Tolerance increases in low-dose oral immunotherapy for multiple nut allergies in children
Key takeaways:
- Nuts included walnut, pistachio, cashew, hazelnut, peanut and macadamia.
- 14 of 15 children who completed the protocol reached maintenance doses of 30 mg.
- There were no severe adverse events related to treatment.
Children with multiple nut allergies experienced significant increases in the amounts of allergens they could tolerate with oral immunotherapy using very low doses, according to data published in Clinical and Translational Allergy.
With three up-dosing visits scheduled every 2 months, the protocol also reduced the burden on families and health care providers, Julia E.M. Upton, MD, head of the division of immunology and allergy, Hospital for Sick Children, Toronto, and colleagues wrote.
“OIT is known to be effective in increasing the amount of food a child with a nut allergy can safely eat,” Upton told Healio.
The researchers sought to address barriers in wide access to OIT for food allergy, she said, such as children who do not like how the food tastes, allergic reactions to doses, the time required for visits among families and health care professionals alike, and the need to weigh foods or have a pharmacy compound them.
“Therefore, we wondered if aiming for just a low dose of a mix of all the nuts a child is allergic to, with visits months apart, dosed with tiny spoons of a mix of nut butter, might be effective,” Upton continued.
Compared with larger or more accelerated doses, Upton said low-dose OIT requires fewer visits and may provoke fewer allergic reactions. Also, she said, children who do not like the food may better accept low-dose OIT.
“Our main question was whether the treatment worked to increase the amount of nuts a child could safely eat,” she said. “We were also interested in allergic reactions and quality of life changes from baseline.”
In the clinic
The study enrolled 18 children aged 6 months to 15 years (12 boys) with a median age of 5 years at the start of the OIT. Allergies included walnut (n = 12), pistachio (n = 14), cashew (n = 14), hazelnut (n = 9), peanut (n = 11) and macadamia (n = 1).
Treatment began with approximately 4 mg of each allergenic nut protein. Clinicians escalated doses during office visits every 2 months. At 18 months, oral food challenges with a cumulative maximum of 2,040 mg of protein per allergen were administered.
The median time from enrollment to the targeted maintenance dose of 30 mg of protein per nut was 304.5 days, which the researchers attributed to delays caused by the COVID-19 pandemic. Also, the median time from enrollment to the was 564 days, which the researchers called very close to their target of 548 days.
Estimated treatment dosing adherence was 99.6% based on the number of missed doses that were reported and on treatment day totals.
Median tolerated doses increased from 10 mg of protein per nut at baseline to 1,000 mg of protein per nut at the OFC (P < .0001). Also, 10 children tolerated the 1,000 mg dose and the cumulative maximum dose of 2,040 mg of protein per nut at the OFC. Reaction severity during the OFC fell for 10 children as well (P < .0078).
Fourteen children reached 30 mg maintenance, with 13 tolerating five times their baseline eliciting dose or more in addition to 300 mg of protein per nut or more (P < .001).
“The most surprising finding was that in one child who only increased to half of the dose we aimed for approximately 15 to 16 mg at 18 months from study start, we still saw this child was able to safely eat more nuts than at the beginning,” Upton said.
At 18 months, this child successfully consumed 300 mg of protein with a cumulative total of 440 mg of protein per nut, which Upton called 100 times greater than the child’s baseline tolerated dose of about 3 mg of protein per nut with a cumulative total of 4 mg of protein per nut.
“This observation suggests that even lower doses than 30 mg may be effective,” Upton said.
There also were significant decreases in skinprick test diameters between baseline and the OFC for walnut (P < .05), pistachio (P < .01), cashew (P < .01) and peanut (P < .05), with a similar trend for hazelnut, the researchers said, indicating multi-desensitization.
“Even with these low maintenance doses, we saw significant immunological improvements,” Upton said. “The skin prick tests reduced, IgG4 went up and the basophil activation test showed reduced degranulation.”
The reduction in allergen-specific IgE from baseline to the OFC was statistically significant as well, the researchers said. Additionally, there was a significant increase in the induction of allergen-specific IgG4 blocking antibodies to 2S albumins of all the allergens except for hazelnut. The researchers called these outcomes similar to those found in regimens that use higher doses.
“Overall, the immunological tests supported what we observed clinically that very low-dose OIT works to increase how much nut protein a child can safely ingest,” Upton said.
Additionally, the researchers administered the Food Allergy Quality of Life Questionnaire at baseline, after escalation and at the OFC to 13 parents, two teenagers and one child.
There were significant improvements in emotional impact, food-related anxiety and social and dietary restrictions among the parental responses, the researchers said, with the median score falling from 3 at baseline to 1 at the OFC.
Responses among the teenagers trended toward falling emotional impact, risk accidental exposure, and allergen avoidance and dietary restriction scores as well, the researchers added.
Adverse events
The children did not experience any treatment-related, protocol-defined severe adverse events, nor were there any hospitalizations or deaths. Epinephrine was not needed for any reactions at home or during any of the escalation visits either. Three children did not have any adverse reactions related to treatment at home or during escalation visits.
