Hindawi Publishing Corporation
Journal of Allergy
Volume 2012, Article ID 253879, 6pages
Quality of Life Improvement with Sublingual Immunotherapy:
A Prospective Study of Efﬁcacy
Mary S. Morris,1, 2 Amanda Lowery,2, 3 Demetrios S. Theodoropoulos,1, 4
R. Daniel Duquette,3and David L. Morris1
1Allergy Associates of La Crosse and Mayo Clinic Health System Franciscan Healthcare-La Crosse-Onalaska, WI 54650, USA
2Allergychoices Inc., Onalaska, WI 54650, USA
3College of Science and Health, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA
4Allergy and Asthma Center, Hagerstown, MD 21740, USA
Correspondence should be addressed to Mary S. Morris, email@example.com
Received 29 September 2011; Revised 23 November 2011; Accepted 24 November 2011
Academic Editor: Nazan Cobanoglu
Copyright © 2012 Mary S. Morris et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Due to its excellent safety proﬁle, ease of administration, and economic considerations, sublingual immunotherapy (SLIT) is
becoming a preferred form of allergen speciﬁc immunotherapy. The eﬃcacy of SLIT is still debated. The purpose of this act of
practice trial is to evaluate quality of life outcomes in patients treated with SLIT. Fifty one patients with allergic rhinoconjunctivitis
demonstrated by skin testing completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at initiation, at four
months and at 10–12 months of SLIT. Signiﬁcant improvement (P<0.05) on six of seven domain categories of the RQLQ
questionnaire was noted. Total RQLQ scores also showed signiﬁcant improvement. This study supports SLIT as a modality eﬀective
in controlling allergic symptoms.
Allergen-speciﬁc immunotherapy in the treatment of IgE-
mediated allergy has been used for longer than a century; yet,
its major form, subcutaneous immunotherapy (SCIT) has
not become a widely accepted routine treatment for allergy.
Patients will often suﬀer from severe symptoms and allergic
comorbidities before consulting with an allergist or consid-
ering immunotherapy. Children especially are unlikely to
adhere to SCIT. Subcutaneous injections for immunotherapy
are believed to be tedious and unlikely to lead to sustained
improvement. Standardization, safety, and eﬃcacy concerns,
along with the inconvenience of injections and frequent
oﬃce visits, keep the vast majority of allergic patients from
receiving SCIT. Recruitment to immunotherapy is poor:
less than 5% of all allergic patients receive immunotherapy.
Compliance is even poorer: among adult patients who agree
to undergo SCIT, adherence is disappointing with more than
two thirds dropping out within a year of initiation. One tenth
of SCIT candidates fail to show up for their ﬁrst injection
. In some countries, the scope of SCIT has been curtailed
substantially by administrative decisions . At the same
time, a wealth of evidence in literature and clinical practice
supports the safety, eﬃcacy, feasibility, compliance, and eco-
nomic proﬁle of sublingual immunotherapy (SLIT) [3–7]. In
the United States, however, SLIT remains uncommon and
is only oﬀered by few practices with special interest in this
method. With this study, we sought to evaluate the subjective
symptom responses of patients treated with multiantigen
SLIT. The information provided with the present study may
lead to better appreciation of the potential of SLIT and may
foster the design of large-scale, multicenter studies for its full
2.1. Subject Selection and Testing. Subjects were recruited
from patients of Allergy Associates of La Crosse, a single spe-
cialty practice that has been oﬀering SLIT for 41 years. The
study was approved by the Mayo Clinic Health System Fran-
ciscan Healthcare-La Crosse, Institutional Review Board. All
2Journal of Allergy
Allergy-related comorbidities among
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Figure 1: Of the 51 study participants, most had one or more comorbid allergic conditions with the average number of 1.9 chronic conditions
subjects were diagnosed with allergic rhinoconjunctivitis on
the basis of their history and positive skin test results. Skin
test positivity was assessed by obtaining a response greater
than the negative control and greater than two thirds of the
histamine control using intradermal dilution testing (IDT)
. Antigens selected for testing were determined by a self-
administered patient history questionnaire and initial con-
sultation with their physician. Patients with dermographism
or systemic mastocytosis were not included. Figure 1 also
shows that the patient population was aﬀected by one or
more comorbid allergic condition upon arrival for their ﬁrst
appointment. Skin test panels included 15–30 antigens rep-
resenting dust mite, weed, tree, grass, and fungal allergens
typical of the northern Midwest (see Ta b le 1 ). The number
of allergen extracts varied by patient, as the number of
oﬀending allergens ranged from six to 24 with the mean
of 15.15. Round one patient enrollment occurred from July
through December and round three visits occurred from
January through November, thus crossing multiple peak
pollen seasons and limiting the inﬂuence of allergen season
2.2. Sublingual Immunotherapy Administration. Sublingual
immunotherapy based on skin test reactivity was initiated
according to the La Crosse Method Practice Protocol .
