Introduction
Allergen immunotherapy (AIT) is the only currently available treatment strategy that targets modifying the immune response to the causative allergen in respiratory allergic diseases [1]. Besides clinical efficacy, the disease-modifying effect of AIT had been demonstrated for pollen and house dust mite (HDM)-induced allergic rhinitis and/or asthma [2–4]. AIT is a novel type of treatment that may be able to change the course of an allergic reaction. Antigen-specific immunomodulatory tolerance is characterized by a lower antigen-specific response, which may be combined with immunological deviation, T-cell anergy, and/or T-cell death [5].
Allergen immunotherapy is another immunomodulatory treatment option being considered for IgE-mediated food allergies around the world. At regular intervals, the patient is exposed to the allergen in increasing doses. It prevents the symptoms of allergy and creates tolerance of the immune system to food allergens by increasing the amount of food that the patient is able to consume at the same time [6].
Specific AIT is the only method that can positively change the development of new allergies, exacerbation of symptoms and the natural course of the disease in allergic rhinitis and asthma. The increase in the number of polysensitized allergic patients poses a serious problem. According to a review by Calderon et al., 50–80% of patients are polysensitized [7].
Reservations about immunotherapy in polysensitized patients still continue today. However, when the development of bronchial symptoms and asthma, which start with allergic rhinitis and add up over time, as well as corticophobia in the patient and his/her relatives, are taken into consideration, the necessity of immunotherapy becomes evident. The studies have focused on the idea that immunotherapy may reduce or eliminate the use of nasal, oral, and inhaled corticosteroids (ICS) in patients with moderate to severe rhinitis and mild to moderate asthma. It is also noteworthy that publications on the adult population are limited in the literature.
AIM
In this study, we aimed to shed light on immunotherapy in polysensitized patients and to evaluate its positive effects on other drug treatments, especially steroids.
MATERIAL AND METHODS
As of August 2020, a group of 150 age- and gender-matched patients with allergic rhinitis and/or asthma, polysensitized and monosensitized, who had been receiving immunotherapy for at least 2 years, were evaluated together with existing patient records and a survey study under observation. The purpose of the study is to provide a response to the following query: How long do patients take oral, nasal, or ICS after starting subcutaneous immunotherapy (SCIT) and using it for at least 2 years? For how long do they discontinue these medications? In other words, the goal of the research is to make sure that the immunotherapy’s steroid-sparing effect – that is, how long the vaccine protects the patient from steroid use? The limited number of publications in the literature on the adult population and the limitations on the effectiveness of immunotherapy in the polysensitized group led us to this study. Pregnant patients were excluded from the study. In our study, it was not possible to start medical treatment or SCIT in patients for research purposes, and a survey was conducted under supervision in patients receiving current treatment, by filling out a consent form on a voluntary basis. Changes in IgE and eosinophil levels of all patients were evaluated.
SKIN PRICK TEST (SPT)
SPTs were performed with common commercially available aeroallergens (grass, weeds, tree pollen, house mites, molds, and animal dander). SPTs were performed with Allergopharma Prick solutions (Germany). Physiological saline was used as a negative control, and histamine (10 mg/ml) was used as a positive control. The SPT results were evaluated after 20 min. A skin induration at least 3 mm larger than the negative control and the presence of accompanying erythema were considered positive.
SUBCUTANEOUS IMMUNOTHERAPY (SCIT)
Vaccines were administered at the initial and maintenance doses recommended by the manufacturer (Allergopharma-Novo Helisen Depot and Allergopharma Allergovit, Germany).
DRUGS
Nasal topical drugs (intranasal corticosteroids (INSs); mometasone furoate, fluticasone furoate, and beclomethasone dipropionate) and ICSs (budesonide/formoterol (160/4,5 or 400/12), salmeterol xinafoate + fluticasone propionate (50/250 or 50/500 ) used by patients are treatment options applied at recommended doses, taking into account the needs of the patient.
This study aimed to evaluate the effects of SCIT treatment on the use of steroid-containing drugs. Although the level of effect called the steroid-sparing effect is considered to be the main target, other medications, such as antihistamines and montelukast, were also evaluated.
Our study was conducted in the Health Sciences University. It was approved by the Ethics Committee of Bursa High Specialty Training and Research Hospital with decision number 2011-KAEK-25 2020/07-07 dated 22.07.2020.
STATISTICAL ANALYSIS
SPSS 27 (Statistical Package for the Social Sciences) program was used for statistical analysis. Descriptive statistical methods (mean, standard deviation, median, frequency, percentage, minimum, maximum) were used when evaluating the study data. The suitability of quantitative data for normal distribution was tested using the Shapiro-Wilk test and graphical analysis. Student-t test was used for comparisons of normally distributed quantitative variables between two groups. Pearson χ2 test, Fisher’s exact test and Fisher-Freeman-Halton test were used to compare qualitative data. Statistical significance was accepted as p < 0.05.
