Research Article

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Real-world study: drug reduction in children

with allergic rhinitis and asthma receiving
immunotherapy
Jorge Sánchez*,1 , Leidy Alvarez2 & Elizabeth Garcı́a3
1
Group of Clinical & Experimental Allergy, University of Antioquia, Hospital “Alma Mater de Antioquia”, Medellı́n, Carrera 51A
#62–42, Colombia
2
Academic Group of Clinical Epidemiology (GRAEPIC), University of Antioquia, Medellı́n, Carrera 51A #62–42, Colombia
3
ORL Quirurgy Medical Unit “UNIMEQ ORL”, Bogotá, Ak. 9 # 116–20, Colombia
*Author for correspondence: Tel.: +57 300 393 4000; jorgem.sanchez@udea.edu.co

Background: The reduction of pharmacological treatment after allergen immunotherapy (AIT) for house
dust mites (HDMs) has been little studied in children. Objective: To evaluate the reduction of
pharmacological treatment comparing children that receive HDM immunotherapy (AIT group) versus only
pharmacotherapy. Methods: A historic cohort of children with rhinitis or asthma was assessed. The main
outcome was the frequency of complete drug discontinuation. Results: 100% drug reduction was higher
for rhinitis (4-year cumulative incidence: 30 vs 10.7%) and asthma (24.1 vs 10.5%) in the AIT group (n = 987)
than in the pharmacotherapy group (n = 2012). Conclusion: Immunotherapy is associated with a significant
reduction of pharmacotherapy in children. This is a marker of clinical control and could be associated with
positive economic impact.

Plain language summary: The benefits of allergen immunotherapy for house dust mites has been little
studied in children. The usefulness of this treatment in asthma over the use of pharmacotherapy has also
not been clearly evaluated. The use of immunotherapy allowed greater reductions in pharmacological
treatment in children with rhinitis and asthma. Immunotherapy is a useful treatment for childhood rhinitis
and asthma and reduces the risk of adverse effects from pharmacological treatments.

Graphical abstract:

Pharmacotherapy group
Immunotherapy group

Rhinitis Asthma
Probability of survival

Probability of survival

* * * * *
100 100

50 50

0 0
0 1 2 3 4 0 1 2 3 4
Years Years
Complete suspension 50% reduction
of pharmacotherapy of pharmacotherapy

30% vs 10.3% 49.9% vs 30.5%

HR 3.126 (2.008–9.696) HR 2.829 (1.805–4.154)

p = 0.05 p = 0.001

10.2217/imt-2022-0215 
C 2023 Future Medicine Ltd Immunotherapy (Epub ahead of print) ISSN 1750-743X
Research Article Sánchez, Alvarez & Garcı́a

First draft submitted: 27 August 2022; Accepted for publication: 24 January 2023; Published online:
15 February 2023

Keywords: allergen • allergy • asthma • immunotherapy • mites • pharmacotherapy • real-life • real-word • rhinitis

