Expert Review of Clinical Immunology

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20

Pharmacoeconomics of allergy immunotherapy

versus pharmacotherapy

Linda Cox

To cite this article: Linda Cox (2021) Pharmacoeconomics of allergy immunotherapy

versus pharmacotherapy, Expert Review of Clinical Immunology, 17:3, 255-268, DOI:
10.1080/1744666X.2021.1886079

To link to this article: https://doi.org/10.1080/1744666X.2021.1886079

Published online: 28 Feb 2021.

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EXPERT REVIEW OF CLINICAL IMMUNOLOGY
2021, VOL. 17, NO. 3, 255–267
https://doi.org/10.1080/1744666X.2021.1886079

REVIEW

Pharmacoeconomics of allergy immunotherapy versus pharmacotherapy

Linda Cox
Department of Medicine, Associate Professor of Medicine Nova Southeastern University, Ft. Lauderdale, Florida, USA

ABSTRACT ARTICLE HISTORY

Introduction: The purpose of this review is to evaluate the cost-effectiveness of allergy immunotherapy Received 26 June 2020
(AIT) in the treatment of allergic rhinitis, asthma, and other allergic conditions. Accepted 2 February 2021
Area covered: An extensive search of the PubMed and Medline database (January 1996 up to June of KEYWORDS
2020) was conducted using the search terms allergy immunotherapy, pharmacoeconomics, cost-effec­ Allergen immunotherapy;
tiveness, allergic rhinitis, and asthma. Studies were included if they included information on the asthma; allergic rhinitis;
economics of AIT in comparison to pharmacotherapy in the treatment of allergic rhinitis or asthma subcutaneous
either as actual costs or based on theoretical models. Systematic reviews were included if they included immunotherapy; sublingual
information about the cost-effectiveness of AIT. immunotherapy; food
Most clinical trials found significant cost-savings with AIT. The cost-effective time-point ranged from allergy; pharmacoeconomic
a few months to several years after treatment initiation.. Cost savings were demonstrated as early as 3
months after treatment initiation and were as great as 80% less than SDT in some studies.
Expert opinion: There is strong evidence in the collective literature that AIT is cost-effective as
compared to SDT alone. The magnitude of AIT’s cost-effectiveness is likely underestimated because
most of the studies considered during treatment costs and not AIT’s long-term benefits or preventive/
prophylactic effects or its impact on co-morbid conditions.

1. Introduction
Allergic conditions represent some of the most common, chronic
diseases worldwide. According to the World Allergy
Organization’s estimate, allergy prevalence ranges between
10% and 40% of the population [1]. Globally, the prevalence of
allergic diseases has been increasing, particularly in industrialized
nations. It is estimated that by 2025, more than half of the
European population will suffer from chronic allergic diseases
[2]. According to the United States (US) Center for Disease
Control (CDC), the incidence of asthma in the US increased by
28% from 2001 to 2011 [3]. There have been similar increases in
other allergic conditions. The incidence of atopic dermatitis has
increased 2- to 3-fold in industrialized nations since the 1970s [4].
The incidence of allergic rhinitis has increased by ~5-10% in
industrialized and developing nations [5,6].
There are three components of allergic disease manage­
ment: allergen avoidance measures, pharmacotherapy, and
allergy immunotherapy. Allergen avoidance measures directed
at reducing or eliminating exposure to the causative allergen­
(s) would be the optimal management approach. This would
remove the disease’s primary trigger and other interventions
may not be necessary. However, complete avoidance is rarely
achievable because common indoor allergens are fairly ubi­
quitous and will be encountered in other indoor environments
[7]. Additionally, there are limited data indicating any single
environmental control measure, e.g. house dust mite
impermeable bedding covers, cat removal, and so on, resulted
in improved outcomes [8,9]. Avoidance of outdoor allergens
can result in a restricted lifestyle. Allergen avoidance can also
be challenging for food allergic individuals. One prospective
study of 1941 children with physician-confirmed peanut
allergy found that the annual incidence of accidental peanut
exposure was 12.4% [10]. The majority of accidental exposures
(37%) occurred in the home environment. Even if an allergic
individual was able to completely avoid all relevant allergens ,
there are nonspecific triggers, such as viral respiratory tract
infections, cold air, and irritant odors that can evoke asthma or
rhinitis symptoms.
Pharmacotherapy is directed at controlling symptoms and
preventing exacerbations. It includes conventional medica­
tions such as nasal/inhaled corticosteroids, oral antihistamines,
and biologics targeting specific components of the immune
system. The medication regimen is generally determined by
the patient’s disease severity, but other determinants include
patient preference, ability to adhere to a particular regimen,
and medication side-effects. Generally, patients with moderate
to severe and or persistent symptoms are prescribed daily
controller medications, e.g. nasal or inhaled corticosteroid
with as-needed rescue medications, e.g., beta-agonists, and
antihistamines. More severe patients with frequent exacerba­
tions may be prescribed a biological agent, such as omalizu­
mab or dupilumab. Pharmacotherapy only controls symptoms
during use but provides no sustained benefits after disconti­
nuation. Additionally, pharmacotherapy may only partially
control symptoms. The three most common allergic diseases,
asthma, allergic rhinitis, and topic dermatitis, are often present

