Patient compliance in subcutaneous immunotherapy

Introduction

Allergen-specific immunotherapy is a treatment modality aiming at ameliorating symptoms for an individual known to be atopic, by means of immunomodulation through application of allergic extracts with gradually increasing doses [1]. In the achievement of the treatment, it is important that immunotherapy is applied with ideal dosage and in regular intervals and patient compliance is essential. This treatment is thought to be complex, expensive and most of the time ineffective. All these together with the related adverse events affect the patient compliance [2]. Identification of the factors known to have an effect on compliance will increase the success of immunotherapy.

Aim

This study was aimed to evaluate the compliance with immunotherapy protocols of patients who were treated with subcutaneous allergen-specific immunotherapy (SCIT) in our clinic and their reasons for terminating the treatment.

Material and methods

This case-control based study was carried out at the Department of Pediatric Allergy and Immunology in Dr Behcet Uz Hospital, Izmir. All patients involved in the immunotherapy program beginning in 1993, which was the foundation year of the clinic, formed the target population of the study. Therefore, all SCIT patients who had completed as well as those who left their conventional immunotherapy program incomplete in 1993-2007 were evaluated retrospectively. Approval by the local etic committee was granted.
Age, gender, diagnosis of the patients, onset age of immunotherapy, number of injections, SCIT termination period and the place where immunotherapy was performed as well as the causes for terminating immunotherapy were examined retrospectively from the patient files. The patients who completed the immunotherapy versus the patients who discontinued were compared in terms of parameters indicated. Cases which discontinued the SCIT treatment were separated into two groups.
Regarding the causes for discontinuation of SCIT therapy; financial causes, negligence and unwillingness of the parents considering the therapy being hard and troublesome were classified as the “family-related causes” group, others discontinued because of the development of systemic reactions, anaphylaxis, additional diseases and refractory asthma were classed as “medical causes” group. The two groups were compared in terms of the parameters mentioned above.

Statistical analysis

Data were analyzed using the Statistical Package for Social Sciences program (SPSS for Windows 15.0 Chicago, USA). Values of continuous variables were given as either mean ± standard deviation or as median, based on the normality of distribution. Student’s independent-t test was used in the comparison of normal and homogeneous distribution of the parametric values. Chi-square and Mann Whitney U test were used to compare nonparametric values, p < 0.05 was considered a significant value.

