Current Medical Research and Opinion

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20

Real-world evidence costs of allergic rhinitis

and allergy immunotherapy in the commercially
insured United States population

Joseph P. Tkacz, Karen Rance, Douglas Waddell, Mark Aagren & Eva
Hammerby

To cite this article: Joseph P. Tkacz, Karen Rance, Douglas Waddell, Mark Aagren & Eva
Hammerby (2021) Real-world evidence costs of allergic rhinitis and allergy immunotherapy in
the commercially insured United States population, Current Medical Research and Opinion,
37:6, 957-965, DOI: 10.1080/03007995.2021.1903848

To link to this article: https://doi.org/10.1080/03007995.2021.1903848

© 2021 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group.

Published online: 02 Apr 2021.

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CURRENT MEDICAL RESEARCH AND OPINION
2021, VOL. 37, NO. 6, 957–965
https://doi.org/10.1080/03007995.2021.1903848
Article RT-0064.R1/1903848

ORIGINAL ARTICLE

Real-world evidence costs of allergic rhinitis and allergy immunotherapy in the

commercially insured United States population
Joseph P. Tkacza, Karen Ranceb, Douglas Waddellb, Mark Aagrenb and Eva Hammerbyb
a
IBM Watson Health, Cambridge, MA, USA; bALK-Abello, Hørsholm, Denmark

ABSTRACT ARTICLE HISTORY

Objective: To assess total and allergic rhinitis (AR)-related healthcare costs among AR patients residing Received 26 January 2021
in the United States with a focus on patients persisting with AIT. Revised 25 February 2021
Methods: AR patients were identified in the IBM MarketScan database between 1 January 2014 to 31 Accepted 8 March 2021
March 2017. Patients receiving allergy immunotherapy (AIT) were identified with relevant billing codes
KEYWORDS
(earliest AIT claim ¼ index date); non-AIT patients were identified with claims containing a diagnosis Allergy immunotherapy;
code for AR (earliest AR claim ¼ index date). AIT patients reaching 25þ injection claims were analyzed allergic rhinitis; healthcare
as a separate maintenance cohort. All patients were required to have continuous enrollment for costs; wastage
12 months preceding and following index.
Results: A total of 2,334,530 AR patients were included; 103,207 had at least 1 AIT claim, with 45,279
(43.9%) of these patients reaching maintenance, and 24,640 AIT patients (23.9%) never presenting a
single injection claim. Compared to non-AIT patients, patients initiating AIT presented higher rates of
baseline comorbidities, including asthma (30.1% vs. 7.5%) and conjunctivitis (21.7% vs. 4.4%). During
the follow-up period, patients reaching the maintenance phase of AIT incurred lower total costs than
the overall AIT cohort ($10,431±$16,606 vs. $11,612±$24,797), and also presented lower follow-up hos-
pitalization costs ($698±$7,248 vs. $1,281±$12,991) and total medical costs ($7950±$13,844
vs. $8989±$22,019).
Conclusions: Continued efforts are needed to increase patient awareness of available options and
adherence to AIT, along with reducing wastage. Despite AIT patients presenting fairly progressed dis-
ease at the time of treatment initiation, this therapy remains an economical treatment option, as it
was not accompanied by substantial increases in overall healthcare expenditure, and may promote
positive societal impacts beyond the direct medical costs.

WHAT IS KNOWN ON THIS TOPIC

 The prevalence of allergic diseases has increased over the past 50 years and affects between
10–30% of the world population.
 Allergic rhinitis (AR) poses a significant economic burden in the form of both direct and indir-
ect costs
 Allergy immunotherapy (AIT) is the only treatment option able to modify the underlying course of
the disease.

WHAT THIS STUDY ADDS

 Specific all-cause and AR-related healthcare costs decreased following the initiation of AIT among
patients diagnosed with AR, with the largest decreases observed among AIT patients reaching the
maintenance phase of treatment, while non-AIT patients showed increases in all categories assessed
over a similar follow-up period.
 Cost decreases among AIT patients were observed despite increased levels of comorbidities com-
pared to non-AIT patients, as the AIT cohort presented elevated rates of atopic dermatitis (7.1% vs.
2.7%), conjunctivitis (21.7% vs. 4.4%), asthma (30.1% vs. 7.5%), and chronic sinusitis (22.6%
vs. 4.9%).
 An analysis of patients’ index subcutaneous AIT consultation revealed substantial variability in the
initial treatment costs, with nearly 20% of paid amounts exceeding $1,000; given nearly 1 in 4 AIT
patients who get AIT mixed never came back for their first injection, this highlights an opportunity
to target frontloaded billing practices and the timing of mixing/injection as an area to minimize
healthcare waste.

