Very Low-Dose OIT Safely Increases Multi-Nut Tolerance in Young Children

A recent study showed that very low-dose oral immunology (VLOIT) significantly increased tolerated doses of multiple nuts.1

“Our findings suggest that a low and slow dose escalation with only three planned up-dosing visits every 2 months may be beneficial for patients, demonstrating similar immunological outcomes to higher dose regimens,” wrote Julia E. M. Upton, MD, MPH, from the Food Allergy and Anaphylaxis Program at The Hospital for Sick Children in Toronto, and colleagues.1

Oral immunotherapy (OIT) typically targets 1 food allergen at a time using maintenance doses ≥ 300 mg protein, but higher doses are linked to adverse events. This can make OIT especially burdensome for children with multiple food allergies, who account for approximately 40% of allergic children, according to a 2024 FARE report.2

Using very low doses in OIT may reduce the risk of adverse events. In this study, investigators assessed VLOIT in 18 children aged 3 – 9 years (mean age, 5 years; 66.7% males) who were allergic to 2 – 5 nuts, including peanut (n = 1), walnut (n = 12), hazelnut (n = 9), cashew (n = 14), pistachio (n = 14), and macadamia (n = 1). The baseline median tolerated dose was 10 mg protein (IQR, 3 – 100 mg).1

The primary outcome was the change in reaction threshold and tolerated dose from baseline to 18 months, specifically looking at participants who reached a dose that was ≥ 5 times greater than the baseline tolerated dose or tolerated a cumulative dose of 2040 mg. Immunological outcomes included changes in allergen-specific IgG4 from baseline to post-escalation (at about 6 months) and study completion (18 months). Secondary outcomes include tolerating 30 mg protein (444 mg cumulative), a dose anticipated to protect against reactions from accidental exposure.1

Oral food challenges (OFCs) confirmed nut allergies at ≤ 444 mg protein each nut. Following the OFCs, participants began an open-label nut mix starting at 4 mg protein, with dose increases every 2 months to a target maintenance dose of 30 mg per nut. An exit OFC at 18 months assessed threshold changes.

During the study, 3 withdrew, and 1 did not reach the target maintenance dose but was still invited for the exit OFC. The participant who did not reach the target dose still increased tolerance from 3 mg to 16 mg.

The median time to reach 30 mg target maintenance dose was approximately 10 months (304.50 days), which investigators attributed to reduced clinic capacity and patient fears during the COVID-19 pandemic. The median time from OIT initiation to exit OFC (564.00 days) was very close to the planned 18 months (548 days).1

At exit OFC, the mean tolerated dose was 1000 mg (IQR, 300 – 1000 mg), which was a significant difference from baseline (P <.0001). In total, 10 out of 15 participants tolerated the maximum dose (P <.0001); 10 out of 15 also experienced a decrease in OFC reaction severity from baseline. Treatment adherence was estimated to be 99.6%, based on the number of reported missed doses and the total treatment days.1

The intention-to-treat analysis revealed that 14 children tolerated 5 times their baseline dose or ≥ 300 mg (P <.001). In total, 10 children tolerated the maximum dose (1000 mg, 2040 mg cumulative; P <.001). No participants required epinephrine during the trial or experienced serious adverse events, hospitalizations, or death. The most reported symptom during home-dosing was abdominal pain, followed by local oral discomfort.1

Patients on multi-OIT were desensitized to several nuts in the prescribed nut mix, reflected in significant reductions in SPT diameters: walnut (P <.05), pistachio (P <.01), cashew (P <.01), and peanut (P <.05). Allergen-specific IgE signficantly decreased, while IgG4 blocking antibodies to two 2S albumins increased from baseline to 18 months.1

“We demonstrate this low maintenance dose provides expected protection against accidental exposure and effectively induces immunoregulatory mechanisms,” investigators concluded.1

References

1. Upton JEM, Li CH, Berenjy A, et al. Safety and Efficacy of Very Low-Dose Multi-Nut Oral Immunotherapy in Children. Clin Transl Allergy. 2025;15(12):e70125. doi:10.1002/clt2.70125

2. Food Allergy Facts and Statistics for the U.S. Food Allergy Research & Education. Food Allergy Research & Education. Published April 18, 2024. Accessed December 15, 2025 https://www.foodallergy.org/sites/default/files/2024-07/FARE%20Food%20Allergy%20Facts%20and%20Statistics_April2024.pdf