CONTACT Linda Cox lindaswolfcox@msn.com Associate Professor of Medicine Nova Southeastern University, 1108 S.Wolcott St Casper, Ft. Lauderdale
Wyoming.
© 2021 Informa UK Limited, trading as Taylor & Francis Group
256 L. COX
Article highlights
● Allergic asthma and allergic rhinitis carry considerable direct and
indirect costs. Both conditions are associated with several comorbid
illnesses that can compound these costs. Both conditions can require
years of symptomatic treatment. All of these factors need to be
considered when considering treatment cost-effectiveness.
● In contrast to pharmacotherapy, AIT can provide long-term clinical
benefits after discontinuation. The sustained benefits of AIT can
translate into cost-savings- as high as 80%as compared to SDT in
one study.
● Two systematic reviews of evaluating the economics of AIT con­
cluded that SLIT and SCIT were cost-effective compared with SDT
with no strong evidence favoring.
● The cost-effective time point was determined to be about 6 years
after AIT initiation in one systematic review but to as early as 3
months in large retrospective claims analyses studies.
during childhood and continue to be symptomatic through­
out adulthood if they are not adequately managed. Concerns
about side effects and costs of long-term pharmacotherapy
may prompt consideration of allergy immunotherapy (AIT),
which is the only intervention with a proven disease-
modifying effect.
AIT involves the administration of the causative allergen­
(s) on a regular basis over a period of several years. AIT-
associated immunological changes may result in long-term
allergen-specific tolerance that can persist for years after
therapy discontinuation [11,12]. The persistent clinical effi­
cacy can translate into significant cost savings related to
reduced medications and other medical costs [13–15].
There are currently two Federal Drug Administration (FDA)-
approved AIT formulations commercially available in the US:
subcutaneous immunotherapy (SCIT) and sublingual immu­
notherapy (SLIT). Each route has its advantages and disad­
vantages. Although SCIT is a well-established effective
treatment for seasonal and perennial allergic diseases,25,35
−37
its disadvantages include the requirement that it must be
administered under direct medical supervision in a facility
with appropriate emergency equipment and personnel able
to recognize and manage serious allergic reactions, e.g.
anaphylaxis. SLIT has emerged as an alternative form of
AIT, which provides the advantage of home administration
due to its superior safety compared with SCIT .
The purpose of this paper is to review the pharmacoeco­
nomics of AIT as compared to standard drug treatment (SDT)
for the treatment of AR, asthma, and food allergy. To conduct
this review, a search of the PubMed and Medline database
(up to June 2020) was performed using the search terms
pharmacoeconomics, cost-effectiveness, allergic rhinitis, and
asthma. Studies were included if they provided economic
data related to AIT as compared to an SDT control group
for the treatment of allergic rhinitis or asthma, either in terms
of actual costs (e.g., claims-based analysis) or based on
a modeled-based economic evaluation (EE). Systematic
reviews were included if they were designed to evaluate
the cost-effectiveness of AIT. All of the studies in the sys­
tematic reviews were separately evaluated (see Table 1 for
a summary of the clinical trials reviewed).
As there are no studies because comparing SDT and AIT in
the treatment of atopic dermatitis this topic will not be
reviewed.
2. Allergic rhinitis
Allergic rhinitis is the most common chronic allergic condition
affecting 10% to 30% of adults and up to 40% of the pediatric
population [1].Global estimates suggest that AR affects
approximately 500 million people with a higher prevalence
in developed countries. According to the Medical Expenditure
Panel Survey, a longitudinal survey on healthcare utilization
and expenditures in the US, 17.8 ± 0.72 million adult patients
reported AR in 2017 [18]. According to the International Study
of Asthma and Allergies in Childhood (ISAAC) study, which
surveyed 1,200,000 children in 98 countries, the reported
incidence of allergic rhinoconjunctivitis (ARC) was 14.6% in
the 13- to 14-year age group and 8.5% in the 6- to 7-year
age group [19] Studies comparing patient questionnaire sur­
veys with physician-confirmed AR diagnosis suggest AR is
often underdiagnosed and undertreated [20–23]. A random-
sample web-based survey of 26,468 adults found that one in
five patients reporting AR symptoms had never been diag­
nosed with AR [24]. One study examined the diagnosis and
treatment of asthma and allergic rhinitis based on standar­
dized questionnaires, skin prick tests, and pulmonary function
tests found that 50% of asthmatics and 32% of rhinitis patients
were not previously diagnosed with these conditions [23]. In
patients diagnosed with moderate to severe rhinitis patients,
83% were undertreated according to guideline recommenda­
tions [23]. In a survey of 2966 adults with allergies, 30.2% of
the respondents preferred nonprescription medication
because it did not require a medical visit and 40.2% cited
medication costs as the reason they do not use an allergy
medication [21].
Consequences of poorly controlled AR can include impair­
ment in health-related quality of life, reduced work productiv­
ity, sleep impairment, and several comorbid conditions, such
as recurrent otitis media and sinusitis [25–33]. AR is also
considered a risk factor for developing asthma. One longitu­
dinal study found that children with AR had a 2- to 7-fold
increased risk of incident asthma in preadolescence, adoles­
cence, or adult life [34]. Several studies have demonstrated
that AIT can prevent the development of asthma in AR
patients [35,36].
In terms of healthcare utilization and costs, AR accounts for
2.5% of all clinic visits, 2 million lost school days, 6 million lost
workdays, and 28 million restricted workdays per year [37].
Annual prescriptions for AR patients are nearly double that for
patients without allergic rhinitis (19 versus 10) [37]. AR direct
costs include prescription and over-the-counter (OTC) medica­
tions, inpatient, and outpatient medical services. AR indirect
costs include lost work/school time, lost wages, reduced pro­
ductivity due to ‘presenteeism’ and fatigue-related injuries
[13,25,38–40].
According to the 2005 Medical Expenditure Panel Survey,
a longitudinal survey on healthcare utilization and expendi­
tures in the US, medical expenditures for allergic rhinitis
almost doubled from 6.1 USD billion in 2000 (in 2005 dollars)
Table 1. Studies comparing allergy immunotherapy with standard drug treatment.
STUDIES COMPARING SCIT WITH SDT

SYSTEMATIC
REVIEWS ALLERGIC TYPE/COSTS COST
STUDY THAT INCLUDED CONDITION ALLERGEN//DURATION CONSIDERED PERSPECTIVE RESULTS