CONTACT Joseph P. Tkacz joseph.tkacz@ibm.com 6710 Rockledge Drive, Floors 2A and 3A, Bethesda, MD 20817, USA
ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/
4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon
in any way.
www.cmrojournal.com
958 J. P. TKACZ ET AL.
Introduction
Allergic rhinitis (AR), also known as hay fever, is a condition
in which inflammatory processes stimulated by environmen-
tal allergens result in sneezing, airflow obstruction, nasal
pruritus, and clear nasal discharge1. Allergic diseases have
increased in prevalence across the globe over the past half
century, affecting between 10–30% of the world popula-
tion2, with sensitization rates to common allergens in
school-aged children approaching 50%3, As a chronic dis-
ease, AR is associated with significant direct costs in the
form of disease management, indirect costs in the form of
decreases in work productivity, and “hidden” costs associ-
ated with the management of comorbidities common to
patients with AR4. As such, AR poses a significant economic
burden to society, particularly if treatment protocols are
not followed5.
Societal estimates of the medical costs attributed to AR in
the United States (U.S.) have consistently returned values
between approximately $3 and $4 billion dollars annually6–9.
A previous analysis of medical and pharmacy claims from a
U.S. managed care plan demonstrated that AR patients
incurred over $650 annually in direct AR-related costs, which
were evenly dispersed between medical and pharmacy serv-
ices, and which were elevated among patients with specific
AR-related comorbidities10. Asthma, atopic dermatitis
(eczema), allergic conjunctivitis, and various sleep disorders
are just a few of the comorbidities commonly associated
with an AR diagnosis11–17, and recent evidence has high-
lighted the substantial economic burden of both asthma,
particularly among those with severe disease18, and atopic
dermatitis19. As such, AR is seldom an isolated disorder, and
the associated sequela contributing to these “hidden” costs
should be taken into consideration when assessing the true
burden of this disease.
Allergen avoidance, pharmacotherapy, and immunother-
apy are the primary options when considering a disease
management approach20. Though pharmacotherapy can sup-
press symptoms of AR, allergy immunotherapy (AIT) is the
only therapy that can modify the underlying course of dis-
ease21. AIT is typically prescribed for the most severe AR,
and persistence with treatment has been associated with
reduced high-cost venue service use and AR-related expend-
iture5. Additionally, a recent review has demonstrated that
AIT is a cost-effective option in the management of AR com-
pared with standard drug treatment22.
However, there remains a dearth of up to date, real-
world evidence studies focused on the costs of AR, par-
ticularly among the subset of patients prescribed AIT.
Further, as adherence and persistence rates to AIT remain
less than optimal23–26, it will be critical to evaluate the
relationship between treatment compliance/non-compliance,
outcomes, and potentially healthcare wastage. Therefore,
the purpose of this exploratory study was to better under-
stand the total and AR-related healthcare costs among a
large, nationally representative sample of AR patients resid-
ing in the United States, with a focus on patients pre-
scribed AIT.
Methods
Study design and data source
This observational, retrospective study used de-identified
healthcare claims from the IBM MarketScan Commercial
Database spanning the period of 1 January 2014, through 31
March 2017 (study period) to evaluate the healthcare cost
profiles of patient diagnosed with AR in the United States.
The database comprises enrollment and demographic infor-
mation, as well as inpatient medical, outpatient medical, and
outpatient pharmacy claims data collected from employees,
dependents, retirees, and members of >300 large self-
insured U.S. employers and >25 U.S. health plans. The data-
base includes employer and health plan sourced data from
approximately 140 million individuals from 1995 to 2017.
All database records were de-identified and fully compli-
ant with the US Health Insurance Portability and
Accountability Act (HIPAA); this compliance with HIPAA regu-
lation meant that patient consent and Institutional Review
Board approval to conduct this study were unnecessary.
Patient selection and cohort assignment
To be eligible for study inclusion, patients were required to
meet the following criteria:
 The presence of  1 medical or pharmacy claim for AIT,
and if an absence of AIT claims,  1 claim with a diagno-
sis of AR (ICD-9-CM 477.x or ICD-10-CM J30.x) between 1
January 2014, and 31 March 2017
 Current Procedural Terminology (CPT) codes for sub-
cutaneous AIT (SCIT) included 95115; 95117; 95120;
95125; 95144; 95165; 95180; and 9519927
 The earliest service date for either an AIT or AR claim
served as the index date
 At least 12 months of continuous enrollment with med-
ical and pharmacy benefits for 12 months preceding the
index date
 At least 12 months of continuous enrollment with med-
ical and pharmacy benefits for 12 months following the
index date
Additionally, for patients in the AIT cohort, the 12-month
pre-index period was required to be absent of any AIT treat-
ment, and patients were excluded if they presented any
claims for venom allergies at any time during the measure-
ment window. As the build-up phase of SCIT may entail 1–2
shots per week for 3–6 months, based on clinician recom-
mendation, AIT patients reaching the maintenance phase of
treatment were operationally defined in the current study as
those presenting 25þ AIT injection claims (CPT codes 95115
and 95117) and were analyzed as a stand-alone cohort.
Review of the frequency distribution of patients meeting this
conservative definition corresponding to a once-weekly shot
regimen for 6 months confirmed this threshold. As such,
three main cohorts comprised the primary study compari-
sons, and included all AIT patients, AIT patients reaching the
maintenance phase of treatment (25þ injection claims), and