A capital aspect of SLIT, at least as practiced in the United
States, is the adjustment of the treating dose to skin reactiv-
ity. For this purpose, allergen extracts are serially diluted
by decrements of ×5. The purpose of such dilution is to
adjust dose to skin reactivity under the premise that adverse
reactions (including local reactions) deﬁne a level of toler-
ance. For many patients, skin test reactivity does not nec-
essarily reﬂect the degree of sensitization. A negative skin
test, however, and minimal/absent late-phase responses do
establish a de facto threshold of tolerance.
Dosing for each patient was tied to skin test results for
each individual antigen and adjusted over the course of
treatment (see Figure 2). With ongoing treatment, the need
to regularly adjust the degree of testing (and dosing) to the
long-term eﬀects of immunotherapy is dictated by the fact
that, over time, skin test reactivity tends to decline with
immunotherapy. Thus, initiation of SLIT at a strength
Tab le 1: Sensitivities detected by skin testing. Grass mix includes
Kentucky Blue/June, Meadow Fescue, Orchard, Perennial Rye,
Redtop, Sweet Vernal, and Timothy. Tree mix includes American
Beech, American/Eastern Sycamore, American Elm, Black Walnut,
Black Willow, Eastern Cottonwood, Red Oak, Red/River Birch,
Shagbark Hickory, Sugar/Hard Maple, and White Ash. Weed mix
includes Cocklebur, Lamb’s Quarter, Common Mugwort, Pigweed
(rough/red), and Dock/Sorrel Mix (red/sheep and yellow dock).
Allergy Associates common environmental allergens and the per-
centage of participants testing positive to the following.
Dust mites 51 (100%)
Ragweed 51 (100%)
Grass mix 48 (94%)
Birch 42 (82%)
Tree mix 50 (98%)
Oak 37 (73%)
Weed mix 42 (82%)
Alternaria 50 (98%)
Cladosporium 49 (96%)
corresponding to the highest dilution that produced a near-
negative skin test establishes a safe threshold of tolerance;
thereafter, upward titration of immunotherapy doses against
declining skin reactivity is used for safe build-up and
unnecessary local or systemic reactions.
A skin test of greater than 7 mm using dilution number 7
correlates with the highest level of reactivity. Thus, the lowest
dose administered of the oﬀending allergen is dilution num-
ber 7. As skin test reactivity improves, doses are escalated
to the next allergen dilution until the patient has reached
dilution number 1 for his/her diﬀerent allergens. The starting
dose of each individual antigen is titrated based on skin test
(or in vitro speciﬁc IgE testing) level of reactivity, (see Tables
2and 3). Sublingual immunotherapy with multiantigen
treatment addresses multiple allergies that are speciﬁc to each
individual patient. Each bottle consisted of a 90-day supply
that was individually prepared for the patient using Greer
Laboratory and ALK-Abello extracts and compounded in the
Allergy Associates of La Crosse clinical laboratory.
