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Allergen Immunotherapy (AIT): Guidelines, Updates and Recommendations of the World Health Organisation

About Dr Sohail Asghar Roomi

Definition: 
Allergen immunotherapy (AIT) is the administration of gradually increasing quantities of an allergen to ameliorate symptoms associated with exposure of causative allergen.

Nomenclature: 
Allergen vaccines were previously referred to as allergen extracts, and have been characterized as vaccines by the WHO to indicate their ability to modify the immune system in a way related to mounting an immune response to an infectious agent following vaccination.

Mechanism: 
Allergic inflammation is characterized by IgE-dependent activation of mast cells and basophils, eosinophilia and alteration in the production of cytokines. Two types of CD4+ T lymphocytes (T helper cells), based on their cytokine profile are recognized. 
T helper-1 cells (Th1) produce interferon-g (IFN-g), and interleukin 2 (IL-2) but no IL-4 or IL-5. T helper-2 cells (Th2) produce mainly IL-4, IL-5 and IL-13 but no IFN-g and IL-2. IL-4 and IL-13 are important for IgE heavy chain isotype switching. This process in inhibited by the Th1 cytokines IFN-g. The mechanism of switch from Th2 to Th1 responses with AIT is under study. High-dose AIT and allergen presentation by macrophage favor a Th1 response. In summary, it is believed that allergic responses are due to aggressive Th2 response, which might be down regulated by AIT by inducing Th1 response.

Indications: 
The following factor should be considered before the beginning of AIT.
a) Demonstration that the disease is IgE mediated;
b) Assessment of the symptoms caused by allergens;
c) Assessment of and attempts to avoid allergen exposure;
d) Assessment of the potential severity of the disease to be treated;
e) Efficacy of other treatment
f) Quality of allergen vaccine to be utilized and availability of standardized allergens;
g) Cost and duration of treatment forms;
h) Risk incurred from the allergic disease and the forms of treatment.

AIT is only indicated in allergic rhinitis, allergic asthma and patients with significant allergic reaction to hymenoptera (bee/wasp) sting.

A) AIT is indicated for subjects with allergic rhinitis:
1) In whom antihistamine and decongestants insufficiently control symptoms;
2) Who do not wish to be on pharmacotherapy; 
3) In whom pharmacotherapy produces undesirable side effects;
4) Who do not desire to receive long-term pharmacological treatment.
AIT administered to children who have only allergic rhino-conjunctivitis may prevent the development of asthma.

B) Asthma with demonstrated allergen sensitization is an indication of AIT. In allergic asthma, AIT is indicated for subject:
1) Who do not present a severe form of the disease: FEV1 should be over 70% of predicted value after adequate pharmacological treatment;
2) In whom symptoms are not adequately controlled by allergen avoidance and pharmacological treatment;
3) Who have both nasal and bronchial symptoms;
4) Who do not wish to be on long term pharmacotherapy;
5) In whom pharmacotherapy produces undesirable side effects.

C) AIT is indicated for the subjects with type-1 hypersensitivity to Hymenoptera stings (commonly honeybee or wasp)
1) Severe allergic reaction (respiratory/cardiovascular symptoms)
2) Positive skin prick/intradermal test and detection of serum allergen specific IgE
3) Professional beekeeper or other such professions where there are more chances of sting in future.
4) Age less than 15 (only in United Kingdom).

Relative Contraindications: 
1) Significant immunodeficiency;
2) Malignancy;
3) Severe psychological disorders;
4) Treatment with b-blocker (including topical administration, e.g. eye drops);
5) Poor compliance
6) Severe asthma
7) Significant cardiovascular disease
8) Children under five years of age
Pregnancy is not considered a contraindication for continuation of AIT, but most allergists do not start AIT during pregnancy.

Safety: 
Reactions to AIT are categorised as local and systemic.

REACTIONS TREATMENT
1) Large local reactions (>12 cm in 30 min) -Antihistamine oral, ice bag Observe for 60 min.
2) Rhinitis -Antihistamine oral, Observe
for 60 min and repeat peak flow.
3) Mild Urticaria -Antihistamine oral or parenteral and Observe for 60 min
4) Systemic reaction (urticaria, angiodema, or asthma) -Adrenaline (1mg/ml) 0.3-0.5 mg deeply S.C or I.M. Site of injection is infiltrated with adrenaline (1mg/ml) 0.2-0.5mg
-Check BP and pulse rate
-A well-acting I.V. line with saline is established.
-Antihistamine oral and Corticosteroid oral or parenteral.
In bronchial obstruction: b2-agonist inhalation and I.V.
-CONSIDER HOSPITALISATION.
5) Anaphylactic shock -Adrenaline (1mg/ml) 0.5-0.8 mg deep I.M (may be 
repeated after 5-15 minutes).
-Patient in Trendelenburg 
position.
-Check BP and pulse rate
-A well-acting I.V. line with saline is established. Volume replacement and plasma expanders if indicated
-Oxygen 5-10 l/min
-A tourniquet is placed proximally (BP cuff)
-In bronchial obstruction: as above
HOSPITALISATION NECESSARY FOR THE RISK OF DELAYED SHOCK.

It is noticed that most of the local and systemic reaction within 30 minutes after reaction. In local reaction, there is usually no change of dosage or injection schedule. AIT should be giving by expert allergists with all resuscitative measurement in hand. 
Patient should be observed for 60 minutes after each injection (UK guidelines). Peak flow should be recorded before and 60 minutes after each injection. Patient should be asked for any local and systemic reaction after last injection before giving next injection. The estimated risk for a systemic reaction is ~1/200 injections.

Efficacy: 
The objectives of AIT are to reduce responses to allergens, decrease the inflammatory response, and prevent the development of persistent disease. The treatment of allergic disease combines immunologic and pharmacologic therapy. Drugs provide symptoms relief. Allergen avoidance and AIT modify the natural course of the disease. 
Several studies show that AIT is effective in seasonal rhinitis, perennial rhinitis, and allergic asthma. Venom immunotherapy also shows protective and effective in all studies.

Conclusion: 
AIT is an effective treatment for allergic rhinitis/conjunctivitis and asthma. Immunotherapy is the only treatment available for venom sensitivity. AIT is indicated in patients with allergic diseases and demonstrated sensitivity to clinically relevant allergens. 
Systemic reactions occur in ~1 in 200 injections.
Identification of patient at risk, adequate waiting time, appropriate equipment, and qualifying experience of physicians and personnel administrating AIT are required for their treatment.

(From recent guidelines published in “Allergy and asthma proceeding” Author Theodoropoulos et al. and United Kingdom Published guidelines)