allergy Organization 35
Sub-lingual immunotherapy
Introduction
Respiratory allergy (allergic rhinitis, allergic asthma,
united airways disease) is not a static entity, but may
change in its clinical presentation over time. Apart from
changes in environmental exposure, which can modify the
severity and presentation of the disease, there seems to be
aÔnatural historyÕof the disorder. One of the paradigmatic
examples of this is the so-called Ôatopic marchÕin children
(1). It is also well known, for instance, that allergic rhinitis
is an independent risk factor for developing asthma and
that allergic rhinitis often precedes asthma. It has been
shown that 16% to about 40% of subjects with rhinitis
develop asthma later in life (2–5), that the relative risk of
rhinitis patients developing asthma varies from 2.2 to 5.4
(review in Ref. 6) and that rhinitis independent of atopy is
a good predictor of adult onset asthma (7). Identically,
prospective studies have shown that allergic rhinitis may
precede the development of bronchial hyperresponsive-
ness (BHR) (8, 9). On the other hand, it has been shown
that in children, asthma may precede rhinitis (10).
Another well recognized aspect of the natural history of
respiratory allergy is the trend to develop new skin
sensitization over time (9), and this has been consistently
demonstrated in both adults and children. On one hand,
this development testifies for an evolution of the immune
response to allergens; on the other hand, it has relevant
clinical implications, since the severity of the disease
directly correlates in part with the number and size of
positive skin tests (11, 12).
Interventions that can alter the natural history of
respiratory allergy may reduce the risk of developing
asthma or prevent the onset of new allergen sensitiza-
tions. Presently, none of the currently available medica-
tions, including H1-antihistamines and inhaled steroids,
display such properties (13–16). Conversely, the disease-
modifying effect of subcutaneous immunotherapy (SCIT)
was described more than 40 years ago. In an observa-
tional study, Johnstone (17) observed that a significantly
smaller proportion of children receiving SCIT developed
asthma, versus children treated with medications only,
over a period of 14 years. Subsequently, the Preventive
Allergy Treatment (PAT) (18) study suggested the
preventive effect of SCIT on the development of asthma
in children with rhinitis, and this effect was shown to
persist 7 years after discontinuation (19). In parallel, it
was consistently shown that SCIT was able to reduce the
onset of new sensitizations in both adults and children
(20, 21). The long-lasting persistence of the clinical
effects of SCIT after discontinuation is an additional
indirect confirmation of the effect on the natural history
(22–25).
The disease-modifying effects of SLIT have only been
apparent in the past 10 years because the previous clinical
trials were aimed at demonstrating the clinical efficacy and
the safety of the treatment. Moreover, studies assessing
long-term and preventive effects require several years of
follow-up of the patients. Nonetheless, there are some
interesting and promising data on the preventive effects of
SLIT.
Prevention of asthma
The first study showing that SLIT may prevent the onset
of asthma in children with rhinitis was published in 2004
(26). This randomised, open, controlled study involved
113 children aged 5–14 years suffering from seasonal
rhinitis due to grass pollen at enrolment. Of these
children, 54 were randomly allocated to drug treatment
plus SLIT and 59 to standard symptomatic therapy alone.
After 3 years, 99 children were re-evaluated: development
of asthma was 3.8 times more frequent (95% CI, 1.5–10.0)
in the control subjects. Another randomised, open,
controlled trial (27) involved 216 children (age 5–17 years)
suffering from allergic rhinitis with or without intermittent
asthma. They were randomly allocated 2 : 1 to drugs plus
SLIT or drugs only, and followed for 3 years. Symptoms
and medication scores were recorded yearly during the
period of exposure, whereas the presence of persistent
asthma was assessed at 3 years. There was a significant
reduction of symptom-medication scores only in the SLIT
group throughout the study. One hundred and ninety-six
patients were evaluated at 3 years, and the occurrence of
persistent asthma was 2/130 (1.5%) in the SLIT group and
19/66 (30%) in the control group, with a number to treat
of four. Overall, the rate of prevention of the onset of
asthma in children, as reported in the aforementioned
trials, is quite similar to that described for SCIT in the
Preventive Allergy Treatment (PAT) study.