Allergic rhinitis is highly prevalent in childhood; it is estimated that 15–30% of children suffer from chronic
rhinitis [1,2]. Patients with allergic rhinitis are prone to other allergic manifestations; 60–80% have conjunctivitis
and 10–30% of patients with rhinitis have asthma [1,3]. During childhood, respiratory allergies are associated
with greater school absenteeism due to exacerbations of symptoms and the need for medical consultations [4,5]
With the COVID-19 pandemic, the fear of people with respiratory symptoms has become greater, generating a
meaningful burden on the quality of life of allergic patients. This produces social and economic effects on the
patient, their family and the health system.
Pharmacotherapy with nasal steroids, antihistamines and antileukotrienes has been shown to be effective in
controlling nasal symptoms, facilitates the reduction of complications and is recommended by multiple guidelines [6–
8]. However, depending on the severity, clinical relapses are frequent, medication use is usually chronic and
the economic cost is high. It is estimated that rhinitis generates an expense of more than 200 million dollars per
year in the purchase of control medications alone in the USA [9,10]. Similar economic costs have been observed in
European, Asian and Latin American countries [11–17]. The economic impact of rhinitis treatment in underdeveloped
countries may be greater due to lower per capita income. During the natural history of the disease, spontaneous
remission of symptoms over time may occur [18,19]. Some studies suggest that the frequency of spontaneous rhinitis
or asthma remission is less than 20%, so the discontinuation of pharmacotherapy is infrequent.
To date, allergen immunotherapy (AIT) is the only treatment that appears to change the course of allergic
disease. Similar to pharmacological treatment, AIT helps in symptoms control, but follows a different approach
to controlling type 2 inflammation, with the production of IgG4 antibodies, regulatory T lymphocytes, cytokines
(IL-10), TGF-β and the reduction of IgE antibodies and allergen recognition, among other mechanisms [20–25].
This control of the inflammatory response seems to persist for several years, even after finishing the immunotherapy
scheme; therefore, unlike pharmacological treatment, AIT allows long-term control [26,27].
The response to AIT varies according to the type of allergen extract used [28]; extracts with pollen grains and
house dust mites (HDMs) have received more attention and had some clinical studies, generally supporting their
efficacy and adequate safety profile, which supports the inclusion of immunotherapy in different guidelines as a
treatment alternative for allergic diseases like asthma and rhinitis [29–31]. However, there is still little information
available on HDM extracts that demonstrates the impact of immunotherapy in the reduction of pharmacological
treatment and the maintenance of clinical control in the long term. The answers to these questions are important
since they allow evaluation of the impact of immunotherapy on respiratory allergies beyond clinical control since
indirectly it could represent a great impact on health systems in terms of economic aspects and risk reduction of
adverse effects secondary to drug treatment. The effect of immunotherapy on other extracts, such as pets, insects
and fungi, has shown that it can be useful, but the results remain controversial [32–34].
Different studies suggest that HDM AIT reduces the symptoms of rhinitis, which in turn makes it possible
to reduce pharmacological treatment. In addition, AIT, especially in children, prevents the development of other
allergies like asthma or conjunctivitis [35]. Therefore, long-term immunotherapy could mean savings in costs for
the patient and the health system. However, according to some recent systematic reviews and meta-analyses,
evidence of the effectiveness of immunotherapy in reducing pharmacotherapy is scarce, and the results of studies
are heterogeneous, so the evidence is weak [36,37].
In most cases, IgE-mediated allergies such as rhinitis, asthma or conjunctivitis begin in the first decade of life.
Since these diseases share a common inflammatory mechanism, it is quite frequent that the presentation of one of
these diseases favors the subsequent development of the others, a process that has been called the allergic march [38–
45]. Even though allergic rhinitis and allergic asthma usually present in the first decade of life, most studies evaluating
the effectiveness of immunotherapy are conducted with adult populations. Consequently, little has been evaluated
in terms of the impact of immunotherapy on the reduction and discontinuation of pharmacological treatment in
the child population [35,46,47]. Studies evaluating the impact of immunotherapy do not usually have a comparator
group, which substantially limits the ability to know the clinical impact of this treatment [48]. The factors associated
with the response to immunotherapy are multiple; sociodemographic factors, the type of allergenic extract and the
number of sources used, the route of administration and adherence to treatment seem to be related to the type of

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 Drug reduction by immunotherapy Research Article

response. The relationship between these factors and the clinical response to immunotherapy with HDM allergens
have been little studied, but could potentially be useful as response predictors, which would allow the selection
of immunotherapy administration in patients with the highest probability of response, achieving personalized
precision medicine.
The current research was designed to provide information in this direction by evaluating the impact of subcu-
taneous AIT on the reduction of pharmacological treatment for rhinitis and asthma in a population of children.
Focused on this objective, the authors sought to reduce some of the limitations observed in previous studies by in-
cluding a significant number of patients and a control group with sociodemographic and clinical characteristics
similar to the group that received immunotherapy.

