RATIONALE: To explore the safety and efficacy of different routes of immunotherapy for cow's milk-allergy, we examined sublingual immunotherapy (SLIT) alone and with oral immunotherapy (OIT).METHODS: Following a baseline DBPCFC, all subjects started with an initial SLIT dose escalation (starting dose: 1.67 × 10-06mg, final: 0.067mg), followed by daily dosing with 4 weekly SLIT escalations. All subjects were then randomized to continue on SLIT (n = 10) with 2 escalations to a 7mg maintenance dose, or to OIT with 12 escalations to 1000mg (n = 10) or 2000mg (n = 10). Maintenance dosing continued for 3 months, followed by a DBPCFC. End-point-titration skin-prick-testing, milk specific-IgE, and IgG/IgG4 anti-milk components (ImmuoCAP) were obtained at baseline, completion of build-up, and the second DBPCFC.RESULTS: Thirty subjects aged 6-17 were enrolled. Baseline median milk-IgE was 37.8ku/L (range 1.08-572). The median baseline milk threshold at DBPCFC was 51mg (range 1-1400mg), which increased in all 4 SLIT/SLIT subjects who have completed the second DBPCFC thus far (median fold increase: 7.4, p = 0.07); one tolerated the full 8140mg. Median end-point skin-test threshold decreased 10-fold (p = 0.014) and milk-component-IgG4/IgE ratio increased 3-fold (p < 0.01) in the 16 subjects who have completed dose escalation. Symptoms occurred in 38% of 2191 SLIT and 37% of 1444 OIT doses (oropharyngeal: 31%/27%, respectively; abdominal: 3%/10%; skin: 2/3%; lower respiratory: 0.3/2%). Treatment included antihistamines (1%/4% of doses), beta-agonists (0.3%/2%), and once each oral steroids and epinephrine.CONCLUSIONS: OIT and SLIT for milk allergy are both generally well tolerated, with rare systemic reactions. Preliminary results suggest that SLIT alone may be efficacious for desensitization of milk-allergic children. RATIONALE: To explore the safety and efficacy of different routes of immunotherapy for cow's milk-allergy, we examined sublingual immunotherapy (SLIT) alone and with oral immunotherapy (OIT). METHODS: Following a baseline DBPCFC, all subjects started with an initial SLIT dose escalation (starting dose: 1.67 × 10-06mg, final: 0.067mg), followed by daily dosing with 4 weekly SLIT escalations. All subjects were then randomized to continue on SLIT (n = 10) with 2 escalations to a 7mg maintenance dose, or to OIT with 12 escalations to 1000mg (n = 10) or 2000mg (n = 10). Maintenance dosing continued for 3 months, followed by a DBPCFC. End-point-titration skin-prick-testing, milk specific-IgE, and IgG/IgG4 anti-milk components (ImmuoCAP) were obtained at baseline, completion of build-up, and the second DBPCFC. RESULTS: Thirty subjects aged 6-17 were enrolled. Baseline median milk-IgE was 37.8ku/L (range 1.08-572). The median baseline milk threshold at DBPCFC was 51mg (range 1-1400mg), which increased in all 4 SLIT/SLIT subjects who have completed the second DBPCFC thus far (median fold increase: 7.4, p = 0.07); one tolerated the full 8140mg. Median end-point skin-test threshold decreased 10-fold (p = 0.014) and milk-component-IgG4/IgE ratio increased 3-fold (p < 0.01) in the 16 subjects who have completed dose escalation. Symptoms occurred in 38% of 2191 SLIT and 37% of 1444 OIT doses (oropharyngeal: 31%/27%, respectively; abdominal: 3%/10%; skin: 2/3%; lower respiratory: 0.3/2%). Treatment included antihistamines (1%/4% of doses), beta-agonists (0.3%/2%), and once each oral steroids and epinephrine. CONCLUSIONS: OIT and SLIT for milk allergy are both generally well tolerated, with rare systemic reactions. Preliminary results suggest that SLIT alone may be efficacious for desensitization of milk-allergic children.