non-AIT patients. Additionally, for the analysis of healthcare
wastage, the proportion of patients who discontinued AIT
after a single visit was also presented.
Measures
Sample characteristics
Patient demographic characteristics were assessed on the
index date and included age, sex, geographic region of resi-
dence (Northeast, North-Central, South, West, and unknown),
urban or rural residency, and index year. Patient clinical char-
acteristics were assessed during the 12-month baseline, and
included the Deyo-Charlson comorbidity index (a claims-
based overall measure of health)28, the presence of comorbid
conditions of interest (asthma, atopic dermatitis, conjunctiv-
itis, depression, eustachian tube disorder, food allergy, head-
ache, heartburn/reflux/GERD, migraine, otitis media,
pneumonia, skin rash [including pruritus], eczema, sleep
apnea, sleep disturbance, nasal polyps, chronic sinusitis,
bronchitis, and any upper respiratory tract infection), the use
of specific prescription medication classes (antihistamines,
decongestants, intranasal corticosteroids, and nasal sprays),
and the frequency of specific surgeries (polypectomy, septo-
plasty, sinus surgey, turbinectomy, and tympanostomy).
Outcomes
All-cause and AR/AR comorbidity-specific healthcare costs
were assessed during each the 12-month baseline and 12-
month follow-up period, and were reported by the following
service categories: inpatient, emergency room (ER), physician
office, laboratory, other outpatient services, outpatient pre-
scriptions, and surgical procedures. AR/AR comorbidity-
related healthcare costs included all inpatient medical claims
with any of the following diagnosis codes in the primary
position or any position on outpatient claims: AR, asthma,
atopic dermatitis, conjunctivitis, eosinophilic esophagitis, eus-
tachian tube disorder, food allergy, headache, migraine, otitis
media, skin rash (including pruritus), eczema, sleep apnea,
sleep disturbance, bronchitis, any upper respiratory tract
infection, nasal polyps, or chronic sinusitis. Additionally, all
pharmacy claims indicated for AR or AR-related treatment,
and any of the five surgeries listed above (polypectomy, sep-
toplasty, sinus surgey, turbinectomy, and tympanostomy)
also contributed to disease-related costs.
As medical coding practices for the reimbursement of AIT,
in particular SCIT, are known to vary, the distribution of paid
amounts appearing on the initial, index SCIT claim were also
examined as a separate outcome given the known issues
with AIT adherence23–26. Costs were presented for the eight
distinct non-venom AIT procedure codes in use at the time
of the analyses, and these visit costs were segmented into
categories of the total amount claimed ($0–$99, $100–$299,
$300–$499, $500–$999, $1000þ). For all analyses of cost met-
rics, dollar amounts were inflated to 2018 USD (the final year
of study data) using the medical component of the
Consumer Price Index29.
CURRENT MEDICAL RESEARCH AND OPINION 959
Statistical analysis
As this was an exploratory study, only descriptive statistics
were reported for demographics, clinical characteristics, and
healthcare cost measures for three cohorts: all AIT patients,
AIT patients reaching the maintenance phase of treatment,
and non-AIT patients. Continuous variables were summarized
using means and standard deviations (SD). Categorical varia-
bles were reported using counts and percentages.
Results
A total of 2,334,530 AR patients qualified for the current
study; 103,207 patients presented 1 AIT claim (either for
preparation or administration), with 45,279 (43.9%) of these
AIT patients presenting 25þ AIT injection claims (mainten-
ance). A total of 17,757 AIT patients (17.2%) only presented a
single AIT claim of any type, while 24,640 AIT patients
(23.9%) only presented without any injection claims (i.e. had
AIT mixed but did not receive it). The remaining 2,231,323 AR
patients did not receive AIT treatment.
Groups were similar demographically, with mean patient
ages in the early 30 s, and a relatively uniform dispersion
between early and middle adulthood (Table 1). A greater
proportion of patients receiving AIT were female compared
to non-AIT patients (58.2% vs. 56.4%), and patients primarily
resided in urban areas of the southern United States. During
the baseline year, discordant rates of a number of comorbid
conditions were observed between AIT and non-AIT cohorts,
with a higher proportion of AIT patients presenting claims
for atopic dermatitis (7.1% vs. 2.7%), conjunctivitis (21.7% vs.
4.4%), asthma (30.1% vs. 7.5%), chronic sinusitis (22.6% vs.
4.9%), and upper respiratory tract infections (60.3% vs.
34.2%; Table 2). Additionally, a higher proportion of AIT
patients filled baseline prescriptions for decongestants
(28.9% vs. 6.2%), nasal sprays (44.3% vs. 11.1%), antihist-
amines (16.8% vs. 4.7%), and intranasal corticosteroids
(36.9% vs. 11.3%), with a higher proportion also presenting a
baseline AR-related surgical procedure (4.1% vs. 0.9%) com-
pared to non-AIT patients.
Table 3 presents all-cause and AR/AR comorbidity-related
healthcare cost metrics during each of the baseline and fol-
low-up periods. In the year leading up to treatment initi-
ation, the AIT cohort presented greater baseline all-cause
total healthcare costs compared to non-AIT patients
($9,418±$20,566 vs. $5,213±$19,503), along with greater total
AR-related costs ($2,482±$5,118 vs. $518±$2,252). The major-
ity of costs were derived from medical expenditure as
opposed to pharmacy expenditure, which was consistent for
both all-cause and AR-related cost metrics. Across all service
categories, AIT patients presented greater mean baseline
costs compared to non-AIT patients, with the subset of
patients who eventually reached the maintenance phase of
treatment (25þ injections) presenting a slightly lower mean
baseline cost compared to the overall AIT cohort
($8,447±$15,467 vs. $9,418±$20,566).
Similar cost patterns emerged during the follow-up
period, with the AIT cohort presenting greater mean
960 J. P. TKACZ ET AL.

Table 1. Demographic characteristics by AIT cohorts.

25þ AIT FILLS ANY AIT FILLS NO AIT FILLS
N ¼ 45,279 N ¼ 103,207 N ¼ 2,231,323
N/Mean %/SD N/Mean %/SD N/Mean %/SD
Age (Mean, SD) 33.2 18.0 34.2 17.3 32.0 19.2
Age categories (N, %)
18–27 4,269 9.4% 12,357 12.0% 263,302 11.8%
28–37 6,848 15.1% 16,885 16.4% 308,516 13.8%
38–47 8,574 18.9% 20,925 20.3% 361,546 16.2%
48–57 8,001 17.7% 18,564 18.0% 394,717 17.7%
58–65 4,306 9.5% 9,396 9.1% 226,072 10.1%
Sex (N, %)
Male 20,004 44.2% 43,162 41.8% 973,797 43.6%
Female 25,275 55.8% 60,045 58.2% 1,257,526 56.4%
Geographic region (N, %)
Northeast 6,751 14.9% 14,107 13.7% 330,536 14.8%
North Central 8,198 18.1% 15,357 14.9% 384,770 17.2%
South 23,725 52.4% 58,137 56.3% 1,186,081 53.2%
West 6,431 14.2% 15,088 14.6% 319,442 14.3%
Unknown 174 0.4% 518 0.5% 10,494 0.5%
Population density (N, %)
Urban 40,055 88.5% 90,275 87.5% 1,948,820 87.3%
Rural 5,051 11.2% 12,440 12.1% 272,742 12.2%
Unknown 173 0.4% 492 0.5% 9,761 0.4%
Index year (N, %)
2014 14,009 30.9% 33,157 32.1% 727,487 32.6%
2015 14,366 31.7% 33,317 32.3% 736,087 33.0%
2016 13,657 30.2% 29,777 28.9% 602,157 27.0%
2017 3,247 7.2% 6,956 6.7% 165,592 7.4%
Abbreviation. AIT, allergy immunotherapy.