Materials & methods

Study design & population
This is a longitudinal study based on a historical cohort of patients between 6 and 14 years old with a diagnosis
of allergic rhinitis who attended three care centers in Colombia with allergology and otorhinolaryngology units
during the period from September 2015 to September 2021. HDMs are one of the main causes of allergies in the
world, ranking first in countries with a tropical climate. The mites of the families Dermatophagoides pteronyssinus,
Dermatophagoides farinae (Der. f ) and Blomia tropicalis (Blo. t) are ubiquitous on all continents and are the mites
most strongly associated with the development of rhinitis, conjunctivitis and allergic asthma [49–53]. Considering
that this study was conducted in centers located in a country with a tropical climate, the effect of HDM AIT was
evaluated. Patients with sensitization to mites Der. f, D. pteronyssinus (Der. p) and/or Blo. t were included, which
are the cause of 90% of allergies in the study region [54]. Patients under 6 years old were not included because in
the study population receiving immunotherapy, they represent less than 5% and to avoid possible measurement
and selection biases due to other transitory illnesses typical of children under six years of age, whose symptoms are
similar to rhinitis or asthma but are not secondary to an allergic process. Sensitization was defined by a positive
skin prick test to HDMs or serum-specific IgE (sIgE) to HDMs. Other sensitizations were present (dog: 27%, cat:
12%, insects: 18%, pollens: 6%) but were less frequent than HDMs. Patients who were receiving concomitant
immunotherapy for allergens other than HDM were not included to avoid confusion in the evaluation of the
principal outcome. Sublingual immunotherapy is administered in less than 10% of the population attending
the three participating centers, therefore it was not included since it was not a population with sufficient data
to be able to study the outcomes of interest. The treatment administered to all patients, both pharmacological
and immunotherapy, should follow international guidelines for allergic rhinitis or asthma and are part of the
conventional management of allergies [6,7,55–57].
From this population, two groups were formed according to whether they received pharmacotherapy alone
(P group) or additionally received subcutaneous AIT with Der. f, Der. p and/or Blo. t mites (AIT group).
Immunotherapy in the participating centers had an indication of a duration of three years. AIT was applied
monthly. The scheme used to start immunotherapy was an ’ultrarush’ scheme (0.2 ml, 30 min later 0.3 ml) with
a monthly maintenance dose of 0.5 ml of a modified extract with glutaraldehyde (polymerized) of Der. p/Der. f
or extract of Der. p/Der. f/Blo. t (Inmunotek, Madrid, Spain) with an allergenic potency of (10.000 UT/ml).
Clinical records for 1 year after immunotherapy were included. The same protocol was done in the three centers.
Because the effect of immunotherapy is detectable after several months of its application, only patients with at least
six doses received in the first year were included in the AIT group. Patients who required the permanent use of
immunosuppressants or biologicals (e.g., Global Initiative for Asthma [GINA] step 5) or who had contraindications
for the use of immunotherapy or conventional pharmacotherapy for the management of asthma and rhinitis were
excluded [58].
Since this study was noninterventional, the administration or not of immunotherapy was determined according
to medical criteria and/or patient preference during the medical appointment. In addition, the severity of rhinitis
and asthma was recorded heterogeneously. This can generate bias, so seeking to reduce heterogeneity between
groups, for each patient who was included in the AIT group, at least two patients in the P group who did not
have a contraindication for IT and had similar sociodemographic and clinical with random matching adjusted
for covariates were included. For random matching, some continuous variables were categorized according to
Colombia’s national administrative department of statistics (economic status: “low,” “medium,” “high.”; place
of residence: “urban,” “rural”) and clinical guidelines according to Allergic Rhinitis and its Impact on Asthma
(ARIA) and GINA (sensitization: “yes,” “no”, “polysensitization”; asthma comorbidities: “yes,” “no”; severity:

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Research Article Sánchez, Alvarez & Garcı́a

“mild,” “moderate/severe”; treatment step). Only patients with moderate/severe persistent rhinitis according ARIA
guidelines were included. Patients with polysensitization were included, but not those receiving immunotherapy
to sources other than mites to avoid measurement bias. In those patients who also had asthma, information was
collected about the frequency of exacerbations, use of salbutamol, emergency assistance or hospitalizations as well as
adherence to pharmacological treatment and daily doses. Patients without clear information on the pharmacological
therapy received (dose, type of medication, frequency) or without sufficient follow-up were excluded. Patients with
other respiratory diseases that could bias the interpretation of the results were also not included.

Outcomes
Considering that the information comes from a historical cohort from three different centers, the evaluation of
outcomes such as quality of life or clinical control of rhinitis and asthma according to clinical scales was not
possible since physicians did not use a unique clinical scale to define control of the disease. As the main outcome,
change in the pharmacological treatment of each patient was assessed and used as measurement variables for the
pharmacological prescription for rhinitis and allergic comorbidities (asthma) according to medical chart notes
of patients. Because it is a historical cohort, there was no predesigned treatment reduction protocol; this was
done according to the criteria of each treating physician. Although the reduction in treatment corresponded to
the decision of the treating physician, this outcome variable had the advantage of being able to be evaluated
cross-sectionally between the centers and the follow-up over time made it possible to assess whether the patient
needed to restart a previously suspended therapy or if, on the contrary, the reduction in treatment was maintained
in the long-term secondary to clinical control. Nasal treatments evaluated were nasal steroids, antihistamines or
antileukotrienes. For asthma treatment, steroids only, steroids/beta-agonists and antileukotrienes were assessed.
The frequency emergency room visits was also recorded. The following definitions were used for the evaluation
parameters:

