Intralymphatic Immunotherapy for House Dust Mite, Dog, and Cat Allergy Using Tyrosine S® in Allergic Rhinitis (ILIT-T)

Intralymphatic Immunotherapy for House Dust Mite, Dog, and Cat Allergy Using Tyrosine S® in Allergic Rhinitis

The Efficacy and Adverse Effect of Intralymphatic Immunotherapy With Tyrosine S®, Allergen Extract for Immunotherapy, in Patients With Allergic Rhinitis Induced by House Dust Mite, Dog, and Cat Allergen

The investigators will perform double-blinded placebo-controlled randomized clinical trial which evaluates the efficacy and safety of allergen-specific intralymphatic immunotherapy (ILIT) for allergens including Dermatophagoides farinae (Df), Dermatophagoides pteronyssinus (Dp), cat, and dog that are sensitized and provoke rhinitis-related symptoms in patients with allergic rhinitis (AR), using allergen extracts for allergen-specific immunotherapy (Tyrosine S, Allergy Therapeutic, West Sussex, UK).

After informed consent, subjects will be randomly assigned to ILIT group or placebo group in double-blind manner. In both group, causal allergen or placebo will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval. In ILIT group, initial dose of allergen will be 1,000-fold diluted solution from maximal concentration of allergen extract for subcutaneous immunotherapy (Tyrosine S, Allergy Therapeutic, West Sussex, UK) in volume of 0.1ml. If skin is highly reactive in skin prick test, the initial dose will be 10-fold dilution from maximal concentration where diameter of wheal is less than that of histamine. After the first dose, allergen concentration will be escalated 3-fold at second dose, and 10-fold at third dose if there are no (or mild) local or systemic hypersensitivity reaction. The allergen concentration will not change at second or third dose if there is moderate local or systemic reaction. The allergen concentration will decrease by 10 or 100-fold from previous concentration or further injection will be held if there is severe local or systemic reaction after sufficient explanation and discussion with subjects. The investigators will evaluate allergic rhinitis symptom score before and 4, 12 months after the initial treatment. Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Sino-Nasal Outcome Test (SNOT-20) will be used. Visual analogue scale (VAS) of symptoms including rhinorrhea, sneezing, nasal obstruction, postnasal drip, eye/nose/ear/palate itching, dyspnea, wheezing, chest discomfort as well as urticaria, angioedema, and itching on exposed skin during exposure to causal allergen in daily life will be also evaluated. Skin prick test (SPT), intradermal test (IDT), blood sampling for serum total immunoglobulin E (IgE), allergen-specific IgE, and allergen-specific immunoglobulin G4 (IgG4), nasal lavage for Th1, Th2, and Treg cytokines, and nasal provocation test (NPT) with Df and/or Dp allergen (in subjects whose AR symptoms are provoked by Df and/or Dp) will be also performed before and 4, 12 months after the initial treatment. In addition, the investigators evaluated the change of subjects' recognition of causal allergens, their avoidance, and AIT during this study. Using VAS, subjects were requested to score the rate of agreement with "Allergen provokes allergic symptoms in daily life", "Allergen avoidance can reduce allergic symptoms", "Allergen-specific Immunotherapy (AIT) can reduce allergic symptoms", "I can pay 50,000 Korean Won (KRW)/month for allergen avoidance", "I can pay 100,000 KRW/month for allergen avoidance", "I can pay 200,000 KRW/month for allergen avoidance", "I can pay 150,000 KRW for each injection of ILIT", "I can pay 300,000 KRW for each injection of ILIT", "I can pay 600,000 KRW for each injection of ILIT" before and after SPT/IDT, after NPT, 4 months and 1 year after ILIT. Adverse events will be recorded and graded according to Muller classification and Ring and Meissner classification.

Allergic rhinitis, Injection, intralymphatic, Immunotherapy, Dermatophagoides farinae, Dermatophagoides pteronyssinus, Dogs, Cats

In active group, extract of causal allergen will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval.

In placebo group, normal saline will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval.

0.5 ml of allergen extract from D. farinae, D. pteronyssinus, cat, and/or dog for allergen specific immunotherapy (Tyrosine S, Allergy Therapeutic, UK) will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval.

0.5 ml of normal saline will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval.

Subjects are requested to administer oral antihistamine (cetirizine) or nasal glucocorticosteroid (ciclesonide) as rescue medication for allergic rhinitis in accordance with severity and frequency of allergic rhinitis symptoms according to Allergic Rhinitis and its Impact on Asthma (ARIA) guideline.

Rates scored by subjects using visual analogue scale regarding allergic symptoms provoked by causal allergen in daily life

Rhinitis symptom (visual analogue scale: 0~100) during nasal provocation test with allergen of D. farinae and/or D. pteronyssinus in subjects in whom D. farinae and/or D. pteronyssinus is causal allergen.

Mean diameters of wheal caused by 1- to 10^7- fold dilution of causal allergen in skin prick test and their allergen histamine ratio

Mean diameters of wheal caused by 10^2- to 10^7- fold dilution of causal allergen in intradermal test and their allergen saline ratio

Allergen-specific IgE for causal allergen of D. farinae, D. pteronyssinus, cat, and/dog using ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden)

Cytokines of Th1, Th2, and Treg immunity including interleukin-4 (IL-4), IL-5, IL-10, IL-12, IL-13, interferon-gamma (IFN-g), and tumor growth factor-beta (TGF-b) in nasal lavage fluid

Subjects' score regarding agreement to "Allergen provokes allergic symptoms in daily life" using visual analogue scale (0~100).

before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT

Subjects' score regarding agreement to "Allergen avoidance can reduce allergic symptoms" using visual analogue scale (0~100).

before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT

Subjects' score (0~100) regarding agreement to "Allergen-specific immunotherapy can reduce allergic symptoms"

Subjects' score regarding agreement to "Allergen-specific immunotherapy can reduce allergic symptoms" using visual analogue scale (0~100).

before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT

Agreement% scored by subjects using visual analogue scale to "I am willing to pay 50,000, 100,000 or 200,000 Korean Won per month for allergen avoidance"

before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT

Agreement% scored by subjects using visual analogue scale to "I am willing to pay 150,000, 300,000 or 600,000 Korean Won for each injection of intralymphatic immunotherapy"

before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT

Nasal cavitary volume decrease (basal%) measured by acoustic rhinometry during nasal provocation test with allergen of D. farinae and/or D. pteronyssinus in subjects in whom D. farinae and/or D. pteronyssinus is causal allergen.

Allergen-specific IgG4 for causal allergen of D. farinae, D. pteronyssinus, cat, and/dog using ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden)

Inclusion Criteria: We enrolled subjects who suffered from AR, symptoms of which were provoked by Dp, Df, dog, and/or cat allergen. Concretely, two inclusion criteria should be met. Sensitization should be verified by skin prick test and the level of serum specific IgE measured by ImmunoCAP® (Thermo Fisher Scientific, Uppsala, Sweden). Subjects should complain of AR symptoms during exposure of house dust, dog and/or cat in daily life. Exclusion Criteria: Uncontrolled or severe asthma according to Global Initiative of Asthma (GINA) guideline including a case in which forced expiratory volume in 1 s (FEV1) was less than 50% of predicted value Significant cardiovascular, hepatic, renal, hematologic, oncologic, or infectious diseases Administration of beta blocker, angiotensin converting enzyme inhibitor, tricyclic antidepressant, immunosuppressant including systemic glucocorticosteroid within last 2 weeks AR caused by other perennial or seasonal allergen Prior history of allergen-specific immunotherapy Rejection or low compliance, Pregnancy or lactation Vulnerable volunteer

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