Results
The study was carried out in our hospital between 2018 and 2021 with a total of 150 cases, 70.7% (n = 106) of which were females and 29.3% (n = 44) were males. The ages of the cases participating in the study ranged between 20 and 61 years, and the average age was 39.12 ±11.01 years. Descriptive characteristics were evaluated according to sensitivity types in Table 1.
TABLE 1
The age and gender distributions of the cases do not differ statistically significantly (p > 0.05) according to sensitization type.
There is no statistically significant difference (p > 0.05) in the rates of smoking, asthma + rhinitis, and asthma across sensitization types.
Conjunctivitis was found to be higher in cases with polysensitization than in those with monosensitization (p = 0.056; p > 0.05), though the difference was not statistically significant.
In Table 2, t-IgE and eosinophil measurements were evaluated according to sensitivity types.
TABLE 2
Patients with polysensitization had significantly higher t-IgE levels before and after immunotherapy compared to those with monosensitization (p = 0.002, p = 0.001, and p < 0.01). However there was no statistically significant difference (p > 0.05) seen between the changes in t-IgE measurement before and after immunotherapy, based on sensitization types. There is no statistically significant difference in eosinophil percentage values between the cases before and after immunotherapy based on sensitization type (p > 0.05). In monosensitized cases, immunotherapy resulted in a significant decrease in eosinophil percentage of 0.92 ±2.40 units compared to pre-immunotherapy levels (p = 0.004; p < 0.01). After immunotherapy, the polysensitized group showed a significant decrease in eosinophil percentage (0.50 ±2.68 units) compared to pre-immunotherapy (p = 0.004; p < 0.01). The changes in the eosinophil percentage and eosinophil levels measurement after immunotherapy compared to before immunotherapy did not differ statistically significantly (p > 0.05) based on sensitization types. The monosensitized group showed a significant (p = 0.012; p < 0.05) decrease in eosinophil levels before and after immunotherapy (66.22 ±203.52 units). In the polysensitized group, there was no statistically significant difference in eosinophil measurement after and before immunotherapy (p > 0.05).
Table 3 shows the evaluation of allergen sensitivities according to sensitivity types. HDM sensitivity rates differed significantly between polysensitized and monosensitized cases (p = 0.006; p < 0.01).
TABLE 3
There was a significant difference in pollen sensitivities between cases based on sensitization type (p = 0.001; p < 0.01). While the monosensitized group had significantly high pollen (grass, weed, or tree) sensitivity, the polysensitized group had significantly higher rates of multiple pollen tree, grass, or weed sensitivity. There was no significant difference in the distributions of other sensitivities (animals dander, molds etc.) in cases based on sensitization type (p > 0.05).
Table 4 shows the evaluation of the drugs used according to sensitivity types. A statistically significant difference was found between the antihistamine use rates of the cases according to sensitization types (p = 0.001; p < 0.01).
TABLE 4
In the monosensitized group, the rate of those who had not taken antihistamines for more than 6 months and those who used them continuously was found to be higher than in the polysensitized group. A statistically significant difference was found between the montelukast usage rates of the cases according to sensitization types (p = 0.010; p < 0.05). The rate of those who did not receive montelukast for 1–5 months in the polysensitized group was found to be higher than in the monosensitized group.
A statistically significant difference was found between the antihistamines + montelukast usage rates of the cases according to sensitization types (p = 0.001; p < 0.01). The rate of those who did not receive antihistamines + montelukast for 1–5 months in the polysensitized group was found to be higher than in the monosensitized group.
A statistically significant difference was found between the olopatadine usage rates of the cases according to sensitization types (p = 0.001; p < 0.01). The rate of those who had not taken olopatadine for 1–5 months and for more than 6 months was found to be higher in the polysensitized group than in the monosensitized group.
A statistically significant difference was found between the rates of mometasone furoate use of the cases according to sensitization types (p = 0.051; p > 0.05). The rate of those who had not used mometasone furoate for 1–5 months in the polysensitized group was found to be significantly higher than in the monosensitized group, although it was not significant.
According to sensitization types, the use rates of beclomethasone dipropionate, fluticasone furoate, formoterol/budesonide 9/320, salmeterol/fluticasone 50/250, salmeterol/fluticasone 50/500, and formoterol/budesonide 12/400 do not show a statistically significant difference (p > 0.05).
A statistically significant difference was found between the budesonide/formoterol 160/4.5 usage rates of the cases according to sensitization types (p = 0.023; p < 0.05). The rate of those who had never taken budesonide/formoterol (160/4.5) in the polysensitized group was found to be higher than in the monosensitized group.