Results

Four hundred and one patients were determined to have been admitted to the immunotherapy program between 1993 and 2007. Of those, 265 (66.1%) patients were males, and 136 (33.9%) were females. The average age of the patients at admission was 8.8 ±3.1 years. The average age for starting immunotherapy was 9.7 ±3.1 years. And the diagnosis distribution for the patients was as follows: 61.3% (n = 246) asthma, 17% (n = 68) allergic rhinitis, 21.7% (n = 87) both asthma & allergic rhinitis. Subcutaneous allergen-specific immunotherapy allergen distribution was found to be house dust – 57.6% (n = 231), grass pollen – 46.6% (n = 187), and olive pollen – 19.5% (n = 78). Examining the injection count for each session of SCIT patients, it was seen that 30 (7.5%) patients were given a double injection and 371 (92.5%) patients a single injection. All the injections were administered in our clinic to 276 (68.8%) cases, whereas 125 (31.2%) cases received their injections after the maintenance treatment in an external center. Average SCIT treatment duration was determined to be 39.6 ±17 months.
The number of the patients completing their program was 296 (73.8%). A total of 105 (26.2%) patients discontinued the treatment for a variety of reasons. Examining the treatment periods it was determined that 23 (21.9%) patients discontinued the treatment at the beginning and 82 (78.1%) patients during the maintenance period. Among the reasons for discontinuation, hardness and troublesomeness of the therapy were placed at the top – 42.8% (n = 45). The other reasons were financial causes followed it – 23.8% (n = 25); systemic reaction development – 20% (n = 21), the family finding the treatment unnecessary – 5.7% (n = 6), anaphylaxis – 4.8% (n = 5), additional disease development – 1.9% (n = 2), and the disease not being under control – 1% (n = 1).
No statistically significant difference was determined between the patients completing and discontinuing SCIT when examining them with regard to age at admission, gender, diagnosis, immunotherapy starting age, and injection count. The compliance of the cases who continued their treatment in our clinic was found to be significantly high (p = 0.001). On the other hand, treatment discontinuation proportion was higher for the cases who received their injections in an external center. Examining the SCIT periods it was seen that a significant proportion of the cases had terminated the treatment during the maintenance period (p = 0.001). The characteristics of the patients who completed or discontinued the treatment are shown in Table 1.
When we categorize the treatment discontinuation reasons in groups, we see that 72.4% (n = 76) of the patients were classified in the “family-related causes” group whereas 27.6% (n = 29) were in the “medical causes” group. The patients who discontinued the treatment because of the family-related causes and the medical causes were examined to determine whether there was a statistical difference between them in terms of application age, diagnosis, sex, SCIT starting age, SCIT discontinuation period, injection count and injection application place. No statistical differences were found between these two groups in terms of sex (p = 0.220), age at hospital admission (p = 0.697), average SCIT starting age (p = 0.915), injection count per session (p = 0.712) and SCIT discontinuation period (p = 0.605). The aver­age SCIT duration for the patients who discontinued the treatment due to “family-related causes” was 17.2 ±10.5 months, whereas due to medical causes was 23.1 ±13.8 months. Discontinuation due to family-related causes occurring in early periods was seen to be statistically significant (p = 0.020). Most of the patients resuming their SCIT program in an external center were found to discontinue the treatment due to family-related causes, whereas the patients resuming their SCIT program in our clinic were mostly found to terminate their treatment because of the medical causes (p = 0.001).
When examining the impact of the allergic disease type on treatment discontinuation, no statistically significant difference was found between the asthma group and the group with the association of asthma and allergic rhinitis (p = 0.297, p = 0.295). However, the treatment discontinuation rate of the patients with allergic rhinitis diagnosis was observed to be higher because of the medical causes (p = 0.002) (Table 2).