Ariano Meadows SAR with Parietaria SCIT for 3 years plus SDT as needed; SDT CCA Societal, SCIT < SDT; 80% cost reduction found 3 years after stopping SCIT. Net savings at six
2006 [52] Asaria allergic Direct costs NHS, years was €623 per year
Hankin asthma patient
Bruggenjurgen Meadows AR ± asthma SCIT for 3 years plus SDT as needed; SDT CUA Societal, 3rd Break-even point = 10 years. ICER = €8308 per QALY
2008 [16] Asaria Direct and party
Hankin indirect payer
costs
Creticos Hankin Asthma Ragweed SCIT vs placebo for 2 years CCA HCS Higher costs with SCIT 1367 USD vs SDT 1194 USD
1996 [74] Direct costs SCIT associated with reduced medication use in the first year which was not
counterbalanced by SCIT costs
Hankin Hankin New-onset Costs 6 months before and 6 months after SCIT CCA HCS Weighted mean 6-month savings/patient: 401 USD
2008 [75] AR Direct costs
Hankin Hankin New-onset SCIT for 18 months plus SDT as needed; SDT as needed for CCA HCS SCIT 18-month total healthcare costs 33% reduction compared with SDT
2010 [76] AR 18 months Direct costs
Hankin Hankin New-onset SCIT plus SDT as needed for 18 months; SDT as needed for CCA HCS SCIT 18-month total healthcare costs compared with SDT: Children: 42% reduction
2013 [85] AR 18 months Direct costs Adults: 30% reduction
Keiding Meadows SAR Grass SCIT for 3 years plus SDT as needed; SDT CEA HCS SCIT cost-effectiveness; range €10,000–25,000 per QALY
2007 [54] Asaria CUA
Hankin Direct and
indirect
costs
Omnes Meadows HDM-PAR HDM or pollen SCIT 3 − 4 years plus SDT as needed: SDT CEA Cost-effective per incremental cost of asthma cases avoided (ICER)
2007 [62] Asaria and SAR Direct and
Hankin indirect
costs
Petersen Meadows Grass or HDM SCIT for 3–5 years plus SDT as needed; SDT CEA Direct cost: SCIT >SDT
2005 [55] Asario Direct and Indirect costs: of sick days included in the economic evaluation, SCIT costs < SDT
Hankin indirect
costs
Schadlich [56] Meadows SAR or PAR Pollen or HDM SCIT for 3 years plus SDT as needed; SDT CEA SCIT< SDT over ten years. Break-even point reached in between 6 to 8 years per all
2000 Asaria ± asthma Direct and perspectives.
Hankins indirect
costs
Studies comparing SLIT with SDT
Ariano Asaria HDM- SLIT drops for 3 years vs SDT CEA HCS Healthcare costs greater for SLIT in the first 2 years, the same in the 3rs year and less
2009 [15] Hankin induced Direct costs in years 4 and 5. 5th-year annual costs: SLIT€2672 vs €2020 = 22% reduction
asthma
Bachert Meadows SAR Grass SLIT tablet (Grazax ) for 3 years plus SDT as needed; CUA
® Societal SLIT cost-effective cost per QALY; average 0.0287 QALYs per season compared with
2007 [48] Hankins SDT Direct and SDT
indirect cost
Berto Meadows SAR or PAR Compare 1 year of SDT before SLIT drops with costs during CEA Societal Reduced exacerbations, lost work/school, and medical visits
2005 [57] Asaria ± asthma SLIT for 3 years Direct and Cost-savings with SLIT:
Hankins indirect
● Pre-SLIT €2672,
costs
● During SLIT €629
Berto Meadows SAR ± Pollen SLIT drops for 3 years plus SDT as needed; SDT CCA Societal, SLIT compared to SDT:
EXPERT REVIEW OF CLINICAL IMMUNOLOGY

● Greater 6-year mean savings from the payer and societal perspective.
2006 [52] Hankins asthma Direct and HCS
indirect
costs More asthma cases avoided and patients improved
(Continued )
257
 258
L. COX

Table 1. (Continued).
STUDIES COMPARING SCIT WITH SDT

SYSTEMATIC
REVIEWS ALLERGIC TYPE/COSTS COST
STUDY THAT INCLUDED CONDITION ALLERGEN//DURATION CONSIDERED PERSPECTIVE RESULTS

Berto 2008 Hankin SAR ± Grass SLIT drops for 1 year vs SDT CCA Societal Mean annual direct costs for SLIT greater than SDT: €311.4 and €179.8, respectively.
[78] asthma Direct costs SLIT reduced medication use by 22% in AR and 34% in asthma
Beriot-Mathiot Meadows SAR Grass SLIT tablet (Grazax ) for 3 years continuous or
® CUA Societal Seasonal SLIT was cost-effective with an ICER of €21,829.
2007 [58] Hankins seasonal; SDT; 9-year horizon Direct and At the 9-year time horizon ICER €7894
indirect
costs
Canonica 2007 Meadows SAR Grass tablet (Grazax ) SLIT for 3 years plus SDT as needed; CUA
® Societal SLIT more cost-effective: cost\per QALY gained was between €13,870 and €21,695:
[59] Asaria SDT Direct and
Hankins indirect
costs
Nasser 2008 Meadows SAR and Grass SLIT for 3 years vs. SDT CUA Societal SLIT “very cost-effective” per QALY gained: ICER per QALY €8816 was equivalent to an
[60] Asaria asthma Direct and extra 72 days of perfect health for patients treated with SLIT
Hankins indirect cost
Ronaldson Asaria SAR Grass tablet (Grazax ) SLI for 3 years: 9-year horizon
® CCU HCS SLIT cost-effective: ICER per QALY:
2014 [17] Direct and £ 12,168
indirect cost
Ruggeri Asaria SAR SLIT grass tablet (Oralair ) for 3 years plus SDT as needed; CEA
® HCS SLIT cost-effective per ICER, which varied with disease severity as measured by
2013 [69] Hankins SDT Direct and adjusted symptoms medication score (AAdSS)
4-year time horizon indirect cost Medium AAdS:€1024 per QALY
High AAdS: €1035 per QALY
Studies comparing SCIT and SLIT with SDT
Omnes Meadows SAR and PAR HDM or pollen SCIT or SLIT 3 − 4 years plus SDT as CEA Direct and HCS From HCS perspective
2007 [62] Asaria ± asthma needed: SDT indirect Both SLIT and SCIT cost-effective per ICER of asthma cases avoided:
Hankin costs SCIT: €583 and €597
SLIT: €3938 and €824
for HDM and pollen allergy, respectively.
Pokladnikova Meadows SAR Open, RC comparing SCIT and SLIT drops for grass pollen CEA Costs after 3 yearsSLITSCITp-value
2008 [24] Asaria AR (both extracts from Stallergenes, Antony, France) Direct and 3rd-party Payer Perspective€416€482<0.001
SCIT+SDT (n = 23) indirect Patient perspective€176€255ns
SLIT+SDT (n = 19) costs Societal perspective€684€1,004<0.001
Guideline based SDT (n = 22) Direct and indirect costs over 3-yar were greater with SCIT as compared to SCIT.
Verheggan Asaria SAR and no SLIT vs allergoid of SCIT for 3 years; 9-year horizon CEA HCS ICER of SLIT vs. SCIT 12,593 per QALY, probability of cost-effective at 20,000 per QALY
2015 [72] asthma Direct and of 76%
indirect cost
CCA = cost-consequence analysis; CEA = cost-effectiveness analysis; CUA = cost-utility analysis; HDM = house dust mite; HCS = Healthcare Sysptem
ICER = incremental cost-effectiveness ratio; PAR = perennial allergic rhinitis; QALY = quality-adjusted life year; SAR = seasonal allergic rhinitis; SCIT = subcutaneous allergy immunotherapy; SLIT = sublingual allergy
immunotherapy; SDT = standard drug treatment,

