Multiple-allergen oral immunotherapy improves quality of life in caregivers of food-allergic pediatric subjects

Food allergy (FA) is an adverse immunologic response to dietary antigen with a reported prevalence of 8% in the United States. Approximately 30.4% of food-allergic participants are multi-sensitized, or allergic to more than one food allergen [1]. In Canada, the prevalence of pediatric food allergy has been reported to be 7.14% [2]. Currently, the only FDA-approved treatment for FA is food allergen avoidance and injectable epinephrine [3].

Food allergies have a significant negative impact on participants’ quality of life [4–6]. The burden of FA on caregivers (buying special foods, limiting social encounters, foregoing full-time employment) has been reported to play a predominant role in the total annual economic burden of FA, $24.8 billion [7]. Compared to those with single food allergies, those with multiple food allergies experience a greater decrease in quality of life [5, 8], are more likely to suffer from dietary deficiencies [9] and are less likely to outgrow their food allergies [10].

Oral immunotherapy (OIT) is a promising investigational therapy for food allergy [11]. We recently conducted two Phase I clinical trials showing the safety and feasibility of 1) an OIT protocol for desensitization to multiple allergens simultaneously (mOIT) [12] and 2) a protocol combining anti-IgE therapy (omalizumab) and a rush mOIT schedule to allow a rapid desensitization (rush mOIT) [13].

Although it is intuitive to think that successful desensitization to multiple food allergens would improve quality of life, safety analyses have shown that allergic reactions are common with OIT dosing. Although the majority of reactions are reported as mild, events requiring injectable epinephrine do occur [12, 13]. This raises the question as to whether reactions with dosing outweigh the benefit gained from therapy, which can only be addressed by an objective evaluation of quality of life influenced specifically by health and disease, or health-related quality of life (HRQL) [14–16]. While single-allergen OIT has been found to result in HRQL improvement in participants with peanut or cow milk allergy [17, 18], this study is the first to investigate the effects of mOIT and of rush mOIT with omalizumab on FA-related HRQL.

At baseline, all three groups had a high and comparable HRQL score (mean 3.6 to 3.9) out of a maximum of 6, indicating that all groups had a poor quality of life at baseline. Caregivers of participants in the mOIT group (n = 29) had a significant improvement in HRQL score at 6-month follow-up (mean 2.5, 95% CI 2.0-30) and 18-month follow-up (mean 1.8, 95% CI 1.4-2.1) compared to baseline (p < 0.0001). Caregivers of participants in the rush mOIT group (n = 11) also had a significant improvement in HRQL score at 6-month follow-up (mean 1.7, 95% CI 0.9-2.6) and 18-month follow-up (mean 1.3, 95% CI 0.3-2.4) compared to baseline (p = 0.001 and p = 0.005, respectively). HRQL worsened significantly (p < 0.01) in the control group (n = 10) from baseline (mean 3.6, 95% CI 2.9-4.3) to 6-month follow-up (mean 4.3, 95% CI 3.9-4.8). However, HRQL at 18-month follow-up (mean 4.3, 95% CI 3.7-4.7) was comparable to baseline HRQL in the control group (Figure 1). We did not find any association between the number of foods or adverse events and the change in HRQL score in either group although we may have lacked power for such sub-group analysis.

With both interventions, the improvement was clinically relevant (decrease greater than -0.5) at both time points (-1.9 and -2.5 at 6 and 18 months with mOIT, -2.6 and -3.1 at 6 and 18 months with rush mOIT). The percentages of participants with clinically relevant changes in FAQL-PB HRQL scores are shown for all 3 groups in Figure 2A (6-month follow-up) and Figure 2B (18-month follow-up).

To assess therapeutic value, we calculated the NNT to induce a clinically relevant improvement in QOL. At the 6-month follow-up time-point, NNT for mOIT was 1.5 and 1.1 for rush multi-allergen OIT. At the 18-month follow-up time-point, NNT was 1.2 for both multi-allergen OIT and rush multi-allergen OIT.

We looked at individual question scores to see if changes seen in overall HRQL scores were distributed across all questions or due to changes in specific question scores (Figure 3). In the mOIT group, caregivers’ answers showed a statistically significant (p < 0.05) and clinically relevant (change < -0.5) change for all 17 questions (Additional file 1: Table S1) at the 6-month follow-up that persisted at the 18-month follow-up. Similarly, in the rush mOIT group, caregivers’ answers showed a statistically significant and clinically relevant change for all but 2 questions at the 6-month and all but 1 question at the 18-month follow-up time-point.

