Anaphylaxis during Peanut Oral Immunotherapy: Looking beyond dose escalation

To the Editor Peanut Oral Immunotherapy (POIT) is shown to be a safe and efficacious therapeutic option for peanutallergic patients corroborated by multiple published studies.1– 3 Limited data exist on anaphylaxis risk and longterm therapy.4– 6 The aim of our study was to investigate anaphylaxis episodes during dose escalation and maintenance, and identify potential risk factors and avoidable triggers for these. We examined anaphylaxis episodes in a cohort of 75 subjects who completed realworld POIT in an academic center. Anaphylaxis was defined based on the NIAID criteria.7 Records of patients who received POIT over a period of 4 years (2017– 2021) were reviewed. The study was approved by the local Institutional Review Board (IRB). A total of 75 subjects reached a maintenance dose of 300 mg of peanut protein (pp) following monthly dose escalation from a starting dose of 2 mg pp, as previously described.8 Demographics and characteristics of our cohort are shown in Tables 1 and 2. Allergic comorbidities (allergic rhinitis, asthma, atopic dermatitis) were controlled prior to starting POIT. All families were educated on how external factors affect dose threshold and written instructions were provided for avoiding exercise and hot showers within 2 h after dose, not dosing on an empty stomach and stopping or reducing dosing during viral illness after discussion with the treating physician. After reaching the maintenance dose, subjects had the option to maintain or increase it. Multivariable logistic regression was used to examine if any factors were still associated with anaphylaxis after adjusting for those found to be significantly different between patients with and without anaphylaxis. To avoid collinearity, correlated variables (r > ±0.5) were not included in the same model. The logistic regression estimated odds ratios (ORs) with 95% CIs for anaphylaxis. p < .05 was considered statistically significant. A total of 15 subjects (20%) opted to increase their maintenance dose higher than 300 mg (range 450– 900 mg). Three subjects decided to stay at a lower maintenance dose (150 mg) due to experiencing anaphylaxis (n = 2) or personal preference (n = 1). After completing dose escalation, (approximately 9 months), the maintenance period started (month 1 maintenance). Median maintenance followup time for subjects was 25 months (range: 8– 42 months), at the time of writing. A total of four subjects discontinued therapy due to eosinophilic esophagitis (EoE)like symptoms (n = 1), taste aversion (n = 2), and anaphylaxis during dose escalation (n = 1). One additional subject was lost to followup (moved out of state). For the subject with eosinophilic esophagitislike symptoms, a biopsy was performed after discontinuing therapy, which was negative for a diagnosis of EoE, but the subject decided to stay off therapy. We identified 13 subjects (17%) who experienced a total of 15 episodes of anaphylaxis during POIT (Table 3). Two subjects (2/13) experienced two episodes of anaphylaxis each. Of the 15 episodes, eight (53%) happened during the dose escalation period and 7/15 (47%) after maintenance was reached. The doses associated with anaphylaxis during dose escalation were: 300 mg (1/15), 150 mg (3/15), 100 mg (1/15), 50 mg (2/15), and 5 mg pp (1/15). We recorded seven episodes of anaphylaxis during longterm maintenance. Specifically, the 300mg dose was associated with five episodes of anaphylaxis (5/15), the 450 mg with one episode (1/15), and the 600 mg with one episode (1/15). The longest followup time during which anaphylaxis was observed was 16 months (Figure 1). No episodes occurred after this period. We noted a statistically significant difference between median levels of baseline peanutspecific IgE and Arah 2; levels were higher in the anaphylaxis group compared with the nonanaphylaxis group (median peanutspecific IgE of 100 versus 14.9 kUA/L, p = .001 and median peanut Arah 2 of 65.3 versus 13 kUA/L, p = .007, respectively). A statistically significant difference was also noted in median age between the two groups, with older median age (11 vs. 7 years) being associated with anaphylaxis (p = .001). We did not find an association with higher (or lower) maintenance dose and anaphylaxis (Table 1). Since peanutspecific IgE and Arah 2 were highly correlated (r = .91, p < .001), separate models were created for each (Table 2). The odds of anaphylaxis increased as patient age increased (1 year increase in age: adj. OR 1.54, 95% CI: 1.14, 2.07) when adjusting for peanutspecific IgE. As peanutspecific IgE increased, so did the odds of anaphylaxis (1 kUA/L increase: adj OR 1.04, 95% CI: 1.01, 1.08). The odds of anaphylaxis increased as patient age increased (1 year increase in age: adj. OR 1.45, 95% CI: 1.14, 1.85) when adjusting for Arah 2. As Arah 2 increased, so did the odds of anaphylaxis (1 kUA/L increase: adj OR 1.03, 95% CI: 1.01, 1.05). In terms of clinical presentation, cutaneous symptoms, such as urticaria, angioedema and/or erythema (11/15, 73%) and respiratory symptoms such as wheezing, coughing, and/or dyspnea (11/15, 73%) were noted in most episodes. Only in 2/15 (13%) episodes,