Bronchial hyperresponsiveness and asthma during oral immunotherapy for egg or peanut allergy in children

Abstract Background Bronchial hyperresponsiveness (BHR) and asthma are frequently present in children with food allergy. We assessed BHR in children receiving oral immunotherapy (OIT) for persistent egg or peanut allergy and examined whether OIT affects asthma control. Methods Methacholine challenge testing was performed in 89 children with persistent egg or peanut allergy diagnosed by double‐blind, placebo‐controlled food challenge and 80 control children without food allergy. Of the 89 food‐allergic children, 50 started OIT for egg allergy and 39 for peanut allergy. Sensitization to aeroallergens was evaluated by skin prick testing. Forty of the 89 children with regular controller treatment for asthma underwent methacholine challenge testing and 34 measurement of exhaled nitric oxide (FeNO) at baseline and after 6–12 months of OIT. Results Methacholine challenge testing revealed significant BHR in 29/50 children (58%) with egg allergy, 15/39 children (38%) with peanut allergy, and 6/80 controls (7.5%). The mean cumulative dose of methacholine causing a 20% fall in FEV1 differed significantly between the egg and peanut‐allergic versus the control children (1009 μg, 1104 μg, and 2068 μg, respectively, p < 0.001). Egg or peanut OIT did not affect lung function, the degree of BHR or FeNO levels in children with asthma and had no adverse effect on asthma control. Lung function or BHR did not associate with the OIT outcome. Conclusion BHR was significantly more frequent in children with persistent egg or peanut allergy than in children without food allergy. Oral immunotherapy did not increase BHR and was safe for children on regular asthma medication.


| INTRODUCTION
Food allergies affect approximately 8%-10% of children in the Western countries. 1,2 The worldwide reported prevalence of egg allergy in children is 1.3%-10% 1,3 and of peanut allergy 1.4%-5%. 1,3 Egg allergy resolves by school-age in most children, while peanut allergy tends to persist. 3 Milk and egg allergy are the most frequent causes of anaphylaxis in children, while peanut allergy is a common cause of anaphylactic reactions in all age groups. 4,5 The frequency of asthma in the European Union countries is approximately 8%-9%. 6 Sensitization to foods increases the risk of asthma 7,8 and bronchial hyperresponsiveness (BHR) [9][10][11] as well as the level of exhaled nitric oxide (FeNO). 7,9 Asthma symptoms are more prevalent in subjects with severe food allergy, and on the other hand, sensitization to foods is higher in children with asthma than in the general population. [12][13][14][15] Up to 50% of patients with severe food allergy have asthma and the prevalence of uncontrolled asthma is higher in these patients. 14 Severe asthma is a risk factor for food-related anaphylaxis because it associates with serious reactions causing bronchoconstriction in food-allergic patients 5,[16][17][18] Asthma is associated with 56%-78% of cases of fatal anaphylaxis to peanuts. 18 Children with a history of an anaphylactic reaction to foods have asthma more frequently than in children with milder allergic reactions. 19 Adequate asthma control is essential for children with food allergy as the coexistence of asthma and food allergy may negatively influence the severity of both conditions. Oral immunotherapy (OIT) is an experimental treatment for persistent food allergy which can desensitize 75%-85% of children with egg or peanut allergy. 20 A subset of patients achieve or longterm immune tolerance or sustained unresponsiveness which is defined as antigen hyporesponsiveness regardless of regular intake. 2,20 Uncontrolled or severe asthma is a contraindication for OIT, and suboptimal asthma control may increase allergic reactions during OIT. 2 Bronchial hyperresponsiveness can be assessed by direct bronchoprovocation tests (methacholine and histamine challenge), which act directly on specific airway smooth muscle receptors, or indirect stimuli (physical exercise, hyperventilation), which release mediators that provoke smooth muscle cells. 21 The provocative dose of methacholine causing a 20% decrease in FEV1 is age-dependent which complicates the use of methacholine challenge tests in children under 12 years 22 Studies examining the effect of OIT on BHR and asthma control in children are limited. We have previously reported that peanut OIT in 39 children had no negative effects on lung function, FeNO, or BHR. 23 This study aimed to examine the rate of BHR in children with persistent egg or peanut allergy compared to non-allergic controls and to investigate differences in lung function, BHR, and FeNO and in children with asthma receiving OIT for egg or peanut allergy.