to 11.2 USD billion in 2005, with prescription medications
accounting for 59% of the costs [41]. Direct cost estimates in
this survey did not include the costs of OTC allergy medication
or treatment of co-morbid conditions. AR OTC medication
costs were estimated at 1.2 USD to 1.7 billion in 2008 [25].
Costs of AR co-morbid conditions, such as asthma, otitis
media, and recurrent sinusitis are estimated to be in the
billions of dollars.
According to the 2007 Medical Expenditure Panel Survey,
AR patients had significantly greater healthcare expenditures
than non-AR patients [18]. The additional healthcare expendi­
tures associated with AR were 1,492 USD ± 346 for total
healthcare expenses, 461 USD ± 122 for office-based visits,
876 USD ± 126 for prescription medications, and 168 USD ± 25
for self-expenditures (all P < 0.001) [18].
The indirect costs associated with AR may be greater than
the direct costs and partially borne by employers [42,43].
A systematic review of studies published between 2005 and
2015 provided a quantitative estimate of the burden of AR on
work productivity [44]. According to a pooled analysis of the
data collected through Work Productivity and Activity
Impairment questionnaires, 35.9% of the workers reported
work performance impairment, and 3.6% reported missed
work time due to AR. In the six studies reporting economic
evaluations, the principal contributor to the total AR costs was
the indirect costs related lost work productivity due to
impaired presenteeism. AR symptom severity was the most
consistent disease-related factor impacting work productivity,
In a survey of US employees, the total annual cost of lost
productivity attributable to AR was significantly higher than
the cost for any other condition assessed including diabetes
and coronary heart disease [45] In Europe, the annual loss to
employers related to untreated AR-related presenteeism has
been estimated to be approximately €100 billion (2011
value) [46].
3. Pharmacoeconomics of AIT versus standard drug
treatment
There are a limited number of studies directly comparing the
actual costs of pharmacotherapy with AIT. Only one of these
studies prospectively examined direct costs. Most of the eco­
nomic evaluations focused on the cost-effectiveness of AIT in
the management of AR and many were sponsored by AIT
extraction manufacturers. The economic evaluations (EE)
employed different methodologies to measure and report
outcomes Besides clinical efficacy, which was measured by
improvement in symptoms and medication use, the EEs
reported other outcomes such as the number of asthma
cases avoided, Visual Analogue Scores (VAS) cost per well-
day, and symptom-free days and break-even points of costs/
expenses per patient. Most EEs included direct costs and
indirect costs related to lost work time and some included
costs related to reduced productivity. Some studies were
based on decision-analytic models, e.g. Markov model. The
studies varied in the cost perspective(s) considered, e.g. socie­
tal, national health service (NHS), health insurers, patient, or
some combination of these perspectives. Some studies
reported outcomes as a single measure of economic benefit,
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 259
the incremental cost-effectiveness ratio (ICER). The ICER is
defined by the difference in cost between two possible inter­
ventions, divided by the difference in their effect. The effect
can be measured in Quality-Adjusted Life Years (QALY), which
is a measure of disease burden that is based on both the
quality and the quantity of life lived. It is reported on a scale
from 0 (dead) to 1 (perfect health). One QALY is equal to
1 year in perfect health. A treatment associated with less
than perfect health would be assigned a lower utility, e.g.
chemotherapy that extends life but has significant side effects
would have QALY <1. In AIT cost-effectiveness evaluation, the
ICER is calculated with the following formula:
ICER = Cost of AIT – Cost of SDT
——————————————
QALYs for AIT – QALYs for SDT
The United Kingdom’s (UK) National Institute for Health and
Clinical Excellence (NICE) considers a threshold range is £20,­
000–30,000 ($25,084–37,626 in 2020 US dollars) QALY gained
as cost-effective [47]. In some countries, medications must
demonstrate cost-efficacy before being approved for coverage
by national health authorities. For example, NICE is more than
twice as likely to recommend medications that are within their
designated cost-effective thresholds [48].
3.1. Systematic reviews comparing the cost-effectiveness
of AIT with SDT
Four systematic reviews have evaluated the cost-effectiveness
of AIT compared with SDT [13,49,50,51]. Two of the reviews
focused on allergic rhinitis and two considered asthma and
AR. One of the reviews only considered the grass-pollen AIT
[51]. One of the most comprehensive and rigorous systematic
reviews was conducted by the National Institute for Health
Research Health Technology Assessment (HTA) program [13].
The HTA program serves to produce high-quality research
information on the cost-effectiveness impact of health tech­
nologies for the UK’s National Health Service (NHS). The HTA
systematic review evaluated randomized controlled trials that
compared SDT with SCIT (5 studies) [52–56], SLIT (6 studies)
[48,57–61], or both SCIT and SLIT (3 studies) [24,62,63] pub­
lished through April 2011. The authors identified 14
Economic Evaluations (EE) that utilized four different meth­
ods of cost analysis. Four different types of cost-analyses
were used in the 14 identified EE studies: cost-effectiveness
analyses (CEA), cost-consequences analyses (CCA), cost-utility
analyses (CUA), and cost-benefit analyses (CBA) (see Table 2
for the description of economic evaluations). Six studies con­
sidered a societal perspective, five studies considered
a combination of perspectives, and two studies considered
the health insurer perspective. One study did not state the
perspective used.
The authors concluded that from a patient’s perspective
AIT may be cost-effective based on £20,000–30,000 per
QALY from around 6 years after treatment. As most studies
evaluated a 3- year course of AIT, the cost-efficacy ‘break-
even’ point would be reached 3 years after treatment dis­
continuation. SCIT was found to be cost-effective after 5
years of treatment, which was 1 year earlier than SLIT. The
260 L. COX

authors noted the ‘estimates were based on limited data and

The cost of treating someone with a rare cancer maybe 400,000 USD that leads to an
Findings: Faster-fed group was less costly but had more disabilities, thus was found

increase in life expectancy of 1 year. The cost-utility of this treatment is 400,000

the use of several assumptions’ and some of the assump­

● Valuation of quality of life and life-years gained due to non-fatal myocardial

tions, such as 100% compliance did not appear realistic,” [13]

