Immunotherapy specific

Repeated, subcutaneous(SCIT), sublingual(SLIT) or oral application (see below immunotherapy, specific, oral) of one or more clinically relevant allergen extracts in increasing concentrations until a so-called maintenance dose is reached

The aim of this immunomodulating therapy is the induction of an immune tolerance of the organism on humoral and cellular level against type I allergens (allergic reaction of the immediate type) under standardized conditions. S.a. immunotherapy, specific, ultra-short term therapy; s.a. immunotherapy, specific, oral; s.a. SCIT.

A prerequisite for successful immunotherapy is a precisely performed diagnostic procedure consisting of anamnesis, in-vitro skin tests (RAST) and/or provocation tests. Patient compliance is essential for the success of the therapy.

If allergens are avoidable (e.g. pets), a leave of absence should be preferred.

With standard immunotherapy, the therapy consists of two phases:

• Dose-increase phase (initial phase)
• Maintenance phase (only for pre-seasonal long-term treatment and perennial therapy).

A distinction is made between different application procedures:

• SCIT (subcutaneous specific immunotherapy)
• immunotherapy, specific, oral
• SLIT (sublingual hyposensitization)

In recent years, various innovative approaches have been developed such as:

• the Cluster and Rush SCIT
• the use of immunomodulators and adjuvants
• the use of recombinantly produced allergen preparations (the use of peptides containing the necessary T-cell epitopes enables a therapy with few side effects if IgE-binding epitopes are eliminated. This approach has been used for the treatment of patients with cat allergy (see also SPIRE)
• new ways of application such as epicutaneous and intralymphatic immunotherapy (in intralymphatic immunotherapy, small amounts of allergens are applied to a groin lymph node)

The indication for specific immunotherapy must be strictly defined (see also ARIA criteria). Specific immunotherapy against bee and/or wasp venom is the only form of immunotherapy that has been proven to have reliable results. Recent studies prove the clinical effects of mite allergoids in house dust mite allergy.

Indication and implementation of SIT should only be reserved for allergologically experienced practitioners. It is necessary to know locally and regionally relevant indoor and outdoor allergens in order to assess the exposure risk. Knowledge of cross-reactions is necessary. The aim is to normalize the mucosal hyperresponsiveness of responders, to avoid the change of level to asthma in rhinoconjunctivitis, to strive for cost savings through reduced drug requirements and to increase the quality of life. SIT can also be used in cases of concomitant (extrinsic) bronchial asthma and reduces nasal and bronchial symptoms.

The indications for SIT are listed below (according to Wedi and Kapp):

Severe allergic reactions with rhinitis or asthma and symptoms with natural exposure to aeroallergens as well as evidence of clinically relevant IgE-mediated sensitization (see also rhinitis allergica; insect venom allergy) and one of the following factors:

• Poor response to pharmacotherapy or allergenic withdrawal
• Unacceptable side effects of pharmacotherapy
• Desire to avoid long-term pharmacotherapy and reduce costs
• Coexistence of allergic rhinitis with allergic asthma
• In children with allergic rhinitis for asthma prevention
• The indication for insect venom allergy depends on the severity of the anamnestic reaction, especially systemic reactions, skin testing, specific IgE levels, RAST, CAP, stimulated leukotriene release and CAST
• Availability of standardized, high-quality allergen extracts with corresponding proof of efficacy.

Indications for SIT in children:

• IgE-mediated disease is present.
• There is a clear correlation with clinical symptoms (clinical relevance of the allergen is assured).
• The spectrum of sensitization is as narrow as possible.
• Availability of standardised or high-quality allergen extracts.
• Proof of effectiveness of the planned SCIT for the respective indication.
• Exposure cannot be avoided.
• Symptoms were observed over at least two seasons.
• There is subjective suffering of the patient.
• Good compliance is present.
• Age of the patient: ≥ 6 years.
• A risk-benefit-cost-balance was made.

The selection of allergens is based on medical history, the presence of specific IgE antibodies and allergen exposure. It includes only clinically relevant allergens. Only allergens that meet international guidelines for the standardization and production of allergen extracts are administered.

Dosages: The initial dose is usually a 1,000-fold or 10,000-fold dilution. After the injections, the patient remains under medical supervision for 30 minutes. The usual maintenance dose for standard inhalation allergens is 600 AUU (allergy units) or 4,000 BAU (bioequivalent allergy units), for insect venoms 100 μg Poison every 4 weeks. If systemic stinging reactions occur (nevertheless) in mastocytosis patients under this maintenance dose, the dose should be increased to 200 μg poison if tolerated.

In the case of seasonal allergens, the SIT is timed so that the maintenance dose is reached before the start of the season. It is interrupted or reduced during the season (reduction to 1/3 down to 1/5 of the last dose applied); then increased to the maintenance dose. The SIT duration for insect venoms is (3-) 5 years.

In case of higher individual risk (higher age, mastocytosis, high risk of exposure), treatment may have to be prolonged or life-long. A higher rate of side effects is to be expected in the case of mastocytosis. This applies in particular to treatment with wasp venom, but not to bee venom. It is recommended to accompany the dosage with an antihistamine therapy (some authors recommend Omalizumab as an accompanying therapy).

Specific immunotherapy with insect venom allergens see below SCIT.

Auxiliary medical personnel must not administer the injections. Allergen vaccines for injections may only be prescribed and administered by doctors with advanced allergological training or allergological experience.