• 100% reduction (R100): complete discontinuation of medication for at least 6 months;

• 50% reduction (R50): partial discontinuation of a least 50% but less than 100% of the treatment or the dose
received at the time of recruitment;
• Increase medication: the increase in medication could be due to new medication due to lack of control, increased
dose or reintroduction of a medication previously withdrawn due to relapse of rhinitis and/or asthma;
• Assistance at medical care center: number of visits to the emergency room or hospitalizations for respiratory
processes in one year.

As secondary outcomes, the relationship between some clinical and sociodemographic factors and the clinical
response to AIT (sensitization to multiple sources, asthma as a comorbidity, adherence to the AIT scheme) were
explored.

Ethical considerations
The three participating institutions gave their permission for the review of records while maintaining the anonymity
of each patient.

Statistical analysis
Analyzes were performed using SPSS version 26 software and Prism 9. Survival analysis was conducted for the
evaluation of outcomes. Analyses with p < 0.05 were considered statistically significant but, considering the
possibility of spontaneous remission for clinical relevance, a net benefit between the groups of at least 20%
was considered for the principal outcome. When appropriate, measures of dispersion are included to compare effect
sizes between groups using the lower and upper limits of normality in each group. Wilcoxon’s U test was used for
intergroup analysis and proportions were analyzed using contingency tables and Fisher’s exact test.

Results
Description of the patients
A total of 5744 records were reviewed. For the analyses, 2012 were included in the P group and 987 in the AIT
group (Figure 1). Patient age, symptom severity, mean age of asthma onset and drug treatment were similar in
the AIT group and the P group without significant differences (Table 1). In the AIT group, the median number

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 Drug reduction by immunotherapy Research Article

Total records reviewed

Total: 5744
Total excluded (n 2500)
Selection criteria (n 1815)
Lack of information (n 685)
Total included (n 3244)

P group P (n 2167) AIT group (n 1077)

Less than six immunotherapies (n 31)

Lost of follow-up (n 43) 1st year 1 (n 2167) 1st year 1 (n 1046) Lost of follow-up (n 16)
Prohibited medication (8) Prohibited medication (n 1)
New exclusion diagnosis (6) New exclusion diagnosis (n 1)
Other reason (8) Other reason (n 2)
2nd year 1 (n 2102) 2nd year 1 (n 1026)
Lost of follow-up (n 32) Lost of follow-up (n 14)
Prohibited medication (4) Prohibited medication (2)
New exclusion diagnosis (3) New exclusion diagnosis (1)
Other reason (6) 3rd year 1 (n 2057) 3rd year 1 (n 1007) Other reason (2)
Lost of follow-up (n 32) Lost of follow-up (n 16)
Prohibited medication (8) Prohibited medication (1)
Other reason (5) Other reason (3)
4th year 1 (n 2012) 4th year 1 (n 987)

Figure 1. Flowchart. Records were obtained from three health centers in Medellin, Colombia. The number of records
reviewed includes those that ended follow-up and those that were withdrawn.

Table 1. Clinical and sociodemographic characteristics.