all-cause total healthcare costs compared to non-AIT patients
($11,612±$24,797 vs. $7815±$27,041), and with patients
reaching the maintenance phase of AIT presenting total
mean costs values lower than the overall AIT cohort
($10,431±$16,606). Compared to the full AIT cohort, AIT
maintenance patients presented lower mean follow-up hos-
pitalization costs ($698±$7248 vs. $1281±$12,991), emer-
gency room costs ($96±$513 vs. $125±$687), pharmacy costs
($2480±$7198 vs. $2622±$8674), and total medical costs
($7950±$13,844 vs. $8989±$22,019). Follow-up AR/AR comor-
bidity-related costs were naturally highest among AIT
patients reaching the maintenance phase of treatment
($4380±$4909), as these patients incurred greater costs for
their extended period of AIT treatment. In assessing the
change in costs from baseline to follow-up, AIT patients pre-
sented reductions in nearly all service categories assessed
with the exception of “other” outpatient services, where AIT
treatment costs are captured. These results were largely
driven by the subset of patients reaching the maintenance
phase of treatment (Figure 1). The non-AIT group showed
increases in all categories assessed.
As less than half of AIT patients reached the maintenance
phase of treatment, with 17% only presenting a single AIT
claim of any type, and 23.9% never presenting a single AIT
injection claim, analyses of the initial SCIT claim were under-
taken to quantify potential AIT-related healthcare wastage.
The cost associated with the index claim for SCIT varied
greatly, with a mean value of $674±$832. Fifty-five percent
of index SCIT claims carried a paid amount of less than $500,
though 20% of these claims were observed with cost values
in excess of $1000. Figure 2 presents the procedure codes
with the largest variance in costs for the index SCIT claim.
Procedure code 95165 (preparation and provision of antigens
for allergen immunotherapy)27 was used in 78% of the first
claims, and carried an average cost of $748±$849 per claim,
with 21% of the paid amounts on these claims exceeding
$1000. Among patients presenting a single AIT claim, 30.4%
of these sole visits were associated with costs in excess of
$1000, with 12.8% in excess of $2000 As such, patients pre-
senting with a single AIT claim managed to incur nearly half
the costs associated with AIT compared to patients present-
ing at least 25 injections ($976±$1367 vs. $2150±$1205).
Discussion
This study presents a real-world examination of the cost pro-
files of patients diagnosed with AR in the United States, with
a focus on those patients prescribed AIT. The AIT cohort pre-
sented higher rates of numerous baseline allergy-related
comorbidities compared to non-AIT patients, including
asthma (30.1% vs. 7.5%), chronic sinusitis (22.6% vs. 4.9%),
and upper respiratory tract infections (60.3% vs. 34.2%), sug-
gesting those patients most severely impacted by the dis-
ease were most likely to initiate AIT. These translated into
higher baseline and all-cause costs for the AIT cohort com-
pared to non-AIT. However, from the year prior to AIT initi-
ation to the year following, patients in the AIT cohort
presented cost decreases in the majority of service categories
assessed, including inpatient hospital and ER costs, while the
non-AIT group showed increases in all categories assessed.
AIT patients reaching the maintenance phase of treatment
were observed to present the largest reductions in expend-
iture from baseline to follow-up
Total annual healthcare costs were relatively low for the
full AIT and non-AIT cohorts ($11,612±$24,797 vs.
 CURRENT MEDICAL RESEARCH AND OPINION 961

Table 2. Baseline clinical characteristics by AIT cohorts.

25þ AIT FILLS ANY AIT FILLS NO AIT FILLS
N ¼ 45,279 N ¼ 103,207 N ¼ 2,231,323
N/Mean %/SD N/Mean %/SD N/Mean %/SD
Deyo-Charlson Comorbidity Index (Mean, SD) 0.46 0.72 0.45 0.76 0.22 0.66
Comorbid conditions of interest (N, %)
Any upper respiratory tract infection 28,568 63.1% 62,229 60.3% 762,433 34.2%
Sinusitis 19,291 42.6% 41,897 40.6% 385,113 17.3%
Asthma 15,689 34.6% 31,031 30.1% 166,674 7.5%
Conjunctivitis 12,277 27.1% 22,372 21.7% 98,447 4.4%
Chronic cough 12,074 26.7% 25,033 24.3% 230,975 10.4%
Upper respiratory tract infection 11,631 25.7% 25,969 25.2% 405,578 18.2%
Chronic sinusitis 11,087 24.5% 23,365 22.6% 108,380 4.9%
Heartburn, reflux, GERD 5,748 12.7% 13,346 12.9% 143,469 6.4%
Headache 5,119 11.3% 12,928 12.5% 117,204 5.3%
Otitis media 4,980 11.0% 10,287 10.0% 196,258 8.8%
Food allergya 4,503 9.9% 9,181 8.9% 20,955 0.9%
Bronchitis 4,347 9.6% 9,851 9.5% 116,626 5.2%
Atopic dermatitis 3,715 8.2% 7,324 7.1% 59,502 2.7%
Depression 3,628 8.0% 9,473 9.2% 126,999 5.7%
Eczema 3,469 7.7% 7,517 7.3% 83,330 3.7%
Sleep apnea 3,365 7.4% 7,662 7.4% 82,031 3.7%
Eustachian tube disorder 3,162 7.0% 6,660 6.5% 49,032 2.2%
Skin rash (including pruritus) 2,634 5.8% 6,488 6.3% 72,505 3.2%
Sleep disturbanceb 2,594 5.7% 6,682 6.5% 79,540 3.6%
Migraine 2,428 5.4% 6,243 6.0% 61,997 2.8%
Pneumonia 1,313 2.9% 2,754 2.7% 39,751 1.8%
Nasal polyps 1,295 2.9% 2,685 2.6% 4,970 0.2%
Chronic tonsillitis 414 0.9% 985 1.0% 7,387 0.3%
Concomitant Therapy (N, %)
Nasal spray 23,653 52.2% 45,766 44.3% 246,566 11.1%
Intranasal corticosteroid 19,435 42.9% 38,058 36.9% 251,121 11.3%
Decongestant 13,626 30.1% 29,796 28.9% 139,088 6.2%
Antihistamine 8,155 18.0% 17,371 16.8% 105,286 4.7%
Surgical Proceduresc (N, %) 2,030 4.5% 4,239 4.1% 20,195 0.9%
a
Food allergy includes peanuts, milk and milk produces, eggs, seafoods, and adverse symptoms related to food contact.
b
Sleep disturbance includes insomnia, hypersomnia, circadian rhythm sleep disorders, and narcolepsy.
c
Surgical procedures include turbinectomy, endoscopic sinus surgery, septoplasty, tympanostomy, and nasal polypectomy.
Abbreviations. AIT, allergy immunotherapy; GERD, gastroesophageal reflux disease; SD, standard deviation.