Table 5 shows the evaluation of symptom and drug scores according to sensitivity types. The severity of the T0 Rhinitis symptom score was found to be statistically significantly higher in cases of polysensitization than in cases of monosensitization (p > 0.05). The distributions of T1 Rhinitis symptom scores in the patients based on sensitization types did not differ statistically significantly (p > 0.05). There was a significant difference in the distribution of T0 Rhinitis medication scores according to the sensitization types (p = 0.001; p < 0.01). The rate of INS administration with or without H1 antihistamines was found to be significantly higher in the cases belonging to the monosensitized group, whereas the rate of INS, montelukast administration with or without H1 antihistamines was found to be significantly higher in the cases belonging to the polysensitized group.
TABLE 5
Regarding the distributions of T1 Rhinitis medication scores in the patients based on sensitization types, no statistically significant difference was found (p > 0.05). There was no statistically significant difference between the distributions of T0 and T1 asthma symptom scores in cases based on sensitization types (p > 0.05). There was no statistically significant difference (p > 0.05) between the distributions of T0 and T1 asthma medication scores in cases based on sensitization types.
DISCUSSION
Allergen-specific immunotherapy is the only treatment that can change the natural course of allergic rhinitis and asthma.
According to the review by Calderon et al., 50–80% of patients with allergies are polysensitized [7]. If patients are sensitive to more than one allergen, the effectiveness of immunotherapy depends on the detection of the actual allergens responsible for the symptoms, but concerns remain about the effectiveness of the vaccine in these patients. Another issue is corticophobia against steroid-containing drugs used by patients.
For this reason, the steroid spare time defined by GINA regarding the effectiveness of immunotherapy is important. According to GINA guidelines, long-term ICS avoidance is accepted as a criterion for good asthma control [8].
Kim et al. administered immunotherapy only against HDM to 30 patients with HDM sensitivity and 40 patients with HDM and pollen sensitivity. They evaluated all patients who received immunotherapy for more than 2 years with serum specific IgE levels, total eosinophil count in peripheral blood, total nasal symptom score, medication score and rhinoconjunctivitis quality of life questionnaire (RQLQ). There was no significant difference between both groups. However, medication score, RQLQ, and total nasal symptom score decreased significantly in both groups [9]. Our study had a larger sample size (n = 150 versus n = 70), and each patient received either mono- or poly-immunotherapy with the causative allergens, rather than just house dust mite immunotherapy. T-IgE, eosinophil count, medication, and symptom scores were used to evaluate patients. Patients with rhinitis and asthma were recruited.
Bahceciler et al. studied 90 asthmatic children aged 4 to 9 years, 60 of whom were polysensitized, who received allergen-specific sublingual immunotherapy (SLIT) for 4 years between 2010 and 2013. The treatment resulted in 93.6, 83.3, and 73.7% ICS avoidance in the mono-allergen, pollen-mixture, and two simultaneous-allergen groups, respectively. ICS was avoided in 70% of patients, and there was no significant difference between mono- and poly-sensitized patients [10]. Patients ranged in age from 20 to 61 and had rhinitis and/or asthma in our study (n = 150 versus n = 90). The patients underwent SCIT rather than SLIT. The effects of immunotherapy on all medications, not just those containing steroids, were examined.
Zielen et al. evaluated 65 asthmatic patients aged 6–17 years who used immunotherapy and fluticasone propionate and those who used fluticasone propionate alone. Their randomized controlled trial reported a steroid-sparing effect with mite allergoid SCIT in children with mite-induced allergic asthma in 2010. Two years after SCIT, the treatment group’s average daily dose of fluticasone propionate decreased to 151.1 μg from 330.3 μg at baseline [11].
In our study, the rate of those who had never used inhaler budesonide formoterol (160/4.5) in the polysensitized group was found to be higher than in the monosensitized group (p = 0.023; p < 0.05). When compared to the monosensitized group, the polysensitized group had a considerably higher rate of people who had not used intranasal mometasone furoate in 1–5 months, though the difference was not statistically significant.
A retrospective study of 117 adult patients with allergic asthma who had used ICS for more than a year at a Korean tertiary hospital found differences in clinical parameters between the group taking SCIT and ICS (n = 48) and the group taking ICS only (n = 69). Changes in ICS dose from baseline were evaluated in both groups over 3 years. The proportion of those who discontinued or reduced their ICS dose after achieving asthma control status was significantly higher in the SCIT group than in the non-SCIT group (52.1% vs. 24.6% at 6 months and 52.1% at 1 month; 70.8% vs. 34.7% annually; 89.5% vs. 35.6% at 2 years; it was found to be 96.3% versus 51.2% at 3 years). Treatment responses did not differ significantly depending on the type of allergen used (single or multiple allergens or 3 different products) during the study period [12].