P group (n = 2012) AIT group (n = 987) p-value
Age 8.5 (SD: 5.3) 8.9 (SD: 5.7) 0.3
Female 1118 (55.5%) 558 (56.5%) 0.5
Der f/Der p sensitization 2012 (100%) 987 (100%) N/A
Blo t sensitization 789 (39.2%) 354 (35.8%) 0.3
Other sensitization 614 (30.5%) 315 (31.9%) 0.7
Rhinitis 2012 (100%) 987 (100%) N/A
Asthma 344 (17%) 171 (17.3%) 0.5
Conjunctivitis 1899 (94.3%) 901 (91.2%) 0.4
Severity
TNSS 6.8 (SD: 6.4) 7.4 (SD: 5.9) 0.2
Asthma GINA step 2:3:4 23.3%:44.4%:32.3% 25.7%:46%:28.3% 0.2
Rhinitis pharmacotherapy
Nasal steroid 1967 (97.7%) 914 (96.5%) 0.3
Antihistamines 1645 (81.7%) 811 (82.1%) 0.3
Antileukotrienes 645 (32%) 302 (30.5%) 0.3
Other pharmacotherapies
Inhaled steroids 131 (6.5%) 43 (4.3%) 0.2
Inhaled steroids/long-action beta agonist 213 (10.5%) 128 (12.9%) 0.2
Eye lubricants 1758 (87.3%) 868 (87.9%) 0.4
Eye antihistamines drop 1657 (82.3%) 799 (80.9%) 0.3
Total Nasal Symptom Score was collected or reconstructed from medical records.
Other sensitizations: dog, cat, insects, pollens.
Atopy: positive skin prick test and/or specific blood IgE.
AIT group: Pharmacotherapy/immunotherapy; GINA: Global Initiative for Asthma; P group: Pharmacotherapy; SD: Standard deviation; TNNS: Total Nasal
Symptom Score.

of immunotherapy doses received per year was 9 (95% CI: 3–12). Most patients completed at least 30 doses of
immunotherapy (30 doses or more: 83%; 24–29 doses: 5%; 12–23 doses: 7%; <12 doses: 5%). The rate of fulfilled
immunotherapy appointments was 76.5%.
The available sociodemographic and allergic disease characteristics of the excluded patients (Figure 1) were like
those of the patients who remained for follow-up (data not shown). The main cause of exclusion was a lack of data

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Table 2. Net medication reduction.

Crude AIT group (%) P group (%) Net difference (%)
Rhinitis R100 30 10.7 19.3
Rhinitis R50 65.6 24 41.6
Asthma R100 24.1 10.5 13.6
Asthma R50 49.9 30.5 19.4
Adjusted AIT group (%) P group (%) Net difference
Rhinitis R100 28.7 6.4 22.3% (95% CI: 17.4–28%)
Rhinitis R50 63.2 20.7 42.5% (95% CI: 30.6–50.1%)
Asthma R100 21.3 4.6 16.7% (95% CI: 12.6–20%)
Asthma R50 46.5 23 23.5% (95% CI: 19–32%)
The difference column indicates the benefit of the group with immunotherapy versus the group with pharmacotherapy alone. (Crude) present crude
outcomes. (Adjusted) we adjusted for re-introduction of a drug, introducing a new drug, or increasing the dose of the control medication.
AIT group: Pharmacotherapy/immunotherapy; P group: Pharmacotherapy; R50: Partial discontinuation of a least 50%; R100: Complete discontinuation.

Table 3. Number of patients receiving each treatment after four years.

Treatment AIT group P group Net difference
Nasal steroids 676 (73.9%) 1849 (94%) 20.1% (95% CI: 12.4–24%)
Antihistamines 584 (72%) 1546 (93.9%) 21.9% (95% CI: 15.6–26%)
Antileukotrienes 211 (69.8%) 516 (80%) 10.2% (95% CI: 6–12.6%)
Inhaled steroids 39 (90.6%) 129 (98.4%) 7.8% (95% CI: 1.6–11.5%)
Inhaled steroids/long-action beta agonist 113 (88.2%) 207 (97.1%) 8.9% (95% CI: 2.6–14.8%)
AIT group:
Pharmacotherapy/immunotherapy; P
group: Pharmacotherapy.

in the clinical history regarding the study variables (e.g., pharmacotherapy dosage; Figure 1). The main lack of
information among the excluded patients was regarding drug treatment, followed by continuity in appointments.
Among the group of excluded patients, there was a tendency to be more frequently located in rural areas, which
might be associated with the lack of continuity in appointments and then the lack of information.

Reduction in the use of medications

During the follow-up after the second year, the reduction in pharmacological treatment for rhinitis and asthma was
greater in the AIT group versus the P group for R100 and R50 (Figure 2). The need to introduce medication due
to lack of control was greater in the P group (Figure 3) but was not statistically significant. When adjusted for the
introduction of new medications, dose modifications or the reintroduction of previously withdrawn medications,
the net reduction in medication was in favor of the AIT group for rhinitis (R100: 22.3% [95% CI: 15.6–28%]
and R50: 42.5% [95% CI: 30.6–50.1%]) and asthma (R100: 16.7% [95% CI: 5.6–20%] and R50: 23.5% [95%
CI: 19–32%; Table 2]). When evaluating patients after one year of discontinued immunotherapy, most patients
who had received at least 24 doses (n = 953) did not have to reintroduce medications or increase doses for rhinitis
(5%), asthma (4%) or conjunctivitis (13%). The net reduction in pharmacotherapy is presented in Table 3.