Journal of Allergy 3
Mean dosing levels for common
Dosing visit 1
Dosing visit 2
Dosing visit 3
over the course of treatment based on skin test reactivity. Dosing
levels are carefully adjusted in an eﬀort to balance therapeutic
beneﬁt without creating unnecessary patient side eﬀects.
Over a 1000-fold range of antigen dilutions have been
reported to produce clinical improvement with SLIT sug-
gesting that a straight dose-eﬀect does not exist . Other
variables such as dosing frequency, extract quality, and
length of treatment also need to be considered. Numerous
studies have observed and suggested a limited capacity of
the sublingual mucosa and have shown clinical improvement
with lower, but more frequent doses [11–13]. Patients were
advised to take their sublingual immunotherapy drops three
times daily. Given that SLIT is retained in the sublingua for
up to 48 hours, administering two to three doses per day
is reasonably expected to secure unbroken allergen-exposure
and overlap generously with antigen uptake by the dendritic
cells and migration to lymphoid organs.
2.3. Questionnaire Administration. Symptom severity was
evaluated by the Rhinoconjunctivitis Quality of Life Ques-
tionnaire (RQLQ). This disease-speciﬁc validated question-
naire was developed by Professor Elizabeth Juniper and
has been used extensively throughout the world in a large
number of clinical trials . New clinic patients were asked
to complete the RQLQ at their ﬁrst visit before the onset of
sublingual immunotherapy treatment and two subsequent
follow-up visits at three- to six-month intervals. The full-
version RQLQ encompasses 28 questions in seven domains
(activity limitations, sleep problems, non-nose/eye symp-
toms, practical problems, nose symptoms, eye symptoms,
and emotional function). Patients were asked to recall their
experiences during the previous seven day period and to give
their responses on a 0- to 6-point scale (none of the time
to all of the time). A total RQLQ score is also calculated by
adding the scores of the individual domains together.
This study was a prospective analysis that compiled and
compared collected RQLQ data from patients undergoing
sublingual immunotherapy. Collected data for each patient
were compared to that particular patient’s baseline data and
Figure 3: Participants’ aggregate RQLQ scores were compared
from their initial appointment and follow-up visits one and
two. Statistical signiﬁcance was achieved within four months of
beginning sublingual immunotherapy and continued through their
second return visit (Round 3). P<0.05. Standard error for Round
1=7.74, Round 2 =6.35, and Round 3 =7.61.
two subsequent patient visits for changes in each RQLQ
parameter as well as total RQLQ score. Timing of follow-
up for visit two ranged from 1.23 months to 10.94 months,
with a mean follow-up time of 4.1 months. Follow-up for
visit three ranged from 2.82 months to 17.94 months with a
mean follow-up time of 7.06 months. The average duration
of treatment during the study was 11.19 months.
2.4. Statistical Analysis. Descriptive and bivariate statistics
were performed using the Standard SPSS data package.
Statistical signiﬁcance was designated as P<0.05.
3.1. Patient Characteristics. Paired RQLQ data were available
for 51 patients who were skin tested and started on SLIT.
Participants were comprised of 13 males and 38 females, with
ages ranging from 22 to 63, and a mean age at initiation of
SLIT of 45.8 years.
3.2. Quality of Life Results. Paired RQLQ results revealed
statistically signiﬁcant (P<0.05) improvement in six of
seven domains evaluated by the RQLQ after four months of
treatment. Improvements were seen in the activities, non-
nose/eye symptoms, practical problems, nasal symptoms, eye
symptoms, and emotional categories. Results are presented
in Tab l e 4 . Statistically signiﬁcant improvements were noted
in 23 of the 28 overall questions. Furthermore, the total
RQLQ for the whole cohort declined signiﬁcantly (P<
0.5) from 126.02 to 74.96 within the ﬁrst four months of
treatment (see Figure 3).