$7815±$27,04) compared to other chronic diseases in which
long-term maintenance treatment may be indicated30,31. The
lack of additional healthcare costs associated with prolonged
use of AIT is noteworthy, as the maintenance group actually
incurred lower annual healthcare costs than the AIT group as
a whole ($10,431±$16,606 vs. $11,612±$24,797). For most
therapeutic classes, adherence and persistence is often asso-
ciated with significantly increased medical and/or pharmacy
costs in the short term, which are not consistently offset by
reductions in other healthcare spend32, and has long been
cited by patients as one of the reasons for medication non-
adherence33. As such, results demonstrate that despite AIT
patients presenting fairly progressed disease at the time of
AIT initiation based on their increased levels of allergy-
related comorbidities compared to non-AIT patients, AIT
remains an economical treatment option and is not expected
to be accompanied by notable increases in overall healthcare
expenditure.
In the current study, less than half of AIT patients reached
the maintenance phase of treatment, which may be partially
explained by the fact that nearly a quarter of patients never
presented a single injection claim. The sub-analysis of the ini-
tial, index SCIT claims revealed a curious pattern of variables
costs, particularly when juxtaposed against this observed low
rate of AIT persistence. Medical procedure coding practices
for the reimbursement of AIT may vary, partly driven by the
discrepancies in accepted code usage across health insurance
plans. Present results demonstrated substantial variability in
the initial treatment costs for SCIT, along with a high mean
cost, and with nearly 20% of paid amounts exceeding $1000.
The observed spread in claimed amounts may be reflective
of certain physicians’ willingness and ability to bill for aller-
gen extracts, which would be administered over multiple
successive office visits. This up front-billing may contribute
to healthcare waste, particularly as almost 1 in 4 patients
never actually received a single AIT injection. Sublingual AIT
(SLIT) tablets, which have been FDA approved since 201434,
may present a better option to promote persistence and
adherence for some proportion of the AR population and
comes with less up front billing. A number of therapy-related
factors have been shown to correlate negatively with treat-
ment adherence, including the route of administration and
complexity of the regimen35. As SLIT is taken at home orally
once a day, this may present a more convenient option for
select patients. Though the direct comparison of adherence
rates between SLIT and SCIT have been variable36,37, these
can often be traced to the inherent difficulties comparing
two routes of administration, often leading to bias grounded
in differences in how adherence is defined and thresholds
for compliance are set. Regardless, improved patient treat-
ment matching efforts and patient education on AIT main-
tenance treatment in general may be warranted, in which
962 J. P. TKACZ ET AL.

Table 3. All-cause and AR-related healthcare costs by AIT cohorts in the baseline and follow-up periods.
25þ AIT FILLS ANY AIT FILLS NO AIT FILLS
N ¼ 45,279 N ¼ 103,207 N ¼2,231,323
N/Mean %/SD N/Mean %/SD N/Mean %/SD
All-Cause Costsa
Pre-Index Period
Inpatient costs $799 $6,815 $1,091 $9,926 $981 $11,811
ER costs $324 $1,095 $432 $1,517 $275 $1,244
Physician office visit costs $1,004 $780 $981 $993 $480 $616
Specialist office visit costs $260 $237 $212 $237 $20 $86
Laboratory costs $399 $1,459 $520 $2,397 $257 $1,292
Other outpatient costs $3,823 $9,410 $4,170 $11,955 $2,075 $10,150
Outpatient prescription costs $2,098 $5,727 $2,222 $6,873 $1,145 $6,123
Total Medical Costs (Mean, SD) $6,349 $13,551 $7,195 $18,270 $4,069 $17,780
Total Healthcare Costs (Mean, SD) $8,447 $15,467 $9,418 $20,566 $5,213 $19,503
Follow-Up Period
Inpatient costs $698 $7,248 $1,281 $12,991 $1,426 $16,790
ER costs $288 $1,079 $416 $1,573 $370 $1,615
Physician office visit costs $903 $802 $898 $1,140 $760 $731
Specialist office visit costs $202 $259 $156 $258 $71 $166
Laboratory costs $355 $1,047 $490 $2,433 $380 $1,606
Other outpatient costs $5,706 $9,478 $5,905 $13,539 $3,180 $13,769
Outpatient prescription costs $2,480 $7,198 $2,622 $8,674 $1,699 $8,529
Total Medical Costs (Mean, SD) $7,950 $13,844 $8,989 $22,019 $6,116 $24,692
Total Healthcare Costs (Mean, SD) $10,431 $16,606 $11,612 $24,797 $7,815 $27,041
AR-Related
Pre-Index Period
Inpatient costs $66 $1,286 $76 $1,577 $29 $1,115
ER costs $96 $513 $125 $687 $61 $434
Physician office visit costs $515 $405 $455 $423 $126 $223
Specialist office visit costsb $240 $217 $192 $216 $12 $63
Laboratory costs $10 $189 $9 $166 $3 $85
Other outpatient costs $1,312 $3,748 $1,254 $3,875 $200 $1,579
Outpatient prescription costs $617 $1,377 $563 $1,807 $101 $535
Surgical procedure costsc $295 $2,339 $271 $2,168 $32 $603
Anaphylaxis costs $0 $0 $0 $0 $0 $0
Total Medical Costs (Mean, SD) $1,998 $4,283 $1,919 $4,568 $417 $2,132
Total Healthcare Costs (Mean, SD) $2,615 $4,668 $2,482 $5,118 $518 $2,252
Follow-Up Period
Inpatient costs $22 $763 $43 $1,043 $35 $1,405
ER costs $74 $458 $107 $671 $88 $561
Physician office visit costs $410 $431 $363 $429 $322 $317
Specialist office visit costs $188 $244 $141 $237 $60 $146
Laboratory costs $4 $81 $6 $136 $5 $145
Other outpatient costs $3,054 $3,855 $2,747 $4,663 $528 $2,749
Outpatient prescription costs $816 $2,119 $749 $2,544 $218 $992
Surgical procedure costs $280 $2,136 $271 $2,145 $104 $1,233
Anaphylaxis costs $6 $90 $5 $99 $0 $0
AIT costs $2,150 $1,205 $1,798 $1,805 $0 $0
Total Medical Costs (Mean, SD) $3,564 $4,163 $3,266 $5,091 $978 $3,352
Total Healthcare Costs (Mean, SD) $4,380 $4,909 $4,015 $5,950 $1,195 $3,597
a
Costs were calculated based on paid amounts of adjudicated claims, including insurer and health plan payments, and patient cost-shar-
ing in the form of copayment, deductible, and coinsurance. All costs were adjusted for inflation using the medical care component of
the Consumer Price Index (CPI) and standardized to 2018 U.S. dollars.
b
Specialist office visits include allergy, immunology, otolaryngology, or pulmonary disease providers.
c
Surgical procedures include turbinectomy, endoscopic sinus surgery, septoplasty, tympanostomy, and nasal polypectomy.
Abbreviations. AIT, allergy immunotherapy; ER, emergency room; SD, standard deviation.