Discussion

Allergen-specific immunotherapy is a treatment method aiming at development of immunological tolerance via the administration of the allergen with controlled increasing doses [3, 4]. This method provides an apparent decrease in the symptoms related to asthma as well as an increase in the quality of life and it reduces the medication need for disease control [5, 6]. Besides blocking the emergence of new sensitizations, SCIT also prevents the development of asthma in patients with allergic rhinitis by having an effect on the natural course of the disease [7]. The application of immunotherapy with proper dosage and in regular intervals is important for the success of SCIT treatment. For this, the compliance of the patients is essential. However, the compliance to this immunotherapy method is limited because of the potential life-threatening systemic side effects and the discomfort caused by repetitive injections in childhood age groups. The other reasons having an impact on compliance are the high cost and difficulty of the treatment, the opinion about the treatment as being ineffective, and family problems [2, 8–10].
In our study, 73.8% of the patients completed the SCIT program. In total 26.2% patients discontinued the treatment for a variety of reasons. Among the reasons for discontinuation, hardness and troublesomeness of the therapy were placed at the top – 42.8%. In this study, no statistically significant difference was determined between the patients completing and discontinuing SCIT when examining them with regard to age at admission, sex, dia­gnosis, immunotherapy starting age, and injection count. In the early studies about SCIT compliance, compliance to the treatment was reported as roughly 50% both for the adults and the children, by Cohn and Pizzi and Lower et al. [11, 12]. It was indicated that the reason for this poor result might be the protocol used which requires one injection weekly in the first year and one injection every two weeks in the second year. Cohn and Pizzi [11] carried out their study on 217 allergic rhinitis and/or asthma patients receiving SCIT treatment. In their study, they stated that 50% of the cases having allergic rhinitis, and 48% of the cases having both asthma and allergic rhinitis had discontinued the treatment. Treatment difficulty was determined to be the most important termination reason representing 55% of the cases. The rate of treatment discontinuation for the same reason for the cases having both asthma and allergic rhinitis was determined to be 22%. Lower et al. [12], in their study involving 315 patients aged between 5–18 years having asthma or allergic rhinitis, stated that 44% of the cases had discontinued the treatment and male patients had shown a higher compliance. In the studies carried out in the subsequent years, more reasonable results started to be obtained and the reason for that was thought to be the use of better injection schemes. In a study implemented by Ruiz et al. [13] on 247 patients, the compliance ratio was reported as 38%. In this study, the reasons for noncompliance were stated to be the high cost of the treatment and the patient’s feeling of being cured. Also the worsening of the disease was determined to be another reason for quitting the treatment. In 1999, Rhodes [14] carried out a study without waiting until the end of the 3-year long treatment period and determined that 12% of the cases had quit the treatment. The most frequent reasons for quitting the treatment were ongoing medical problems, difficulty of the treatment and side effects of the treatment.
In consistency with the literature, the compliance of the cases taking the treatment in our clinic was found to be significantly high. The compliance ratio of the patients taking the injections outside of our allergy center was found to be lower. Tinkelman et al. [15] carried out a study with special patients and in this study they determined the compliance ratio as being 35% for the cases that had their injections in an external center. Continuing the treatment in a different center after the maintenance period appears to be a risk factor for compliance.
In our study, a significant number of the cases were determined to withdraw from the immunotherapy treatment in the maintenance period (p = 0.001). The average SCIT duration for the patients who discontinued the treatment due to family-related causes was 17.2 ±10.5 months, whereas due to medical causes was 23.1 ±13.8 months. Discontinuation due to family-related causes occurring in early periods was seen to be statistically significant. Most of the patients resuming their SCIT program in an external center were found to discontinue the treatment due to family-related causes, whereas the patients resuming their SCIT program in our clinic were mostly found to terminate their treatment because of medical causes. These results show that SCIT program should be arranged and continued by the allergy specialists in experienced centers. In the study of Pajno et al. [16] in hospital and clinics with 2774 patients having one of SCIT/sublingual immunotherapy (SLIT)/LNIT treatments, 10.9% of the cases were found to have compliance problems. When the treatment discontinuation period is examined, no difference in terms of compliance was determined between the starting and the maintenance periods. It was seen that most of the patients receiving treatment in the hospital withdrew in the beginning or in the second year of the treatment, whereas the patients taking the treatment in external centers generally terminated the treatment at the end of the first year.
It is seen that the compliance varies between 44% and 89% when the studies with adults and children about SCIT compliance are analyzed (48% in SCIT in adults by Cohn and Pizzi, 44% in SCIT in children by Lower et al., 65% in adults SCIT by Tinkleman et al., 62% in adults by Ruiz et al., 88% in adults by Rhodes, 89% in children SCIT by Pajno et al.) [11–17]. The main reasons for quitting the treatment were put in order as follows: frequent injection intervals, difficulty of the treatment and insufficient information for the patients concerning the treatment. In the study of Sade et al. [18], it was emphasized that the patients taking SCIT treatment were barely informed and had great expectations. While 40% of the patients thought that their allergy conditions would recover completely, 20% of them expected recovery in days or weeks. One quarter of the patients were determined to know the allergen with which the SCIT was applied and one third of the patients had knowledge regarding side effects. In our study, the reason for quitting the SCIT treatment which ranked first was family-related causes. The subsequent reasons were medical causes, which are more difficult to improve. We suppose that informing the parents about the effectiveness and adverse effects related to immunotherapy from the beginning and during the progress should decrease the rate of discontinuation due to family-related causes. As a mutual outcome of all these studies, it is accepted that the SCIT compliance can be increased by the use of optimal allergen extracts, appropriate treatment schemes and the cooperation between the doctors and the family. Moreover, arranging the treatment by considering social factors, education, the economic status of the family, and informing the patients about the progress of the disease and the immunotherapy program may help to improve compliance [2, 18].