Although just shy of achieving statistical signiﬁcance,
participants that adhered to three times daily dosing of
sublingual immunotherapy showed better improvement in
RQLQ scores than participants who were suboptimally
compliant. Advised compliance to treatment declined from
round two to three, which may have aﬀected round two
to round three overall RQLQ scores (see Figure 4). Further
studies with larger study populations are needed to validate
4Journal of Allergy
Tab le 2: Serial dilutions are then used to expand La Crosse Method doses from one to seven.
Antigen La Crosse method concentrate Concentration number 1 dilution
Pollens 1 mL 1 : 20 w/v 1 : 100 w/v
Mold 1 : 20 w/v 1 : 100 w/v
Mite mix 1 mL conc + 2mL diluents for 10,000 AU/mL 2000 AU/mL
Cat 1mL + 4 mL diluents for 2000 BAU/mL 400 BAU/mL
Epithelias (except cat) 1 : 20 w/v 1 : 100 w/v
Grass mix 100,000 BAU/mL 20,000 BAU/mL
Bermuda grass 10,000 BAU/mL 4000 AU/mL
Short ragweed 100,000 AU/mL 20,000 AU/mL
Tab le 3: How 1 : 5 serial dilutions are made: from La Crosse Method
number 1 dilution.
1 mL of dilution number 1 + 4 mL of diluent =dilution number 2
1 mL of dilution number 2 + 4 mL of diluent =dilution number 3
1 mL of dilution number 3 + 4 mL of diluent =dilution number 4
1 mL of dilution number 4 + 4 mL of diluent =dilution number 5
1 mL of dilution number 5 + 4 mL of diluent =dilution number 6
1 mL of dilution number 6 + 4 mL of diluent =dilution number 7
treatment compliance and multiple versus single daily dos-
A number of studies have demonstrated statistically sig-
niﬁcant eﬀects on allergic rhinoconjunctivitis and asthma
symptoms in SLIT [15–20]. These studies, however, were all
heterogeneous and of small magnitude. More importantly
since no two studies used the same protocol, the value of their
meta-analysis is questionable. They all used single-allergen
monotherapy to evaluate eﬃcacy, an approach which does
not reﬂect the sensitization status of patients with allergic
rhinoconjunctivitis, and may in fact have led to undertreat-
ment and subsequent under-appreciation of the eﬃcacy of
SLIT. The number of SLIT (or even SCIT) eﬃcacy studies
employing multiple allergens in the treatment regimen is
so surprisingly small that their low number and insuﬃcient
data on eﬃcacy have been addressed unfavorably . These
studies were characterized by their sporadic nature. They
were not followed by subsequent studies that would have
established a continuity of approach which might have made
up, to some extent, for methodological defects. Signiﬁcantly,
the ultimate end-point, which is improvement of symptoms,
was not assessed by a validated instrument, developed by an
independent party, such as the RQLQ . To our knowledge,
a modiﬁed, shortened version of the RQLQ, the mini-RQLQ,
has been used in one study employing SLIT for multiple
allergens but this study relied on retrospective selection of
subjects and only enrolled ﬁfteen patients, thus raising
signiﬁcant questions as to both its power and freedom of
bias . Our study is the ﬁrst prospective study of SLIT
eﬃcacy, employing multiple allergen extracts for treatment,
a protocol for SLIT which has been applied for 41 years,
Figure 4: Patients were advised by their providers to take sublingual
immunotherapy drops three times daily. Patient records showed
a greater adherence to three times daily dosing from their initial
appointment to second visit than from their second appointment
a validated questionnaire, and a number of subjects large
enough to satisfy power requirements.
In the present study, SLIT, as formulated by the La Crosse
Method Protocol, is eﬀective in reducing symptoms and
improving quality of life after four months of treatment (see
Tab l e 4 ). This improvement was most prominent in activity,
non-nose/eye symptoms, nasal symptoms, and emotional
domains. Improvement in the sleep domain of the RQLQ
was also observed, but did not reach statistical signiﬁcance.