the timing and proportion of AR patients identified for candi-
dates for SCIT or SLIT is maximized.
As AR has also been shown to have significant impacts on
quality of life and work productivity, there is more than a dir-
ect economic benefit to be realized when the disease is
treated timely and appropriately. Studies have reported the
direct impact of AR on mood, anxiety, depression, social life,
sleeping, cognitive function, school performance, and overall
quality of life38,39, with specific clinical, immunological, and
functional parameters of the disease directly tied to quality
of life indices40. Further, results of a systematic review dem-
onstrate that 35% of patients with AR report impairment on
the job, also with a direct relationship to symptom
severity41,42. The total indirect cost estimates of AR vary
considerably from 0.1 billion to 9.7 billion USD annually,
with per-person costs of $5939,43. Improving the overall
quality of life for these patients, along with the promotion
of increased productivity, will result in significant societal
cost savings beyond direct medical expenditure, which will
be critical as the increasing trend in the prevalence of AR
is likely to continue due to a variety of environmental and
lifestyle-based causes44,45]. Thus, it may be advantageous
for patients to initiate AIT earlier in the course of their dis-
ease, which could hinder the development of a more
severe disease and minimize the onset of allergy-related
comorbidities.
 CURRENT MEDICAL RESEARCH AND OPINION 963

Change
Allin All-Cause
Cause CostsFigure
Cost Change Pre to Post Index
25+ AIT FILLS ANY AIT FILLS NO AIT FILLS
Inpatient costs -$101 $190 $445
ER costsLaboratory costs -$36 -$17 $94
Physician office visit costs -$101 -$83 $280
Specialist office visit costs -$58 -$56 $51
Laboratory costs -$44 -$31 $123
Other outpatient costs $1,882 $1,735 $1,106
Specialist office visit costs
Outpatient prescription costs $382 $400 $554
Total Medical Costs (Mean, SD) $1,601 $1,794 $2,047
Total Healthcare Costs (Mean, SD) $1,983 $2,194 $2,602
Physician office visit costs

AR-Related Cost Change Figure

ER costs 25+ AIT FILLS ANY AIT FILLS NO AIT FILLS
Inpatient costs -$44 -$33 $7
ER costs -$22 -$18 $27
Physician office visit costs -$105 -$92 $196
Inpatient
Specialist office costs
visit costs -$51 -$51 $48
Laboratory costs -$6 -$3 $3
Other outpatient costs $199 $186 $117
Outpatient prescription-$200
costs -$100 $0 $100 $200 $300 $400 $500

NO AIT FILLS ANY AIT FILLS 25+ AIT FILLS

Surgical procedure costs3 $15 $0 -$72
Anaphylaxis costs -$6 -$5 $0
Total Medical Costs (Mean,Change
SD) in$1,566
AR-Related Costs$1,346
Pre to Post Index$560
Total Healthcare Costs (Mean, SD) $1,764 $1,533 $677

Other outpatient costs

Laboratory costs

Specialist office visit costs

Physician office visit costs

ER costs

Inpatient costs

-$150 -$100 -$50 $0 $50 $100 $150 $200 $250

NO AIT FILLS ANY AIT FILLS 25+ AIT FILLS

Figure 1. All-cause and AR-related cost differences baseline to follow-up by AIT cohorts.