Outcome assessed: survival with or without neurodevelopmental disability at

[56]. Many models assume that resource use would be sus­
tained for the period of extrapolation. For example, two
economic models extrapolated the RCT outcome results in

Cost averted (medical costs & productivity losses): -$76.4 billion

a 9-year horizon assuming the treatment effect persisted for

Net costs (negative value means cost savings): -$68.9 billion

Direct and indirect costs and different outcomes of all alternatives are listed separately with no specific Cost of two speeds of milk-feeding to preterm infants [65]

6 years after discontinuation [48,54]. The authors noted that

Places a monetary value on health outcomes so that both costs and benefits are in monetary units. It Intervention to reduce trans fats in the food supply [68]
the cost-benefits of AIT might be underestimated as ‘poten­
tial cost savings resulting from future cases of asthma
avoided were not included in the analysis, but would likely

Cost to consumer and industry = 6 USD billion

Example

lead to an increase in cost-effectiveness.’ [13]

Costs of implementation: 7.5 USD billion

Another systematic review was conducted by the

Benefits considered = 140 USD billion

European Academy of Allergy and Clinical Immunology in
Compares an intervention to another intervention (or the status quo) by estimating how much it costs Pediatric Vaccination Program [66]

preparation for the development of clinical guidelines for

AIT in the management of AR, allergic asthma, food allergy,

Net savings: 134 USD billion

to be not cost-effective

and venom allergy [49]. Search of the published literature

with benefits gained from an intervention, such as reduced medical costs, improved productivity, and ● Direct medical costs
24 months of age.

from inception to October 2015 yielded 19 studies focused

infarction averted

on AR. Nine studies compared SLIT with SDT [15,48,59–­

USD per year.

48,59–61,69,70], three studies compared SCIT with SDT

[53,54,71], seven studies compared SLIT and SCIT with SDT
or each other [13,24,51,62,71–73] and two studies compared
unspecified AIT with SDT [55,56]. Three studies were
reported from a societal perspective and 16 from
consequences of the health outcomes by adjusting the outcomes by health state preference scores or
utility weights, which can be collected from either patients or the general public (via a survey) [67].

a healthcare system perspective. Three of the studies

Compare two different interventions whose benefits may be different. It attempts to value the

focused on asthma, but only one of the three evaluated

to gain a unit of a health outcome, e.g. QALY. Results are typically reported in ICER [66].

asthma patients without AR. They found no eligible studies

investigating the cost-effectiveness of AIT for food allergy.
One economic modeling study suggested that venom AIT
was only cost-effective for high-risk groups at risk for recur­
rent stings. Seven studies reported results against disease-
specific outcome measures, e.g. VAS, the number of patients
improved and 12 reported results based on QALYs. The
review included 11 of the EEs considered in the HTA sys­
tematic review. Not surprisingly, the authors came to
a similar conclusion regarding AIT cost-effectiveness that it
compares the costs of implementing an intervention.

‘would be considered cost-effective using the NICE thresh­

the monetized value of health improvements [68].

old of £20,000 per QALY.’ [49]

Results are reported as a net economic benefit.

However, the authors noted that the overall quality of

preference for one outcome measure [64].

the studies was low. The limitations of the studies reviewed

Results are generally expressed as ICER

included unclear and difficult to interpret cost or utility

data, missing data, and the assumption-based extrapola­
tions noted in the Meadows review. One of the interesting
findings was that ICER for AIT varied substantially with
different healthcare systems, e.g. £2360 in Denmark to
£22,374 in the Netherlands [54]. The authors stated that it
was unclear how comparable the patient populations were
Table 2. Description of economic evaluation.

between studies and ‘ . . . straightforward conclusions may

not be generalizable even across seemingly similar coun­
tries’ [49]
Another systematic review of studies indexed in MEDLINE
through March 2014 identified 24 studies that reported health
Cost-consequences analysis

Cost-benefit analysis (CBA)

Cost-effectiveness analysis

Cost-utility analysis (CUA)

economic outcomes of AIT studies [50]. Nine of the studies

pertained to SCIT [52–56,74–77,80], 10 studies evaluated SLIT
(8 studies on SLIT tablets) [48,57,58,60,61,69,78,79] and 2 stu­
dies on SLIT liquid drops [15,80]. Four studies compared eco­
nomic outcomes among SLIT, SCIT, and SDT [24,51,62,73]; and
(CCA)

(CEA)

one compared the health economic outcomes for SCIT with

SLIT [81].