This improvement was sustained and demonstrated again
at 10–12 months of treatment. Given the high compliance
rates with the La Crosse Method SLIT, it is expected that the
improvement achieved is likely to be sustained and possibly
expanded with ongoing treatment beyond the ﬁrst year.
Sneezing and irritability, two parameters, which in a previous
SLIT eﬃcacy study employing the mini-RQLQ were found
unaﬀected, are demonstrated to decline in the course of the
ﬁrst four months of SLIT .
The mechanism underlying SLIT has been reviewed .
Although not fully delineated, it appears that a systemic
alteration of the Th1/Th2 balance is eﬀected in SLIT by
the promotion of tolerogenic T-cell clones. Interaction of
dendritic cells with na¨
ıve T-cells is necessary for this change
to occur. Production of TGF-β, IL-10, and possibly other
regulatory cytokines appears to be critical. Ongoing changes
may in some cases be reﬂected in skin reactivity as well as
Journal of Allergy 5
Tab le 4: Mean RQLQ Scores Presublingual Immunotherapy and at Subsequent Visits.
Category sum Round 1 Round 2 Round 3
Mean (SE) Mean (SE) Mean (SE)
Activity sum 8.14 (.57) 4.92∗(.44) 4.63∗(.52)
Sleep sum 5.84 (.68) 3.61 (.45) 3.92 (.63)
Non-nose/eye sum 17 (1.37) 10.59∗(1.04) 10.71∗(1.22)
Practice problem sum 8.43 (.65) 4.63∗(.50) 5.06∗(.54)
Nasal symptom sum 11.69 (.74) 7.25∗(.60) 7.63∗(.64)
Eye symptom sum 8.92 (.82) 5.49∗(.67) 6.16∗(.67)
Emotional sum 10.55 (.87) 4.27∗(.59) 4.82∗(.67)
∗Denotes RQLQ domains found to have a statistically signiﬁcant decrease in symptom scores throughout the duration of sublingual immunotherapy
in speciﬁc IgG and IgE production changes. The protocol
used in the present study may be well suited to eﬀect these
changes. It can be summarized in three cardinal points:
(i) initial and thereafter regular titration of treating SLIT
doses against skin reactivity and symptom response with
skin reactivity meant as a biphasic response whose late
phase reactions are also taken into account; (ii) frequent
administration of SLIT doses to secure continuous, maximal,
and uninterrupted saturation of the sublingual dendritic
cells’ potential for phagocytosis and migration, that is, three
doses per 24 hours; and (iii) maintenance of allergens in high
glycerin solutions in order to prevent decay and suppress
proteolytic activity .
In summary, this study represented a preliminary
attempt to investigate the eﬀectiveness of multiantigen SLIT
in a complex patient base. Experience with this protocol over
the years has been rewarding and has shown clinical beneﬁt
with a wide variety of allergic conditions including advanced
respiratory disease in adults with mold allergy , asthma
prevention in pediatric patients , and contact allergies
including nickel  and poison ivy  while maintaining
a remarkable paucity of adverse reactions of any signiﬁcance.
The present study underscores the eﬃcacy of SLIT; however,
we recognize that the absence of a placebo group limits the
interpretation of results. Given the large number of patients
currently treated and high rates of compliance, multicenter,
controlled studies are needed of greater magnitude and
expanded scope to include morbidities and associations such
as recurrent/chronic sinusitis, atopic dermatitis, gastroe-
sophageal reﬂux, and migraines. Sustained suppression of
symptoms after eventual completion of SLIT will also need
to be studied.
Statistically signiﬁcant reduction of symptoms and improve-
ment of quality of life are demonstrated during the initial
four month period of SLIT. After the ﬁrst four months,
reduction of symptom scores is sustained and continuous.
These data support the eﬃcacy of SLIT and need to be
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