| METHODS
The primary outcome was assessment of BHR by methacholine challenge testing in egg and peanut-allergic children compared to children without food allergy. Secondary outcomes included investigation of differences in BHR, lung function, and FeNO between desensitized and failed patients receiving egg or peanut OIT, as well as the effect of OIT on BHR and emergency department visits in children with asthma.

| Study population
The study included 89 children aged 6-17 years from the Helsinki University Skin and Allergy Hospital, Finland, with moderate to severe reactions 23 to egg (n = 50) or peanut (n = 39) in a double-blind, placebo-controlled food challenge (DBPCFC) (Figure 1). The median cumulative protein dose was 455 mg (5-1777 mg) in children with egg allergy and 55 mg (5-1255 mg) in children with peanut allergy.
Forty of the 89 children (45%) had asthma. Asthma diagnosis was based on the presence of respiratory symptoms consistent with asthma combined with the presence of variable expiratory airflow obstruction in lung function tests according to the Finnish National Guidelines. 24 The 39 peanut-allergic children (56% boys, mean age The families completed a questionnaire on the child's previous medical history, including asthma diagnosis in childhood ever, other allergies, and current medication. Details on previous allergic reactions to foods and the use of rescue medication were collected from the medical records.

| Oral immunotherapy
Oral immunotherapy for egg or peanut allergy was carried out as previously described 23

| Allergen-specific IgE and skin prick tests
We measured blood eosinophil levels and specific IgE to egg white and Gal d 1-4 in patients with egg allergy, and to peanut, and Ara h 2 in patients with peanut allergy by ImmunoCAP (Thermo Fisher, Uppsala, Sweden). We performed skin prick tests (SPT) with peanut, raw egg, birch, timothy, cat, dog, and house dust-mite (ALK, Horsholm, Denmark) as previously described. 23

| Methacholine challenge and FeNO
We performed baseline spirometry tests according to the European Respiratory Society criteria. 26 All 89 food-allergic children performed a methacholine challenge test with a cumulative dose of 2600 μg methacholine as previously described. 27 The controls performed a methacholine challenge test at the University Hospital of Kuopio, Finland 28 where the cumulative dose of methacholine was 4800ug.
Bronchoconstriction occurring at a dose above 2600ug of methacholine was registered as 2600ug. Bronchial hyperresponsiveness was considered mild if the cumulative methacholine dose causing at least a 20% fall in FEV1 was more than 600 μg and significant if it was 600 μg or less. 29 The concentration of fractional exhaled nitric oxide (FeNO) was examined in the 89 food-allergic children following the international guidelines as previously described. 30 34 of the 40 children with asthma who underwent OIT repeated methacholine challenge tests and FeNO measurements after 6-12 months of OIT.

| Severe asthma exacerbations
To assess asthma control and the number of severe exacerbations during OIT in the 40 children with asthma, we reviewed the medical records 12 months before and after the beginning of OIT. We examined the records of the asthma follow-up visits at the outpatients' department as well as any acute asthma-related emergency room visits.

| Subject characteristics
The study enrollment is shown in Figure 1 and the baseline characteristics of the study subjects in Table 1. The children with peanut F I G U R E 1 Flowchart of the study BURMAN ET AL.
-3 of 8 allergy were younger than the children with egg allergy or the controls (9.4 vs. 11.2 vs. 10.4 years, p = 0.003). There were no significant differences between the children with egg and peanut allergies in gender or the percentage of atopic eczema, asthma, or allergic rhinitis (Table 1). Altogether 40 of the 89 children (45%) who started OIT for egg or peanut allergy had doctor-diagnosed asthma with regular controller medication ( Figure 1). None of the controls had asthma and they had less frequently allergic rhinitis and atopic eczema ( Table 1).

| Specific IgE and skin prick tests
The median egg white specific IgE was 26.6 (1.0-1200.0) kU/L in the 50 children with egg allergy and the median peanut specific IgE was 74.6kU/l (1.8-1818.2) kU/L in the 39 children with peanut allergy. 23,25 The egg white or peanut specific IgE levels did not differ significantly between asthmatic and non-asthmatic children, nor did we observe any significant correlation between egg or peanut specific IgE levels and BHR.
The egg-and peanut-allergic children had similar aeroallergen sensitization profiles in SPT. Aeroallergen sensitization or the presence of allergic rhinitis did not correlate with BHR. Sensitization to at least two aeroallergens was present in 84/89 (94%).
Sensitization to birch, timothy, dog, and cat was common, while house dust mite sensitization was rare. The children with egg allergy were more frequently sensitized to dog compared to children with peanut allergy (91% vs. 77%, p = 0.028). Of the children with egg allergy, 36/50 (72%) were sensitized to peanut, whereas 11/39 (28%) of the children with peanut allergy were sensitized to egg (

| Oral immunotherapy outcome
After 18 months of OIT, a total of 72/89 (81%) children were successfully desensitized, while 17 discontinued (Figure 1). Desensitization was achieved in 44/50 (88%) of the children receiving egg OIT and 28/39 (72%) of the children receiving peanut OIT. Age, gender, or the proportion of children with asthma or allergic sensitization did not differ between the groups (Table 3).