Again, there was considerable overlap in the studies
reviewed, with two systematic reviews discussed above. The
findings were presented in a binary manner as positive or
negative cost-savings. The review found that 23/24 studies
demonstrated cost-savings (expressed as actual costs, ICER,
or other calculated measures) with AIT as compared with
SDT. The one study that failed to demonstrate AIT cost-effec­
tivenss was a 2-year study of AIT for ragweed-induced asthma
[74]. Although the study demonstrated reduced medication
use with AIT, the reduced medication costs did not outweigh
the costs of AIT. In the studies that compared cost outcomes
of SLIT to SCIT, 4/6 reported greater cost-savings with SLIT.
The review concluded the preponderance evidence compara­
tive cost studies provided ‘compelling evidence for the cost
savings of AIT (whether delivered subcutaneously or sublin­
gually)’ [50]
Dranitsaris and Ellis conducted a systematic review of the
published literature to evaluate the cost-effectiveness of
two SLIT tablets; Oralair® (Stallergenes, London, UK) and
Grazax® (ALK Hørsholm, Denmark) and SCIT for grass-
pollen induced AR from the Canadian healthcare system
[51]. They identified 20 DBPC trials that compared SDT
with Oralair® (five studies), Grazax® (eight studies), and
SCIT (seven studies) with SDT. The economic evaluation
included direct and indirect costs for the Canadian setting.
The study considered resource use data collected from
expert opinion and monthly drug costs to perform cost
comparison analysis for the first year of therapy during the
first year of treatment. The study found Oralair® was asso­
ciated with significant cost savings as compared with year-
round SCIT ($2471), compared with seasonal SCIT ($948)
and Grazax® ($1168) in the first year of treatment. As
none of the studies directly compared different AIT pro­
ducts, this evaluation was based on indirect comparisons.
The authors noted limitations of the indirect analysis
included a lack of consistent data regarding medication use.
3.2. Markov models
In 2020, two studies comparing the cost-effectiveness of grass-
pollen AIT using a Markov model reported results that differed
from Dranitsaris and Ellis [82,83]. A Markov model assumes
that the patient is always in one of the finite number of states
of health (referred to as Markov states, e.g. dead, well, dis­
abled). A hypothetical algorithm divides the possible course of
disease progression into different heath states, e.g. asthma,
poorly or well-controlled AR. Each state is assigned a utility,
which represents the quality of life in that state relative to
perfect health. The time horizon is divided into equal incre­
ments of time, which are referred to as Markov cycles [84].
One Markov cycle in a particular state is referred to as the
incremental utility. Healthcare outcomes and costs are mod­
eled to reflect the natural progression of the disease with and
without the intervention.
Di Bona et al.’s Markovian model evaluated a hypothetical
cohort of adult patients suffering from moderate-to-severe
rhinoconjunctivitis with or without allergic asthma over a 9-
year horizon [83]. Cost-effectiveness analysis included direct
and indirect non-medical costs (travel time and lost
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 261
productivity). The defined health states were asthma, no
asthma, death, no AIT and no asthma, and no AIT and
asthma. Results were reported as ICER as compared with
SDT alone. The study found that SCIIT was slightly more
expensive but the most cost-effective treatment; ICER for
SCIT, €11 418 vs. €15 212 for SLIT. However, when indirect
costs were considered, SLIT was more cost-effective; ICER for
SCIT, €17 318 vs. €15 212 for SLIT. The authors noted that in
scenarios assuming low persistence, i.e., low adherence, the
ICER for SCIT and SLIT was greater than €120 000. The
authors concluded that ‘AIT for grass pollens may be a cost-
effective option only in patients with low discontinuation
rates. SCIT, which is less affected by this limitation than
SLIT, seems the most cost-effective AIT form.’ [83]
In a separate study, the same group found that SCIT ‘sys­
tematically outperformed SLIT, except when a full societal
perspective is considered.’ [82] The example cited was
a 60 day pollen season over a 9-year horizon that resulted in
ICER of €16,729 for SCT and €15,116 for SLIT. The authors
noted that the ICER may decrease with longer pollen seasons
or longer follow-up duration as the QALY gained per cycle
increases accordingly. The authors concluded that ‘even
though there is a considerable evidence that SCIT outperforms
SLIT, we could not state that both SCIT and SLIT (or only one
of these two) can be considered cost-effective for ARC, as
a reliable threshold value for cost-effectiveness set by national
regulatory agencies for pharmaceutical products is missing.’
3.3. Real-life claims-based cost analyses
Although AIT’s persistent -post-treatment efficacy and
potential preventive effects can confer significant cost-
savings, it is important to note that economic evaluations
that depend on these assumptions are speculative and the
speculations may not be borne out in real-life application.
Additionally, the results in clinical trials may not apply to
the general population as inclusion criteria may exclude
individuals with more severe disease and participation in
the trial requires a certain level of adherence. In Bilancia’s
economic model that assumed 3 years of AIT was required
for persistent clinical efficacy, premature discontinuation
increased AIT’s ICERs to far greater than €30,000. Studies
reporting actual costs based on claims analysis and/or
healthcare utilization provide compelling evidence that AIT
is cost-effective.
A randomized controlled trial of 30 patients with
Parietaria-induced allergic rhinitis and asthma compared
the healthcare of patients treated with SCIT (n = 20) and
SDT (n = 10) over a 6-year period, which encompassed 3
years during treatment and 3 years after treatment disconti­
nuation [52]. Healthcare costs included medications, AIT, and
medical visits. Cost-savings were seen in the second year of
treatment (15%), but they did not reach a significance until
the third treatment year (48%, p = <.001). The cost-savings