Using a quality of life questionnaire specifically validated for food allergy, we have shown that two protocols for mOIT were associated with clinically and statistically significant increases in caregiver quality of life. This change persisted with 18 months of ongoing therapy and included all areas covered by the questionnaire. The effect was most pronounced after 18 months of rush mOIT combined with Omalizumab which showed a HRQL score decrease of 3.1 from median 3.9 to 0.8 (score ranked on a maximum of 6).

These findings are of major importance given the current question surrounding the role for OIT in the care for children with multiple food allergies. The efficacy of OIT is typically measured by the ability to tolerate food allergen after discontinuation of therapy (clinical tolerance or sustained unresponsiveness). Recent studies have shown limited rates of sustained unresponsiveness with OIT, raising concern about its relevance as an intervention for food allergy [26]. This study shows that desensitization itself, even without discontinuing therapy, provides significant and persistent improvement in caregiver quality of life. This suggests OIT can be of benefit to caregiver quality of life even in the absence of sustained unresponsiveness.

These results also suggest that the reaction profiles of mOIT and rush mOIT are acceptable and justified from a caregiver point-of-view and are much preferred to allergen avoidance. Home dosing reactions, which are expected and for which the patient is prepared may be less anxiety-producing than the constant fear of accidental reactions and uncertainty of day to day living with food allergy. In a review of 352 subjects desensitized to peanut, Wasserman and colleagues showed that severe reactions requiring epinephrine in the context of OIT were recognized and treated promptly and did not require additional intervention [27].

In addition to reducing reaction anxiety, the FAQL-PB questionnaire showed that mOIT had an impact on various aspects of day to day living associated with an economic burden for families with food allergy. These include arranging special diets ($1.7 billion spent annually in the United States) and avoidance of unintentional exposure to food allergens including childcare arrangements ($857 million), changing schools ($650 million), and attending special summer camps ($125 million) [8].

This study is the first to examine the effects of multi-allergen OIT protocols in caregivers of multi-sensitized participants. Two prior studies showed improvement in FA-specific HRQL with single-allergen OIT. These studies used a different questionnaire so their results cannot be directly compared to those presented here. To the best of our knowledge, the effect of single-allergen oral immunotherapy on HRQL has never been studied in participants with multiple, severe food allergies but one could assume that the effect would not be as drastic given it would only allow them to be less vigilant about one of their food allergens.

When comparing the two interventions, the magnitude of improvement was greater for the rush mOIT group, especially at the 6-month time point. Also, at 6-month follow-up, a larger percentage of participants had improved HRQL scores in the rush mOIT group (91%) when compared to the mOIT (66%) group, whereas at 18-month follow-up, the percentage of participants with improved HRQL scores was similar between the rush mOIT (91%) and mOIT (84%) group. The greater and more rapid HRQL improvement with rush mOIT probably reflects the fact that subjects reach maintenance much faster in this group (median 18 weeks) compared to mOIT without omalizumab (median 85 weeks) [12, 13]. It is unlikely to be related to a protective effect of omalizumab as reaction rates were similar in both groups.

One limitation to consider is that all subjects were recruited from volunteers. Although this potentially introduced selection bias toward more severely affected families, this bias reflects the patient population that would seek out additional therapy such as oral immunotherapy. Also, these were Phase I studies. Although the control group was not placebo-controlled, it would not have been possible to test the full psychosocial effect of the intervention if subjects were blinded and did not know they were protected. Despite the control group being comparable and selected using the same criteria, it is possible that the intense follow-up with bi-weekly visits to see food allergy specialists during OIT escalation phase positively affected the treatment group caregiver quality of life. However, previous studies looking at allergist interventions such as DBPCFC (positive outcome) and self-regulation telephone intervention did not show significant impact on overall HRQL scores [22, 28].

In conclusion, our findings suggest that mOIT, with or without omalizumab, can lead to significant improvements in caregiver HRQL that persist with ongoing treatment. These findings support OIT as a promising therapy for food allergy and suggest that OIT can help relieve the psychosocial burden food allergy imposes on caregivers of food-allergic children. Validated measures of quality of life should be included in future phase II clinical trials.