Attendance at a medical center & number of asthma exacerbations

After the first year, a lower frequency of visits to a medical center due to asthma exacerbation was observed in
the AIT group versus the P group (Figure 4). In both, there was a similar reduction in the frequency of asthma
exacerbations. Among patients who completed immunotherapy with at least 24 doses, there was no significant
increase in the number of exacerbations after 1 year of follow-up.

Discussion
AIT is the only etiology-based treatment for allergic diseases capable of disease modification. Several meta-analyses
and systematic reviews support the usefulness of immunotherapy in the control of respiratory symptoms, prevention
of new allergic sensitizations and prevention of disease progression [36,37]. Despite some articles suggesting a possible
effect of immunotherapy in the reduction of pharmacotherapy, the evidence is controversial, especially in children.

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Group P/IT
Group P
* * *
100 100 * * *
Probability of survival

Probability of survival
50 50

0 0
0 1 2 3 4 0 1 2 3 4
Years Years

Rhinitis R100 AIT group P group Rhinitis R50 AIT group P group

Baseline 100% 100% Baseline 100% 100%

1st year 93.3% 96.6% 1st year 82.7% 93.3%

2nd year 80% 93.3% 2nd year 58.6% 83.3%

3rd year 70% 89.7% 3rd year 34.4% 76.6%

4th year 70% 89.7% 4th year 34.4% 76%

HR 3.126 (2.008–9.696) HR 3.226 (1.491–6.678)

p = 0.05 p = 0.002

* *
100 100 * *
Probability of survival
Probability of survival

50 50

0 0
0 1 2 3 4 0 1 2 3 4
Years Years

Asthma R100 AIT group P group Asthma R50 AIT group P group
Baseline 100% 100% Baseline 100% 100%
1st year 96.6% 100% 1st year 82.7% 93.3%
2nd year 82.8% 93.1% 2nd year 65.5% 80%
3rd year 75.9% 89.5% 3rd year 50.1% 69.5%
4th year 75.9% 89.5% 4th year 50.1% 69.5%

HR 2.441 (0.706–8.434) HR 2.829 (1.805–4.154)

p = 0.166 p = 0.001

Figure 2. Reduction of pharmacotherapy. Reduction of medication during follow-up. Hazard ratio is present as AIT
group in direction to P group.
AIT group: Pharmacotherapy/immunotherapy; P group: Pharmacotherapy.

The reduction of pharmacological treatment has several benefits: it is a surrogate marker of clinical control, facilitates
adherence to treatment, reduces the risk of adverse effects, improves quality of life and, in the medium term, reduces
the economic burden for the patient and the health system. Some of these aspects were not explored directly in
this investigation, but similar to previous real-life studies [48,59,60], in this research, immunotherapy significantly

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100 100

Probability of death

Probability of death
Group P/IT
Group P

50 50

0 0
0 1 2 3 4 0 1 2 3 4
Years Years

Rhinitis up-pharmacotherapy AIT group P group Asthma up-pharmacotherapy AIT group P group
1st year 3.3% 10% 1st year 3.3% 10%
2nd year 10.2% 16.6% 2nd year 10.2% 16.6%
3rd year 13.9% 20% 3rd year 17.7% 20%
4th year 13.9% 20% 4th year 17.7% 20%
HR 0.662 (0.191–2.288) HR 0.858 (0.263–2.801)
p = 0.510 p = 0.795

Figure 3. Up-pharmacotherapy. Up-pharmacotherapy refers to the reintroduction of a drug, introducing a new drug
or increasing the dose of the control medication. Hazard ratio is present as AIT group in direction to P group.
AIT group: Pharmacotherapy/immunotherapy; P group: Pharmacotherapy.