| Lung function and bronchial hyperresponsiveness
The baseline lung function was similar in the children with egg or peanut allergy and the controls (

| Asthma control during oral immunotherapy
Based on the examination of medical records, OIT did not affect asthma control in the 40 children with regular asthma medication.
During the 12 months before starting OIT, one child had one asthmarelated emergency room visit, and during the 12 months after starting OIT there was one emergency room visit in another child.
None of the children needed to be admitted for inpatient treatment 12 months before or after starting OIT. The children with asthma showed no differences in lung function, measured in FEV1 [94.9%

| DISCUSSION
We compared BHR and lung function in 89 school-aged children with persistent egg or peanut allergy and 80 non-food-allergic controls and assessed whether OIT for egg or peanut allergy affects asthma control. Three key findings emerged from this study. First, BHR was significantly more common in children with persistent food allergy than in non-food-allergic controls regardless of allergy to egg or peanut or the presence of asthma. Second, lung function or BHR did not associate with the OIT outcome. Third, OIT for egg or peanut allergy had no adverse effect on asthma control in children with regular asthma controller treatment.
We observed significant BHR in 58% of the egg-allergic and 38% of the peanut-allergic children. Of them, 47% had asthma and 53% were asymptomatic These results are consistent with earlier studies describing increased BHR in children with food allergy compared to healthy controls. 9 Asthma was diagnosed in 50% of the peanut-allergic and 42% of the egg-allergic children. This is in line with previous studies where the prevalence of asthma in children with food allergy is approximately 45%-50%. 14, 17 We found significant BHR in less than half of our patients with asthma and the frequency of BHR was no different from the non-asthmatic children. We showed that OIT to egg or peanut was safe for children with asthma. Their asthma symptom control remained stable and there was no need to step up medication. The number of exacerbations requiring emergency room visits did not increase during OIT. There was no difference in baseline lung function, BHR or FeNO levels before and after OIT, which corresponded well with our previous study, where BHR was measured in children receiving peanut OIT. 23 Oral immunotherapy was successful in altogether 72 (81%) of our patients after 18 months. We have previously shown that high egg white IgE levels and polysensitization to Gal d 1-4 in egg OIT relate with a slower response and discontinuation. 25 Here we examined whether sensitization to aeroallergens, baseline lung function, FeNo levels, and the presence of BHR associate with the outcome of OIT to egg or peanut, but we found no correlation.
The strength of this study was a well-characterized cohort of children with persistent egg or peanut allergy confirmed by DBPCFC.
After starting OIT, the patients were followed for 18 months, which provided real-life confirmation of successful desensitization. We performed post-OIT methacholine challenges only in 34 patients with asthma, and due to limited resources, the time varied from 6 to 12 months. We did not, however, observe any significant differences in BHR between these timepoints. Additionally, we had access only to asthma follow-up and emergency room visits, but not to possible family doctor visits. Although we assessed asthma symptom control during each visit, it is possible that some asthma exacerbations remained unnoticed.
In conclusion, our study shows that BHR occurs more frequently in children with persistent egg and peanut allergy than in non-foodallergic controls. Lung function and BHR remain stable during OIT and do not predict the outcome. We do not recommend assessing BHR before starting OIT in children without asthma. The finding that OIT is safe for children with asthma is of particular interest as this area has been under-researched in the past.

CONFLICTS OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

DATA AVAILABILITY STATEMENT
The individual participant data collected during the trial are not available for sharing.

IMPACT STATEMENT
Children with persistent egg or peanut allergy had BHR in methacholine challenge test more frequently than children without food allergy. Oral immunotherapy for egg or peanut allergy was safe for food-allergic children with asthma requiring regular controller treatment. Oral immunotherapy did not affect their lung function, the degree of BHR, the level of exhaled nitric oxide, or the number of acute asthma-related emergency hospital visits. Based on our study, we do not recommend assessing BHR before starting OIT in children without asthma.