$0 - $99 $100 - $299 $300 - $499 $500 - $799 $800 - $999 $1,000+
Current Procedural Terminology Code

9514495199 30% 51%

65% 2% 2% 34% 0% 7%
2%
95165 13% 23% 15% 18% 10% 21%
95180 5% 24% 15% 20% 12% 25%
95199 51% 34% 3% 1% 4% 7%
95180 5% 24% 15% 20% 12% 25%

95165 13% 23% 15% 18% 10% 21%

95144 30% 65%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

$0 - $99 $100 - $299 $300 - $499 $500 - $799 $800 - $999 $1,000+

Figure 2. Cost distribution of index SCIT claims by select Current Procedural Terminology codes.
964 J. P. TKACZ ET AL.
Limitations
Studying AR in administrative claims data does come with
some limitations. First, AR can often be managed without
intervention of a physician (e.g. over the counter medications),
meaning there will be a period of time where AR patients do
not generate any claims with an AR diagnosis until the disease
reached more severe levels. As such, the true length of dis-
ease for patients in the current sample is unknown.
Additionally, the current study required a minimum of 2 years
of continuous commercial health coverage. Therefore, results
of this analysis may not be generalizable to AR patients who
change or lose insurance, to those with Medicare/Medicaid
insurance, and to the uninsured. Also, though patients were
followed for two years, the long-term clinical outcomes of AR
will likely require an extended follow-up window, as AIT will
require multiple years before its full therapeutic benefit is real-
ized. Additionally, administrative claims data are subject to
data coding limitations and data entry error, which may result
in missing or erroneous data. Finally, patient receiving SLIT
tablet prescriptions were also included in the analyses, and
may differ in some ways from those receiving SCIT. Analyses
focused solely on SLIT tablet patients may be warranted as a
follow-up to the current investigation.
Conclusion
In summary, this study presents the results of a real-world
examination of the direct costs associated with AR in the
United States, particularly among those treated with AIT,
which remains the only available treatment option which
can induce allergen-specific immune tolerance. Results dem-
onstrate that despite AIT patients presenting fairly pro-
gressed disease at the time of treatment initiation, this
therapy remains an economical treatment option, as it was
not accompanied by increases in overall healthcare expend-
iture. In fact, from baseline to follow-up, patients receiving
AIT presented cost decreases in the majority of service cate-
gories assessed, including inpatient hospital and ER costs,
while the non-AIT group showed increases in all categories
assessed. The observed increase in the allergy-related comor-
bidity load at the onset of AIT suggest these patients are
delaying this therapy until their disease is severe, while anal-
yses focused on patients’ initial AIT claim revealed substantial
variability in costs for these visits, highlighting an area of
healthcare wastage for patients who do not persist with ther-
apy. Taken together, continued efforts are needed to
increase patient awareness of available options and adher-
ence to AIT to improve patient treatment matching efforts,
including use of SLIT tablets. Given the known indirect costs
of AR and the toll this disease can take on general quality of
life, the full societal impact of optimal disease management
approaches will extend beyond the direct medical costs.
Transparency
Declaration of funding
.
This work was supported by ALK-Abello
Declaration of financial/other relationships
KR, DW, MA and EH were employed by ALK-Abello  during the execution
of this study. JT is employed by IBM Watson Health as a consultant and
received funding from ALK-Abello  to conduct this study. Peer reviewers
on this manuscript have no relevant financial or other relationships
to disclose.
Acknowledgements
Lisa Elliott is greatly acknowledged for her assistance with the develop-
ment of various elements of the initial study design.
Previous presentation
A preliminary analysis of select data appearing in the current manuscript
was presented at the AMCP 2020 annual meeting, April 21-24.
References
[1] Khan DA. Allergic rhinitis and asthma: epidemiology and com-
mon pathophysiology. Allergy Asthma Proc. 2014 Sep-Oct;35:
357–361.
[2] Mims JW. Epidemiology of allergic rhinitis. Int Forum Allergy
Rhinol. 2014; 4 Suppl(2) :S18–S20.
[3] World Health Organization. White Book on Allergy 2011–2012
Executive Summary Milwaukee, WI2012 [December, 12, 2019.
Available from: https://www.worldallergy.org/UserFiles/file/WAO-
White-Book-on-Allergy_web.pdf.
[4] Blaiss MS. Allergic rhinitis: direct and indirect costs. Allergy
Asthma Proc. 2010; 31:375–380.
[5] Allen-Ramey F, Mao J, Blauer-Peterson C, et al. Healthcare costs
for allergic rhinitis patients on allergy immunotherapy: a retro-
spective observational study. Curr Med Res Opin. 2017; 33:
2039–2047.
[6] Law AW, Reed SD, Sundy JS, et al. Direct costs of allergic rhinitis
in the United States: estimates from the 1996 Medical
Expenditure Panel Survey. J Allergy Clin Immunol. 2003; 111:
296–300.
[7] Meltzer EO, Bukstein DA. The economic impact of allergic rhinitis
and current guidelines for treatment. Ann Allergy Asthma
Immunol. 2011;106:S12–S6.
[8] Mudarri DH. Valuing the economic costs of allergic rhinitis, acute
bronchitis, and asthma from exposure to indoor dampness and
mold in the US. J Environ Public Health. 2016;2016:2386596.
[9] Reed SD, Lee TA, McCrory DC. The economic burden of allergic
rhinitis: a critical evaluation of the literature. Pharmacoeconomics.
2004;22:345–361.
[10] Dalal AA, Stanford R, Henry H, et al. Economic burden of rhinitis
in managed care: a retrospective claims data analysis. Ann
Allergy Asthma Immunol. 2008;101:23–29.
[11] Shaaban R, Zureik M, Soussan D, et al. Rhinitis and onset of
asthma: a longitudinal population-based study. Lancet. 2008;372:
1049–1057.
[12] Guerra S, Sherrill DL, Martinez FD, et al. Rhinitis as an independ-
ent risk factor for adult-onset asthma. J Allergy Clin Immunol.
2002;109:419–425.
[13] Hopper JL, Bui QM, Erbas B, et al. Does eczema in infancy cause
hay fever, asthma, or both in childhood? Insights from a novel
regression model of sibling data. J Allergy Clin Immunol. 2012;
130:1117–1122.e1.
[14] Bielory L. Allergic conjunctivitis and the impact of allergic rhinitis.
Curr Allergy Asthma Rep. 2010;10:122–134.
[15] Hadley JA, Derebery MJ, Marple BF. Comorbidities and allergic
rhinitis: not just a runny nose. J Fam Pract. 2012;61:S11–S15.
[16] Celakovska J, Bukac J. Food allergy in patients suffering from
atopic dermatitis – association with concomitant allergic diseases.
Food Agr Immunol. 2015;26:325–339.