increased to 80% by the fourth year (first post-treatment
year), which was maintained 3 years after AIT discontinua­
tion. Presumably, the post-treatment cost-savings were the
result of persistent clinical efficacy. Although this was a small
262 L. COX
study, it is important in that it demonstrated the cost savings
with AIT can be maintained at least for 3 years after treat­
ment termination.
Persistent cost savings after treatment discontinuation
have been demonstrated in other studies. A claims-based
analysis of the Florida Medicaid database compared the total
healthcare costs of before and after SCIT in a pediatric
population with newly diagnosed AR. AR diagnosis was
based on ICD-9 codes, newly diagnosed AR was defined
first, and AR diagnosis was preceded by a full year of claims
with no ICD-9 AR code. Total healthcare costs, which
included pharmacy, outpatient, and inpatient services were
based on a retrospective analysis of Medicaid claims from
1997 to 2004. Medicaid is a government-funded insurance
for low-income individuals. During these 7 years, 2,718,101
children were enrolled in Medicaid. Among the 102,390
children with were newly diagnosed AR only 3048 (3%)
were prescribed SCIT. The claims analysis found significant
reductions in pharmacy, inpatient, and outpatient costs dur­
ing the 6-month after SCIT discontinuation as compared
with the 6 months before SCIT initiation. The average
6-month weighted cost savings per patient with SCIT was
401. USD
In an extension of this study, Hankin et al. conducted
a retrospective, matched-cohort analysis of 10 years of
claims data (1997–2007) comparing healthcare costs and
utilization of children with newly diagnosed AR who
received SCIT to a matched group of children with AR
who did not receive SCIT [76]. They found that children
treated with SCIT incurred significantly lower 18-month
median per-patient total healthcare: 3247 USD versus
4872, USD p < .001.
The same investigators performed a similar analysis of
12 years of Florida Medicaid data (1997–2009), to deter­
mine whether SCIT-related cost benefits conferred to chil­
dren similarly extended to adults with newly diagnosed
AR [85]. The study compared 18-month healthcare costs
(pharmacy, outpatient, and inpatient services) of 1319
adult and 3,648 pediatric patients with newly diagnosed
AR who received SCIT to a matched-cohort that did not
receive SCIT (19,278 patients). The groups were matched
on eight variables, which included age, demographic,
comorbid atopic conditions, and illness burden (the
Charlson Comorbidity Index). Overall, the 18-month total-
mean healthcare cost was 38% lower SCIT treated as
compared with the matched control group ($6,637 vs
10,644, USD P < .0001). Significant cost-savings were
seen in both the adult (30%) and pediatric (42%) popula­
tions: 18-month healthcare costs.
● Adults: 10,457 USD SCIT versus 14,854 USD matched
controls, P < .0001,
● Children 5,253 USD AIT versus matched 9,118 USD con­
trols, P < .0001.
The healthcare cost savings were evident within the first 3
months of treatment and continued throughout the
18 months of follow-up. These studies were unique in
that they examined cost-effectiveness at different time
points during treatment and demonstrated AIT cost-
savings can be appreciated as early as 3 months after
treatment initiation.
4. Pharmacoeconomics of AIT for asthma
Most of the AIT pharmacoeconomic studies evaluated the
cost-effectiveness of AIT in the management of AR, but
many of the included patients had co-existing asthma. Only
one health economic study specifically evaluated patients with
allergic asthma [71]. In this RCT of 65 children with HDM-
induced asthma, treatment costs, and effects (measured as
morning peak flow) were monitored over a 3-year treatment
period. Over the 3 years, SCIT was associated with improved
lung function and a steady decline in medications that
became significant in the third year. Overall costs were more
expensive in the SCIT group, but the authors concluded: ‘addi­
tional costs associated with SCIT may be completely compen­
sated by drug cost savings 4 years after the end of SCIT.’ [71].
In the systematic review conducted by Asaria et al., it was
concluded that SLIT may be cost-effective for patients with
both allergic asthma and allergic rhinitis from the English NHS
perspective at an ICER of 10,7727 per QALY.” [15].
5. Food immunotherapy
The standard of care for food allergic individuals is the
avoidance of the food and carriage of a self-injectable epi­
nephrine treatment in the event of an accidental. Clinical
trials investigating oral (POIT) and epicutaneous (EPIT)
immunotherapy for peanut allergy have demonstrated
improved tolerance. However, in most cases, the tolerance
is not maintained after treatment discontinuation. In 2020,
the FDA approved the first peanut oral immunotherapy
product, Palforzia (Airimmune Therapeutics, Brisbane,
California) [86]. An epicutaneous form of peanut immu­
notherapy, Viaskin™ Peanut Patch (DBV Technologies,
Montrouge, France), submitted a Biologics License
Application (BLA) in October 2019. The product was granted
Fast Track and Breakthrough Therapy designation by the
FDA. However, questions regarding the efficacy and the
patch’s adhesion to the skin prompted the FDA to cancel
the advisory committee meeting convened to discuss
approval for the patch’s approval [87].One study performed
an economic evaluation of peanut POIT and EPIT from
a societal perspective [88]. Microsimulation with Markov
modeling evaluated virtual children over an 8-year time
horizon. Outcomes included treatment-related adverse
effects, anaphylaxis, QALY, and fatalities. The model
assumed 35% of those with anaphylaxis due to accidental
exposure were hospitalized and all were evaluated in the
emergency room. As this analysis predated product
approval, the actual product cost was not known.
The authors noted that the cost-effectiveness of both
therapies was ‘‘sensitive to rates of sustained unresponsive­
ness, improvements in health state utility, and risk reduction
of anaphylaxis.” [88] The authors concluded EPIT and POIT
may be cost-effective if the annual costs did not exceed 1568
USD and 1235 USD, respectively, but that more research is