Concerning bronchial hyperresponsiveness (BHR), Pa-
jno et al. (28) demonstrated in a double-blind placebo-
controlled study of 30 children with Parietaria-induced
asthma, that SLIT was capable of preventing the onset of
bronchial hyperresponsiveness to methacholine during the
Parietaria pollen season. In an open randomised con-
trolled study (29) of 52 birch-monosensitized patients (29
SLIT + 23 controls; followed for five pollen seasons)
with allergic rhinitis and asthma, there was a significant
and progressive increase in the methacholine provocation
dose in the SLIT group (that become near normal at the
fifth pollen season), with no change in the control group.
As for the PAT study, the severity of asthma in the control
groups was never presented.
Prevention of new skin sensitizations
There is no double-blind study with SLIT specifically
designed to study the preventive effect on the development
of new allergen sensitizations. However, some randomised
controlled open trials have suggested this preventive effect
with SLIT. Marogna et al. (30) assessed the onset of new
allergy skin test sensitizations after 3 years in 511 patients,
36 2009 World Allergy Organization
G. Walter Canonica
randomly allocated to SLIT (319 subjects) or drugs alone
(192 subjects). SLIT was given for mites (166), grass (89)
or trees (64). At the end of the study, new sensitizations,
compared with baseline, appeared in 64/170 (38%) of
controls and 16/271 (5.9%) of SLIT patients (P< 0.001).
In the study mentioned earlier, conducted in children (27),
at the third year of follow-up, the rate of onset of new
sensitizations was 4/130 in the SLIT group and 23/66 in
the control group.
Long-lasting effect
Few studies have investigated the long-term effect of SLIT.
Di Rienzo et al. (31), in a prospective controlled open study,
followed 60 children (mean age 8.5 years) with asthma/
rhinitis due to dust mites for 10 years. They were subdivided
into two matched groups with 35 subjects undergoing 4–5-
years of SLIT and 25 subjects receiving only drug therapy.
The patients were evaluated at baseline, at the end of SLIT
and 4–5 years after SLIT discontinuation. In the SLIT
group there was a significant difference compared with
baseline for the presence of asthma (P£0.001), whereas
no difference was observed in the control group. This
difference was also seen 5 years after the SLIT discontin-
uation.
A 15-year follow-up of mite-allergic patients treated
with SLIT for 3, 4 or 5 years has suggested that a 4-year
course represents the best combination of clinical efficacy
and long-term effect (32). Patients who received 4 years of
SLIT had significantly better monthly symptom scores
7 years after discontinuation compared with the groups
that were treated with 1 or 3 years of SLIT and the
untreated control group. Again, a retrospective study on
59 patients allergic to HDM (33) suggested that 4 years of
SLIT achieved a long-lasting effect of 7–8 years, whereas
this effect was lost with shorter courses of treatment.
Tahamiler et al. (34), in a 6-year randomised prospective
trial, evaluated two groups of patients up to 3 years after
SLIT discontinuation. One group of 67 patients received
SLIT for 2 years and placebo in the subsequent year. The
other group (70 patients) received SLIT for 3 years.
Symptoms and specific nasal reactivity improved in both
groups during treatment. The improvement was main-
tained 3 years after stopping SLIT, although the 3-year
group displayed a more pronounced, long-term effect.
Unmet needs
The available experimental data suggest that SLIT can
exert some effects on the natural history of respiratory
allergy, resembling those of SCIT. These studies can be
considered suggestive, but not conclusive, due to the
relatively small number of subjects and the methodo-
logical problems.
In particular, the long-term effect of SLIT after its
discontinuation needs to be confirmed in randomised
controlled trials, possibly double-blinded in the first
years, and involving large numbers of patients (35).
The demonstration of a preventative effect on the onset
of asthma would also require DBPC-RCTs, where
objective respiratory parameters are assessed.
The severity of asthma in patients on placebo needs to
be assessed.
Specific factors that can predict those patients that are
protected against new sensitizations and new develop-
ment of asthma, need to be identified: this issue also
applies to SCIT.
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