Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial

Abstract

The only causative treatment for IgE-mediated allergies is allergen-specific immunotherapy. However, fewer than 5% of allergy patients receive immunotherapy because of its long duration and risk of allergic side effects. We aimed at enhancing s.c. immunotherapy by direct administration of allergen into s.c. lymph nodes. The objective was to evaluate safety and efficacy compared with conventional s.c. immunotherapy. In a monocentric open-label trial, 165 patients with grass pollen-induced rhinoconjunctivitis were randomized to receive either 54 s.c. injections with pollen extract over 3 years [cumulative allergen dose 4,031,540 standardized quality units (SQ-U)] or 3 intralymphatic injections over 2 months (cumulative allergen dose 3,000 SQ-U). Patients were evaluated after 4 months, 1 year, and 3 years by nasal provocation, skin prick testing, IgE measurements, and symptom scores. Three low-dose intralymphatic allergen administrations increased tolerance to nasal provocation with pollen already within 4 months (P < 0.001). Tolerance was long lasting and equivalent to that achievable after standard s.c. immunotherapy (P = 0.291 after 3 years). Intralymphatic immunotherapy ameliorated hay fever symptoms (P < 0.001), reduced skin prick test reactivity (P < 0.001), decreased specific serum IgE (P < 0.001), caused fewer adverse events than s.c. immunotherapy (P = 0.001), enhanced compliance (P < 0.001), and was less painful than venous puncture (P = 0.018). In conclusion, intralymphatic allergen administration enhanced safety and efficacy of immunotherapy and reduced treatment time from 3 years to 8 weeks.

Trial registration: ClinicalTrials.gov NCT00470457.

Fig. 1.

Trial design. Patients treated by s.c. immunotherapy received a cumulative allergen dose of 4,031,540 SQ-U in 54 injections over 3 years. Patients treated by intralymphatic immunotherapy received a cumulative dose of 3,000 SQ-U within 8 weeks. All patients were evaluated at baseline and after 4 months, 1 year, and 3 years.

Fig. 2.

Flow of patients. A total of 183 patients suffering from hay fever during the summer months May to July were assessed for eligibility. Eighteen did not meet inclusion criteria. A total of 165 patients with allergy to grass pollen were randomized 3:2 into s.c. and intralymphatic immunotherapies, respectively. Of the 99 patients randomized into the s.c. arm, 54 showed up for the first injection at the baseline visit. Of the 66 patients assigned to the intralymphatic arm, 58 showed up for the first injection at the baseline visit.

Fig. 3.

Pain of intralymphatic (IL) immunotherapy. Patients were asked to compare the pain of injection into a lymph node to a venous puncture during the same visit on a visual analogue scale ranging from 0 to 100 mm (n = 53). Box plots show mean (dotted line), median (continuous line), 25th and 75th percentiles (box), 5th and 95th percentiles (whiskers), and outliers. The paired-samples t test showed a significant difference between intralymphatic injection and venous puncture (P = 0.018).

Fig. 4.

Efficacy of intralymphatic (IL) vs. s.c. (SC) immunotherapy. (A) Intralymphatic therapy rapidly induced tolerance to grass pollen: Symptom scores during nasal provocation testing with grass pollen extract at baseline (●) and 4 months after initiation of treatment (○). Symbols show median and error bars for the 25th and 75th percentiles. The threshold shift in the intralymphatic group was significant (P < 0.001), whereas the shift in the s.c. group was not (P = 0.425). (B) Intralymphatic therapy induced long-term allergen tolerance: maximal tolerated pollen concentrations (pollen concentrations inducing scores ≥4) were evaluated in nasal provocation tests with grass pollen at baseline and after 4 months, 1 year, and 3 years. Symbols show means, and error bars 95% C.I.. A statistically significant increase of the maximal tolerated pollen concentration (P < 0.001) was already observed after 4 months and was long lasting. In contrast, s.c. immunotherapy did not significantly increase allergen tolerance within 4 months, but required 1 year of treatment. After 1-year (P = 0.856) and 3-year (P = 0.291) time points there was no significant difference between the 2 test groups (Mann–Whitney U test). (C) Patients in the intralymphatic group used less rescue medication. Rescue medication during the first year: antihistamine tablets (medication 1; desloratidine), nasal corticosteroid sprays (medication 2; mometasone furoate), asthma inhaler (medication 3; budesonide with formoterol), and antihistamine eye drops (medication 4; emadistinum). The percentage of patients using antihistamine tablets was significantly lower in intralymphatic than in s.c. patients (P = 0.020, χ² test with continuity correction). No significant differences were seen for other medications (nasal sprays P = 0.416; asthma inhaler P = 0.787; and antihistamine eye drops P = 1.000). (D) Intralymphatic and s.c. therapies comparably ameliorated hay fever symptoms. Patients were asked to score the symptoms of hay fever, congested nose, itchy nose, sneezing, red eyes, itchy eyes, asthma, and cough, at baseline, after 1 year, and after 3 years on a visual analogue scale ranging from 0 to 10. Symbols show means, and error bars 95% C.I.. Both intralymphatic (●) and s.c. (○) therapies significantly ameliorated subjective symptoms (within-subjects effect P < 0.001). Amelioration in both patient groups was not significantly different (hay fever P = 0.597; congested nose P = 0.503; itchy nose P = 0.926; sneezing P = 0.739; red eyes P = 0.328; itchy eyes P = 0.678; asthma P = 0.727; and coughing P = 0.485).

Fig. 5.

Skin prick test reactivity and serum IgE. (A) Reduction of reactivity to allergen in skin prick tests. Wheal areas in titrated skin prick tests at baseline and after 4 months, 1 year, and 3 years. Both the intralymphatic (●) and s.c. (○) patients showed significantly reduced reactivity (P < 0.001 for all allergen doses; general linear model repeated-measures analysis). Symbols show means, and error bars show SD. (B) Decrease of allergen-specific serum IgE. Timothy grass-specific serum IgE (kU/l) decreased significantly both in patients receiving intralymphatic (●) and s.c. (○) immunotherapies (within-subjects effect P < 0.001; general linear model repeated-measures analysis). Symbols show means, and error bars show SE. The difference between intralymphatic and s.c. immunotherapies was not statistically significant (between-subjects effect P = 0.204).