[17] 
Celakovsk a J, Ettlerova K, Ettler K, et al. Food allergy, asthma
bronchiale, and rhinitis in atopic dermatitis patients with total
immunoglobulin E under and above 200 IU/ml. Food Agricult
Immunol. 2015;26:671–681.
[18] Settipane RA, Kreindler JL, Chung Y, et al. Evaluating direct costs
and productivity losses of patients with asthma receiving GINA 4/
5 therapy in the United States. Ann Allergy Asthma Immunol.
2019; 123:564–572 e3.
[19] Adamson AS. The economics burden of atopic dermatitis. Adv
Exp Med Biol. 2017;1027:79–92.
[20] May JR, Dolen WK. Management of allergic rhinitis: a review for
the community pharmacist. Clin Ther. 2017;39:2410–2419.
[21] Burks AW, Calderon MA, Casale T, et al. Update on allergy
immunotherapy: American Academy of Allergy, Asthma &
Immunology/European Academy of Allergy and Clinical
Immunology/PRACTALL consensus report. J Allergy Clin Immunol.
2013;131:1288–1296 e3.
[22] Cox LS, Murphey A, Hankin C. The cost-effectiveness of allergen
immunotherapy compared with pharmacotherapy for treatment
of allergic rhinitis and asthma. Immunol Allergy Clin North Am.
2020;40:69–85.
[23] Tinkelman D, Smith F, Cole WQ, 3rd, et al. Compliance with an
allergen immunotherapy regime. Ann Allergy Asthma Immunol.
1995;74:241–246.
[24] Silva D, Pereira A, Santos N, et al. Costs of treatment affect com-
pliance to specific subcutaneous immunotherapy. Eur Ann
Allergy Clin Immunol. 2014;46:87–94.
[25] Hsu NM, Reisacher WR. A comparison of attrition rates in patients
undergoing sublingual immunotherapy vs subcutaneous
immunotherapy. Int Forum Allergy Rhinol. 2012;2:280–284.
[26] Cohn JR, Pizzi A. Determinants of patient compliance with aller-
gen immunotherapy. J Allergy Clin Immunol. 1993;91:734–737.
[27] American Medical Association. CPT 2019 Professional Edition. 5th
revised ed. Chicago (IL): American Medical Association; 2019.
[28] Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity
index for use with ICD-9-CM administrative databases. J Clin
Epidemiol. 1992;45:613–619.
[29] United States Bureau of Labor Statistics. Consumer Price Index
for All Urban Consumers: Medical care in U.S. city average, all
customers, not seasonally adjusted Washington; 2019 [2019
December 19]. Available from: https://www.bls.gov/cpi/
[30] Chapel JM, Ritchey MD, Zhang D, et al. Prevalence and medical
costs of chronic diseases among adult medicaid beneficiaries. Am
J Prev Med. 2017;53:S143–S154.
CURRENT MEDICAL RESEARCH AND OPINION 965
[31] Yu H, MacIsaac D, Wong JJ, et al. Market share and costs of bio-
logic therapies for inflammatory bowel disease in the USA.
Aliment Pharmacol Ther. 2018;47:364–370.
[32] Gillespie CW, Morin PE, Tucker JM, et al. Medication adherence,
health care utilization, and spending among privately insured
adults with chronic conditions in the United States, 2010-2016.
Am J Med. 2020;133:690–704 e19.
[33] Mojtabai R, Olfson M. Medication costs, adherence, and health
outcomes among medicare beneficiaries. Health Aff (Millwood)).
2003;22:220–229.
[34] ALK-Abello  A/S. Grastek (timothy grass pollen allergen extract)
[package insert]. U.S. Food and Drug Administration 2014.
Available from: https://www.fda.gov/media/88510/download
[35] Jin J, Sklar GE, Min Sen Oh V, et al. Factors affecting therapeutic
compliance: a review from the patient’s perspective. Ther Clin
Risk Manag. 2008;4:269–286.
[36] Vogelberg C, Bruggenjurgen B, Richter H, et al. Real-world adher-
ence and evidence of subcutaneous and sublingual immunother-
apy in grass and tree pollen-induced allergic rhinitis and asthma.
Patient Prefer Adherence. 2020;14:817–827.
[37] Borg M, Lokke A, Hilberg O. Compliance in subcutaneous and
sublingual allergen immunotherapy: a nationwide study. Respir
Med. 2020;170:106039.
[38] Meltzer EO, Gross GN, Katial R, et al. Allergic rhinitis substantially
impacts patient quality of life: findings from the Nasal Allergy
Survey Assessing Limitations. J Fam Pract. 2012;61:S5–S10.
[39] Ozdoganoglu T, Songu M, Inancli HM. Quality of life in allergic
rhinitis. Ther Adv Respir Dis. 2012; 6:25–39.
[40] Ciprandi G, Klersy C, Cirillo I, et al. Quality of life in allergic rhin-
itis: relationship with clinical, immunological, and functional
aspects. Clin Exp Allergy. 2007;37:1528–1535.
[41] Vandenplas O, Vinnikov D, Blanc PD, et al. Impact of rhinitis on
work productivity: a systematic review. J Allergy Clin Immunol
Pract. 2018;6:1274–1286 e9.
[42] Maoua M, Maalel OE, Kacem I, et al. Quality of life and work
productivity impairment of patients with allergic occupational
rhinitis. Tanaffos. 2019;18:58–65.
[43] Simoens S, Laekeman G. Pharmacotherapy of allergic rhinitis: a
pharmaco-economic approach. Allergy. 2009;64:85–95.
[44] Akinbami LJ, Simon AE, Schoendorf KC. Trends in allergy preva-
lence among children aged 0-17 years by asthma status, United
States, 2001-2013. J Asthma. 2016;53:356–362.
[45] Cingi C, Bayar Muluk N, Scadding GK. Will every child have aller-
gic rhinitis soon? Int J Pediatr Otorhinolaryngol. 2019;118:53–58.