reduced controller medications for respiratory symptoms and also reduced the frequency and severity of asthma
exacerbations compared with patients using only pharmacotherapy. Therefore, immunotherapy achieved several of
the proposed benefits of reducing pharmacological therapy, but also achieved objectives that only a therapy that
modifies the natural course of the disease can do. Most of the real-life studies published about this topic have
some limitations that we tried to avoid in this investigation; the cohort design, systematic recollection of the data,
paired sampling and evaluation with an objective and quantifiable outcome, allowed measurment of the impact of
immunotherapy compared with pharmacological treatment, reducing selection and measurement biases.
Although clinical trials are useful to evaluate the efficacy of therapies, they are not useful for evaluating some
outcomes with clinical relevance for patients and health system programs (e.g., adherence, patient preferences
and economic impact) that may affect their applicability in daily routine. On the contrary, real-life studies allow
evaluation of the impact of immunotherapy and pharmacotherapy in conditions where aspects such as adherence
are not controlled. Most of the patients completed at least 30 doses of immunotherapy in four years and more than
30% had to suspend at least three doses per year but, even so, the pharmacotherapy reduction was maintained in
the group receiving immunotherapy, which served as a proxy for symptom control.
Based on these results, we can see that, as with other therapies, adherence to immunotherapy is not 100% [61–65].
Among the reasons for the lack of adherence are the economic implications of the treatment, the time required and
the preferences of the patient. Most patients received 9 of 12 possible doses per year, but even so, the superiority
of immunotherapy in reducing drug treatment was observed. When we reviewed the patients with less than seven
doses per year, we did not observe a clear advantage in the application of immunotherapy, which would indicate
that the number of minimum annual doses recommended for immunotherapy is between eight and nine doses.
Although we did not have sufficient data to carry out the appropriate statistical analyses, there seems to be a
relationship between a greater clinical response and a greater number of doses, so although a clinical response is
seen even with eight annual doses, the ideal is to achieve the greatest adherence.
From an economic point of view, AIT introduces an additional expense. According to the social organization
of each country, this additional expense must be assumed by the patient or the health system [66,67]. Therefore,
in some economic evaluation studies, AIT is cost-effective and in others, it is not. We observed that in the case
of patients with rhinitis, a high percentage achieved a complete or partial reduction of medications and did not
have to reintroduce medications later, which suggests that the additional expense could be compensated by the
reduction of pharmacotherapy, reduction of absenteeism and a better quality of life. This result was similar for
asthma medications, where additionally the patient required less assistance from the health centers with economic
and time savings for the patient. In addition, patients receiving immunotherapy tended to develop less asthma. Two

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Attendance to health care center

1.2 Group P Group P/IT

* * * *
0.99
1.0 0.95 0.93

0.79
Event/person/year

0.79
0.8
0.71 0.69

0.6 0.55
0.5
0.45
0.4

0.2

0.0
Baseline 1st year 2nd year 3rd year 4th year

Asthma exacerbations
18
Group P Group P/IT
16 15.4 15.7

14 13.8
12.9
Event/person/year

12
10.8 10.9
9.8 9.5
10
8.5 8
8

0
Baseline 1st year 2nd year 3rd year 4th year

Figure 4. Attendance to a healthcare center for asthma attacks and number of exacerbations. The number of
asthma exacerbations and the number of visits to the emergency room were calculated as the number of events per
person in one year.
Group P: Pharmacotherapy; Group P/IT: Pharmacotherapy/immunotherapy.

economic evaluations carried out in the study population suggest that, in the first year, immunotherapy generates an
additional expense in the treatment of rhinitis and asthma. After the first year, patients who receive immunotherapy
with allergens have a lower cost in their treatment for rhinitis compared with before receiving immunotherapy
and, in the case of asthma, the cost of treatment was equal [17,68]. Another economic aspect of immunotherapy is
its impact on reducing possible complications of drug treatment (e.g., nosebleeds) and the cost of emergency care
for asthma. Although the study did not have the objective of carrying out an economic evaluation, we observed a
lower need for rescue treatment for asthma and lower emergency care for asthmatic attacks in the immunotherapy
groups, recommending future evaluation of these aspects.
AIT has different forms of application [69–71]; however, the two routes with the most clinical information available
are subcutaneous application and sublingual application. Although both routes are widely recognized, we focused
on evaluating the subcutaneous route since it is used in 90% of patients located in tropical countries where mites
are the main source of IgE sensitization and allergies.
Conjunctivitis and asthma are the two most frequent comorbidities in patients with allergic rhinitis [72–74]. In
the case of asthma, we observed outcomes that suggest better clinical control secondary to AIT. Unfortunately, we
did not collect data that would allow us to assess the impact of AIT on allergic conjunctivitis. Previous studies