Common side effects of SIT are transient reactions in the injection area.

Rare are persistent subcutaneous nodules as a side effect of a specific immunotherapy.

Severe, life-threatening systemic reactions occur with SIT with unmodified extracts in 0.002-0.008% of cases, with semidepot preparations in 0.005-0.01% of cases (surveys of the Paul-Ehrlich-Institute, cited after Lüderitz-Püchel U et al.)

Rare are so-called AEFI (adverse events following immunisation) or ASIA (autoimmune syndrome induced by adjuvants), which are also observed with other immune therapies (e.g. flu vaccinations) (see below contraindications - protective vaccinations).

Relative contraindications:

• Age < 5 years
• Pregnancy (a well-tolerated therapy already started at the beginning of pregnancy can be continued; skin testing is not considered dangerous)
• Biologics: Therapy with TNF-alpha-blocker (no verified literature)
• Severe atopic eczema (possible exacerbation)
• multiple sclerosis
• Strong late reactions after i.c. testing (after 6-24 hours)
• Taking of beta-blockers (also in eye drops; increase in airway resistance, hypotonic circulatory reactions, anaphylaxis becomes more difficult to treat!), it is recommended to implement the therapy before SIT If the therapy is not discontinued, it is recommended for forensic reasons not to perform an SIT with aeroallergens. In case of insect venom allergy a SIT may be performed, whereby a cardioselective agent is recommended.

Absolute contraindications: .

• ACE inhibitors (excessive anaphylactic activity. Reactions - Angiotensin I and II in the plasma of allergy sufferers reduced!)
• Acute febrile diseases
• Immunodeficiencies, therapy with immunosuppressive drugs
• Severe chronic infections, active tuberculosis
• Autoimmune diseases (collagenoses, rheumatic diseases)
• Secondary damage to the reaction organ (emphysema, bronchiectasis, cor pulmonale CHD, arterial hypertension (adrenaline therapy can lead to severe side effects!)
• Hyperthyroidism
• Cancer diseases
• Compliance Issues
• Severe mental illness
• Vaccinations (It is generally recommended that a vaccination whose concrete benefit is higher than its abstract risk be administered 1 week after the last hyposensitization injection. After an interval of 1-2 weeks the hyposensitization can be continued, whereby the dosage should be reduced by one step).
• haemophilia.

Hyperergic local reactions at the injection site (regarding a necessary dose adjustment in case of strong local side reactions, see below) insect venom allergy).

Allergic system reactions up to anaphylactic shock (very rare, especially in the case of improper, i.e. intravascular injection or failure to observe the contraindications), unspecific general reactions (fatigue, headaches, etc.). Systemic immediate type reactions are generally classified according to 4 degrees of severity (see below shock, anaphylactic):

• Grade 1: disseminated or generalized skin symptoms
• Grade 2: mild to moderate general symptoms
• Grade 3: Grade: Shock (often with syncope)
• Grade 4: Grade: Cardiovascular arrest.

An increase in dose can only take place if the patient tolerated the previous injection without problems. For patients with a high degree of sensitization, a slower dose increase or a 10-fold dilution of the starting solution is recommended.

If the patient has exceeded the therapy interval by 3 weeks, the dose is not increased. If the interval is 4 weeks, the dose is reduced by 1 step, and by a further step every week thereafter. The guidelines of the manufacturer must be observed.

If remote symptoms (urticaria, asthma, circulatory dysregulation) have occurred after the injection, the dose must be individually reduced by several levels during the following injection. Increases in 0.1 ml steps are then recommended.

A 16-week pre-treatment with the anti-IgE antibody Omalizumab ( off-label use) significantly reduced the rate of systemic side effects of SIT.

An antihistamine before injection is not recommended as a general prophylactic therapy. If, however, an antihistamine is given in case of an expected strong local reaction, the effect of the immunotherapy will not be reduced according to current studies.

Furthermore, it is controversially discussed in the literature whether the performance of a SIT contributes to the improvement of an atopical eczema. So far, there is no such indication, and reliable study results must be awaited.

SIT is urgently recommended in cases of mastocytosis and insect venom allergy, since a high percentage of allergic reactions are severe.

For indication and study situation of specific immunotherapy in children see there.

1. GOÄ-Tip (2014) Billing for hyposensitization. Skin XXV:106
2. Koschel D et al (2008) Hymenoptera venom immunotherapy and autoimmune diseases. Allergy 63: 81
3. Kroth J et al (2011) Persistent subcutaneous nodules as a side effect of a specific immunotherapy. Abstract-CD 46th DDG meeting: P02/12Liu
   Z ett al. (2019) Predictive methods for efficacy of house dust mite subcutaneous immunotherapy in
   allergic rhinitis patients: a prospective study in a Chinese population. Int Forum Allergy Rhinol doi: 10.1002/alr.22508.
4. Ring J et al (2018) Immediate type allergy: Rhinoconjunctivitis, bronchial asthma, anaphylaxis. In: Braun-Falco`s Dermatology, Venerology Allergology G. Plewig et al. (Hrsg) Springer Verlag S 454-456
5. Wedi B et al.(2011) Pharmacoprophylaxis and concomitant medication for specific immunotherapy. Dermatologist 62: 663-670
6. Wollenberg A, Vogel S, Renner ED (2010) Vaccinations for neurodermatitis and other chronic inflammatory skin diseases. dermatologist 61: 985-993

Possible specific immunotherapies and therapeutic success