Conclusions

In the studies performed with pediatric age groups, SCIT compliance differs in a wide range from 44% to 89%. In our study SCIT compliance was found to be 73.8%. The most frequently encountered treatment discontinuation reason was determined to be family-related reasons, and not side effects or complications. Family-related reasons do not appear only because of sociocultural deficiencies but also because the patients and their families are not sufficiently informed about the necessity and efficiency of the treatment, in other words due to lack of education. Owing to these motives, to perform the SCIT treatment more effectively, it is considered that information about the progress of the disease and the immunotherapy program should be given not only at the beginning but also repeated in regular intervals. Therefore, we think that immunotherapy should be carried out in experienced centers under the supervision of allergy specialists to ensure the compliance.

Authors declare no potential conflict of interest.

References

1. Malling HJ, Weeke B. Position paper: Immunotherapy. Allergy 1993; 48: 9-35.
2. Incorvaia C, Mauro M, Ridolo E, et al. Patient’s compliance with allergen immunotherapy. Patient Prefer Adherence 2008; 2: 247-251.
3. Holt PG. A potential vaccine strategy for asthma and allied atopic diseases during early childhood. Lancet 1994; 344: 456-458.
4. Durham SR, Till SJ. Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol 1998; 102: 157-164.
5. Nelson HS. Advances in upper airway diseases and allergen immunotherapy. J Allergy Clin Immunol 2005; 115: 676-684.
6. Till SJ, Francis JN, Nouri-Aria K, Durham SR. Mechanisms of immunotherapy. J Allergy Clin Immunol 2004; 113: 1025-1034.
7. Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002; 109: 251-256.
8. Jourdy DN, Reisacher WR. Factors affecting time required to reach maintenance dose during subcutaneous immunotherapy. Int Forum Allergy Rhinol 2012; 2: 294-299.
9. Scurati S, Frati F, Passalacqua G, et al. Adherence issues related to sublingual immunotherapy as perceived by allergists. Patient Prefer Adherence 2010; 4: 141-145.
10. Passalacqua G, Baiardini I, Senna G, Canonica GW. Adherence to pharmacological treatment and specific immunotherapy in allergic rhinitis. Clin Exp Allergy 2013; 43: 22-28.
11. Cohn JR, Pizzi A. Determinants of patient compliance with allergen immunotherapy. J Allergy Clin Immunol 1993; 91: 734-737.
12. Lower T, Henry J, Mandik L, et al. Compliance with allergen immunotherapy. Ann Allergy Asthma Immunol 1993; 70: 480-482.
13. Ruiz FJ, Jiménez A, Cocoletzi J, Durán E. Compliance with and abandonment of immunotherapy. Rev Alerg Mex 1997; 44: 42-44.
14. Rhodes BJ. Patient dropouts before completion of optimal dose, multiple allergen immunotherapy. Ann Allergy Asthma Immunol 1999; 82: 281-286.
15. Tinkelman D, Smith F, Cole WQ 3rd, Silk HJ. Compliance with an allergen immunotherapy regime. Ann Allergy Asthma Immunol 1995; 74: 241-246.
16. Pajno GB, Vita D, Caminiti L, et al. Children’s compliance with allergen immunotherapy according to administration routes. J Allergy Clin Immunol 2005; 116: 1380-1381.
17. Blaiss MS. Important aspects in management of allergic rhinitis: compliance, cost, and quality of life. Allergy Asthma Proc 2003; 24: 231-238.
18. Sade K, Berkun Y, Dolev Z, et al. Knowledge and expectations of patients receiving aerallergen immunotherapy. Ann Allergy Asthma Immunol 2003; 91: 444-448.