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Research Article Sánchez, Alvarez & Garcı́a

suggest an important impact of AIT at the level of ocular allergies [30,36,75,76], which, added to the impact at levels
of respiratory allergies (asthma and rhinitis), suggests that AIT is a holistic treatment with an important clinical
impact, which allows reducing drug treatment, potentially improving the health status of patients and having a
positive impact on health systems.
Different factors have been suggested as possible predictors of response to immunotherapy [77–82]; sensitization
to multiple sources, allergy to cockroaches and the presence of asthma have been associated with a poor response
to immunotherapy, while monosensitization and initiation of immunotherapy in childhood have been associated
with a higher probability of a good clinical response. Due to the design of the study, the evaluation of these
factors was only exploratory, and we did not find a statistically significant difference in the possible responses
to immunotherapy. The controversial results observed between different studies regarding the possible variables
associated with the response to immunotherapy may be due to different reasons: the allergenic source used during
immunotherapy, adherence to treatment and route of administration. As previously mentioned, the response was
more dependent on adherence than on other factors.
Due to the study design, there are some biases that could not be fully controlled. Despite the active search, we
were unable to define the criteria for physicians to order or not immunotherapy or for patients to accept or not
this treatment. However, we controlled most of the variables that have been clinically recognized to potentially
affect the comparison of the groups or the incidence of the outcome of interest, age, atopy, severity of disease
and pharmacotherapy. Although clinical control was not directly measured, the high reduction in AIT versus
pharmacotherapy group suggests that immunotherapy has an important impact; the magnitude of the difference
was pronounced (>20% reduction) for most of the principal outcomes.
Despite these weaknesses, this study also has some strengths from a methodological point of view and allowed
for robust results that complement previous studies. In a population with a representative number of patients, we
were able to have a control group with characteristics comparable to the active group. We evaluated not only the
response during immunotherapy but also one year after finishing, which allows us to confirm that the reduction
of pharmacotherapy as an effect of immunotherapy started approximately one year after AIT began and this was
maintained even one year after completing the immunotherapy administration scheme. We evaluated the impact
of immunotherapy in different respiratory allergic diseases (asthma and rhinitis) in the same cohort, which allowed
us to establish the individual impact of immunotherapy in each disease, but also the overall impact in patients
with multiple allergic diseases. We were able to assess not only the reduction in pharmacological treatment but
also how many patients were required to receive pharmacotherapy again and how many patients who completely
discontinued pharmacotherapy did not present relapses during follow-up, which allowed us to establish the real net
effect of immunotherapy over time.

Conclusion
In conclusion, due to symptom control, patients receiving HDM AIT have a greater probability of reducing
treatment with controller medications, which possibly improves clinical control (with reductions in possible
adverse effects) and economic costs and reduces the risk of new allergic processes. It is necessary to evaluate whether
these results also occur with the sublingual route and to compare whether the age at which immunotherapy starts
could modify the results obtained.

Author contributions
J Sánchez provided the core idea. J Sánchez, L Alvarez and E Garcı́a contributed equally to the writing and analysis of the manuscript.

Financial & competing interests disclosure

The article was financed by the clinical and experimental allergology group, Hospital “Alma Mater de Antioquia,” University of
Antioquia (Medellı́n, Colombia). The authors have no other 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 apart from
those disclosed.
No writing assistance was utilized in the production of this manuscript.

10.2217/imt-2022-0215 Immunotherapy (Epub ahead of print) future science group

 Drug reduction by immunotherapy Research Article

Summary points
• Reduction in pharmacological treatment is an indirect marker of clinical control.
• Using a historical cohort, the authors followed up a significant number of patients with rhinitis and compared
the reduction in pharmacotherapy between those who received immunotherapy and those who did not receive
immunotherapy.
• Immunotherapy reduced pharmacotherapy in children with rhinitis and asthma over the control group.
• Complete discontinuation of pharmacotherapy for rhinitis was three times higher in the immunotherapy group
versus the control group.
• Complete discontinuation of pharmacotherapy for asthma was higher in the immunotherapy group but the
difference was not statistically significant.
• Reduction of pharmacotherapy for rhinitis and asthma was higher in the immunotherapy group versus the
control group.
• These results are of great importance in the establishment of public policies that are safe and cost-effective.
• Immunotherapy reduces controller medications, which possibly improves clinical control with reductions in
possible adverse events.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined
in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human
subjects, informed consent has been obtained from the participants involved.

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