The sample size was larger in our study (n = 150 vs. n = 117). Our study included subjects with both asthma and rhinitis. When monosensitized and polysensitized patients receiving SCIT were compared, it was observed that the doses of ICS, INS, and other drugs decreased in both groups. In the patients with rhinitis (monosensitized group), the INS use rate before SCIT (n = 69/71) was 97.1%, and after SCIT (n = 22/71) was 30.98%. In the polysensitized group, the INS use rate before SCIT (n = 79/79) was 100%, and the INS use rate after SCIT (n = 17/79) was 21.5%. ICS use rate before SCIT (n = 15/17) in the asthmatic monosensitized group was 88.2%, 23.5% after SCIT (n = 4/17), and 62.5% before SCIT in the polysensitized group (n = 10/16) was 12.5% after SCIT (n = 2/16).
Unsel et al. studied 104 patients with asthma and rhinitis, 50 children and 54 adults aged 6 to 55 years, who received SCIT for at least 12 months. After SCIT, 64.5% and 57.1% of patients could discontinue ICS and INS, respectively. The mean time to INS and ICS dose reduction was 6 months, and SCIT containing one allergen or multiple allergens effectively reduced the dose of ICS and INS and achieved control of asthma and rhinitis symptoms [13].
Our study included patients aged between 20 and 61 years with rhinitis and/or asthma who had received SCIT for at least 24 months (n = 150 vs. n = 104). The effect of the immunotherapy on all medications and not just on those containing steroids was studied. INS and ICS doses and symptom and medication scores decreased in both the polysensitized and monosensitized groups. Pediatric patients were not included in the study. In the monosensitized group receiving SCIT (n = 40/71), the rate of those who have not used INS for more than 6 months was 56.3%, while in the polysensitized group receiving SCIT (n = 36/79), the rate was 45.56%. The ICS use rate before SCIT (n = 15/17) was 88.2% in the asthmatic monosensitized group, 23.5% after SCIT (n = 4/17) and 62.5% before SCIT in the polysensitized group (n = 10/16), and 12.5% after SCIT (n = 2/16).
The steroid-sparing effect of SCIT in moderate-to-severe house dust mite (HDM) allergic asthmatics was investigated by Blumberga et al. 54 adult asthmatics with an HDM allergy who required ICS at a dose equivalent to at least 500 µg of fluticasone propionate per day were randomized to receive SCIT or placebo for a period of 3 years. In patients with moderately persistent asthma, those treated with SCIT showed a statistically significantly greater reduction in the dose of ICS at 2 and 3 years compared with those treated with placebo. Median 3-year ICS reductions were 90% for SCIT and 42% for placebo (p = 0.04). The protective effect of SCIT on ICS was significant in patients with moderate persistent asthma [14].
The difference between our study and the others is that our sample group was larger and there was no placebo group that did not have SCIT. Our study included not only HDM, but also rhinitis and/or asthma patients with pollen, mold and other aeroallergen allergies. Budesonide/formoterol, salmeterol/fluticasone, but not fluticasone propionate, were used as ICS, and mometasone furoate, beclomethasone dipropionate, and fluticasone/furoate were used as INS. There was a decrease in the medication scores of ICS, INS, and other drugs in both our study groups.
After a year of treatment with SLIT tablets, inhaled budesonide was reduced by more than 80 μg/day when compared to placebo in a study comprising 602 individuals with mite allergy asthma [15]. Our sample group was smaller, with 150 patients. All of our patients received SCIT for at least 24 months with the aeroallergens to which they were allergic. In our study, ICS use rate before SCIT (n = 15/17) in the asthmatic monosensitized group was 88.2%, 23.5% after SCIT (n = 4/17), and 62.5% before SCIT in the polysensitized group (n = 10/16), and it was 12.5% after SCIT (n = 2/16). In our study, there was a noticeable decrease in the rates and dosages of ICS use after SCIT.
A meta-analysis evaluating nine studies including 452 patients treated with SLIT for HDM-allergic asthma was reported in 2009 by Compalati et al. [16]. They noted a considerable improvement in the scores for asthma-related symptoms and medications. Similar to SCIT, SLIT is a steroid sparing action that has also been shown in a few recently released research [15, 17].
Conclusions
Immunotherapy remains the most effective treatment for changing the course of the disease in both polysensitized and monosensitized patients. T-IgE and eosinophil levels did not change significantly after SCIT. However, the effect of SCIT can be seen in both symptom and medication scores. SCIT also reduced both groups’ use of INS and ICS. SCIT also had a strong steroid-sparing effect. In this area, there is a need for studies with larger sample sizes.