needed to understand the degree of health state utility
improvement and the protection conferred with each
therapy.
6. Limitations of this review
The primary challenge and limitation of this review were the
lack of ‘gold-standard’ data from prospective, double-blind,
placebo-controlled studies. Except for one study, actual costs
were derived from retrospective data, which may subject to
recall bias. However, this bias would be less pertinent to
claims-based analysis because these studies are designed to
collect data through billing codes, which are submitted when
the medical event occurs, e.g. the Florida Medicaid database
[85]. In this respect, a claims-based analysis study prospec­
tively collects data. A limitation of claims-based analysis stu­
dies is that billing codes only provide information regarding
the diagnosis and medical services provided on each encoun­
ter. They do not provide information about the patient’s dis­
ease severity or physician’s rationale for prescribing AIT or
other treatment. As these studies reflect a real-life scenario,
one might presume that the patients who were prescribed AIT
had allergic diseases with greater severity. If so, this would
make the cost-savings more significant.
The EE studies applied assumptions from DBPC trials to
prospective theoretical models. The primary limitation of this
approach is the assumption that the benefits seen in clinical
trials can be applied to the general population and translated
into a monetary figure.
Lack of information about co-morbid conditions and actual
indirect costs was another limitation of this review. One can
presume claims-based analyses capture all medical costs, but
they do not provide specific information about the relation­
ship between the co-morbid events and the allergic disease.
Additionally, they do not provide information about indirect
costs. The EEs considered some co-morbid conditions, such as
asthma, but generally did account for the spectrum of co-
morbid conditions associated with poorly controlled AR.
Collectively, these limitations suggest that the current stu­
dies evaluated the cost-effectiveness of AIT may be under­
estimating its cost-benefits as most do not account for co-
morbid conditions, indirect cost, and disease-modifying
impact.
7. Conclusion
Allergen immunotherapy has well-established proven clinical
efficacy in the treatment of allergic rhinitis that may persist
years after treatment discontinuation. In addition to persistent
post-treatment clinical improvement, there is evidence that AIT
can prevent the progression of the allergic disease. In contrast,
pharmacotherapy only confers benefits during treatment. Both
conditions may require years of symptomatic treatment and can
be with comorbid conditions, e.g., acute sinusitis, that contribute
to treatment costs All of these factors need to be considered
when considering the cost-effectiveness of AIT compared with
pharmacotherapy.
The cost-effectiveness of AIT has been evaluated in several
studies and systematic reviews, which varied in the way the
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 263
economic outcomes were expressed and/or measured. Some
studies reported outcomes in terms of a calculated ICER based
on a theoretical economic model and others reported direct
costs. The preponderance of evidence suggests that AIT is
cost-effective for AR. The limited data on asthma and food
allergy suggest AIT may be cost-effective for these conditions
as well. Individual studies have demonstrated cost-savings as
high as 80% and as early 3 months after treatment initiation.
Only three of the studies evaluated multiallergen immu­
notherapy, which is the usual treatment in the US [89]. The
cost-effective ‘break-even time-point’ varied in these studies
but one systematic review suggested that both SCIT and SLIT
may become cost-effective compared with SDT at around
6 years after beginning treatment [13]. Overall, there was
evidence that one AIT route is more cost-effective. Further
pharmacoeconomic research comparing the direct and direct
costs of SLIT and SCIT in the treatment of multiallergen AR is
needed.
8. Expert opinion
This expert opinion is based on the perspective of
a clinician and researcher with nearly 30 years of clinical
experience treating allergic patients, with several published
studies and review papers examining the cost-effectiveness
of AIT compared with pharmacotherapy. The clinician’s per­
spective is important in that some AIT economic evaluations
are based on health outcome assumptions extrapolated
from clinical trial data. Although clinical trials are essential
for establishing the safety and efficacy of an intervention,
their results may not be generalizable to the general popu­
lation for several reasons. Clinical trial inclusion criteria may
exclude patients with more severe diseases, e.g., recent
hospitalization, or oral corticosteroid use. This could result
in underestimating the cost-benefits of AIT, as the magni­
tude of improvement may be diluted by patients with mild
symptoms. Studies suggest the magnitude of improvement
with AIT is greater with higher pollen exposure or allergen
sensitivity [90] [91–93]. In a post hoc analysis of three AIT
trials that compared the treatment effect in patients cate­
gorized by symptom severity, the magnitude of improve­
ment was considerably greater in the most symptomatic
group [92]. Additionally, clinical trial participation requires
a high level of adherence, which has generally not been
observed in ‘real-life’ studies examining AIT renewal rates
through pharmacy claims or medical record analysis [94]. As
AIT’s persistent post-treatment efficacy appears to require
several years of treatment, economic evaluations that
assume a high level of adherence may overestimate AIT
cost-efficacy. There are limited data on the optimal duration
of AIT for persistent clinical efficacy. Several studies have
demonstrated sustained clinical efficacy for up to 2 years
after completion of a 3-year course of SLIT or SCIT [95–97].
One prospective study compared three durations of SLIT
[12]. The investigators found that the clinical benefits of
a four- and -year course of SLIT persisted for 8 years,
which was one-year longer than a 3-year course of AIT.
They concluded that a 4-year course of AIT was the optimal
duration because it induces a long-lasting clinical
264 L. COX
improvement similar to the benefits seen with a 5-year
course. One of the challenges in studying the long-term
efficacy of AIT is that patients can be lost to follow-up or
withdrawal from treatment for various reasons, including
lack of efficacy. In economic evaluation model scenarios
that assumed poor treatment adherence, the calculated
ICER for AIT was far greater than the threshold deemed to
be cost-effective. One study found that 2 years of SLIT were
not significantly different from placebo in the primary out­
come, nasal response to allergen challenge at the 3-year
follow-up [90]. However, there were significant improve­
ments in the secondary outcomes, such as skin test reactiv­
ity and allergen-specific IgG levels, which are biomarkers for
sustained immunological tolerance. It is also likely that indi­
viduals completing less than 3 years of AIT will maintain
some degree of clinical improvement after discontinuation.
It is important to understand the limitations of clinical
trials as they apply to clinical practice. It is likely patients
prescribed AIT in clinical practice have greater disease
severity than patients included in clinical trials. Thus, the
magnitude of improvement (aka clinical efficacy) may be
greater than the 20–30% reduction in symptom and med­
ication scores seen in most AIT clinical trials.
Pharmacoeconomic studies compare the costs
(expressed as monetary units) and effects (expressed in
terms of monetary value, disease-specific outcomes, or
enhanced quality of life) of one intervention with another
intervention. Cost-effectiveness analysis estimates how
much it costs to gain a unit of a health outcome, which
is often expressed as QALY gained or ICER. When consid­
ering whether AIT is cost-effective as compared with phar­
macotherapy, it is important to consider during and post-
treatment efficacy. Cost-effectiveness analysis should also
include an appropriate time-horizon as the cost-savings
associated with clinical efficacy may lag behind treatment
costs by several years. Overall, the pharmacoeconomic
studies have demonstrated that AIT is cost-effective as
compared with pharmacotherapy at an ICER below the
threshold established by NICE. Additionally, studies com­
paring actual costs have reported significant cost-savings
as early as 3 months after initiation [98] and as high as
80% 3 years after discontinuation [52].
Most cost-effectiveness AIT studies considered single
allergen AIT for SAR. Most allergic patients are sensitized
to more than one allergen. It is not known if the cost-
effectiveness of single allergen AIT can be assumed with
multiallergen AIT. However, it is likely the majority of
patients in the 12-year Florida Medicaid database study
received multiallergen SCIT, as the typical US approach to
AIT is to include all allergens identified in allergy testing.
The cost difference between multiallergen and single aller­
gen SLIT may be significantly greater because of SLIT’s
dosing frequency. More research is needed to compare
the cost-effectiveness of multiallergen SCIT and SLIT and
different durations of AIT. In the next 5 years, data from
clinical registries, such as the American Academy of
Allergy, Asthma, and Immunology’s Quality Clinical Data
Registry and government insurance databases may
provide useful information about healthcare utilization
and costs of AIT for different conditions and duration.
Abbreviations
AA: allergic asthma
AIT: allergen immunotherapy
AR: allergic rhinitis
ARC: allergic rhinoconjunctivitis
CE: cost-effectiveness
DBPC: double-blind, placebo-controlled
EMA: European Medicines Agency
FDA: Food and Drug Administration
HDM: house dust mite
ICER: incremental cost-effectiveness ratio
NHS: National Health Service
RCT: randomized clinical trial
QALY: quality-adjusted life year
SAR: Seasonal allergic rhinitis
SCIT: subcutaneous allergen immunotherapy
SLIT: sublingual allergen immunotherapy
SDT: Standard Drug Treatment
US: United States
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers in this manuscript have no relevant financial or other
relationships to disclose.
Funding
This paper was not funded.
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