“A welcome finding was that no child required epinephrine autoinjector use with dosing at home, even though this was multi-nut OIT, and we included teenagers and elementary school children in the study,” Upton said.
There were 348 cases of abdominal pain, which was the most common symptom, among seven children during dosing at home, but 285 of these instances were experienced by one child who had mild gastrointestinal discomfort each day before leaving the study.
Local oral discomfort was the second most common symptom, with 10 children experiencing 241 cases of itch on their lip, mouth, throat or tongue.
Most of the adverse events related to dosing at home happened during the dose escalation period, with a median of 0.016 adverse events per treatment day among the 18 enrolled children. During maintenance, less than half of the children experienced adverse events, with an overall median of 0.014 adverse events per treatment day.
There were 10 mild adverse reactions among seven children during the escalation visits, including four cases of local oral itch, one case of discomfort in the mouth, four cases of sneezing and one case of abdominal pain.
Next steps
Based on these findings, the researchers said that OIT with low doses and slow escalation protects children with multiple nut allergies against accidental exposure, effectively induces immunoregulatory mechanisms and reduces health care burden.
“This work shows that one simple approach we have to potentially shift the risks and benefits of multi-nut OIT is by changing the way we deliver the treatment,” Upton said.
Families and clinicians challenged by higher doses may want to use a lower dose instead of discontinuing treatment, she continued.
“Lowering the maintenance dose may also be a consideration rather than, or in addition to, adding a biologic,” Upton said. “Furthermore, families and clinics may not need to arrange frequent up-dosing appointments.”
However, Upton noted that this study did not include comparisons with larger doses, nor did the researchers compare the 2-month up-dosing interval with a shorter interval.
“We recently reported our more rigorous trial where children are assigned to 30 mg or 300 mg in a blinded and randomized trial and the food challenges are also performed in a rigorous blinded and placebo-controlled manner,” Upton said.
Up-dosing occurred every 2 weeks until the participants reached 30 mg or 300 mg.
“Children assigned to a top dose of 30 mg had fewer systemic allergic reactions than those assigned to 300 mg and a trend toward fewer withdrawals zero in the 30 mg group and three in the 300 mg group,” Upton said. “Both doses were able to significantly increase the amount of peanut the child could safely consume.”
Next, the researchers will report on the results of their real-world, randomized trial of 30 mg and 300 mg maintenance doses at 21 months.
“The lowest effective dose of OIT has not been found, so there is also the opportunity to explore even lower maintenance dosing,” Upton said.
“It will also be valuable to consider if an application of this work may be to get started with very low doses, stay on that dose for 1 to 2 years and then move to a much larger dose if desired, thereby removing many up-dosing visits,” she said.
For more information:
Julia E.M. Upton, MD, can be reached at allergy@healio.com.
Perspective
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The findings are not necessarily surprising since there are prior studies of long-term treatment with low doses of allergen showing that significant improvements in threshold can occur, and there are prior studies where multiple foods are addressed in at the same time.
However, the results are significant for several reasons related to how the approach was designed to address true, important needs in the field. Here are the needs met by giving multiple nuts as OIT in low amounts and with infrequent visits for increasing doses.
First, many families with children with nut allergies want their child to be “bite safe,” meaning that they would be safe from a small accidental ingestion (likely achieved with low doses) and are not necessarily looking to have them eat the food in full amounts (more likely achieved on high doses).
Second, having OIT to multiple tree nut foods (that are not common elements of the diet milk, eggwheat) often meets with resistance by the child who may find eating “larger” amounts of multiple nuts unappealing and resists, and so this problem is significantly reduced with this approach.
Third, resource issues are increasing as interest in pursuing OIT has become more common, and so this protocol is easier and less burdensome (fewer visits) on families and medical offices.
In many current OIT practices, as interests grow and getting children “started” is a need, and allergy offices and parents also have limited time for these multi-hour visits, it is getting hard to schedule the many “up-doses” that have been traditionally performed in published protocols.
Traditionally these protocols include visits every 2 weeks and aim for relatively larger final amounts via many visits. I have counseled parents that even staying on the lower amounts is “good,” and this study further supports that idea.
While the study showed very good success and revealed potential pitfalls of note, and it was designed and reported very well, it is a very small study that I would consider a valuable proof of concept. Larger studies with more diverse groups of people with tree nut allergies will add additional understanding for this approach.
Sources/Disclosures
Source:
Upton JEM, et al. Clin Transl Allergy2025;doi:10.1002/clt2.70125.
Disclosures:
Upton reports receiving grants and personal fees from ALK-Abelló and DBV Technologies; personal fees from Bausch Health, Pfizer, Viatris and Pharming Group NV; a donated drug from Novartis; and grants from the Canadian Institutes of Health Research, Canadian Society of Allergy and Clinical Immunology Board of Directors, Food Allergy Canada Healthcare Advisory Board and SickKids Food Allergy Anaphylaxis Program.
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