Synonyms: Desensitization, Hyposensitisation, Allergy “shots” or Allergy vaccination.
Written by Dr. Adrian Morris.

Introduction.

The only compelling argument in favour of establishing a specific diagnosis in allergic disease is that when the offending allergen is identified, a specific treatment can be instituted. Only two specific treatments are available to the allergic patient – allergen avoidance and allergen-specific immunotherapy (SIT). Medication although useful, will only suppress symptoms but do little to modify the long-term disease process. When one considers the expense of long term allergy medication, immunotherapy must be viewed as a cost-effective treatment option.

 

A very old and controversial practice

Few medical treatments have been shrouded in as much controversy as the practice of allergen-specific immunotherapy or desensitisation. The use of allergen-specific subcutaneous injection immunotherapy spans 80 years. The procedure was pioneered by Noon at St Mary’s Hospital, London in 1911. Noon and Freeman successfully treated hay fever sufferers by injecting them with pollen extracts.

 

beesting.jpg - 9.26 KImmunotherapy has been enthusiastically adopted as the treatment of choice for allergic rhinitis and asthma in North America and Europe. In the UK and South Africa, the procedure has never become as popular but is used as a treatment option in grass pollen allergic rhinitis and for bee or wasp sting anaphylaxis.

 

In 1986, the practice of immunotherapy was practically halted in the UK when the British Medical Journal published its damning Committee on the Safety of Medicines (CSM) report. This report cautioned against the use of immunotherapy in general practice and cited 26 anaphylactic deaths over 30 years. These deaths arose mainly as a result of inappropriate and injudicious use of the procedure in treating uncontrolled asthma.

 

Critics would therefore say that immunotherapy is a potentially life-threatening treatment for rather harmless, although inconvenient diseases. Immunotherapy does however definitely have a place in selected patient groups. The risk of adverse reactions is greatly reduced by careful patient selection and adoption of “good clinical practices” in immunotherapy(Table: 1.).

 

Table: 1. “Good Allergy Practice”

Factors to consider before commencing allergen immunotherapy

 

 

  1. Are specific allergens important in exacerbation’s and in the overall severity of this particular allergic disease?
  2. Have allergen avoidance procedures been implemented as much as possible?
  3. Is the overall severity of allergy adequate to warrant the risk of this type of therapy?
  4. Is an adequate allergen preparation available?
  5. Have the potential risks and benefits been weighed and discussed with patient?

 

 

 

How does immunotherapy work at a cellular level?

The exact immuno-modulatory mechanism by which immunotherapy switches off allergies is uncertain. It was hypothesised that specific “IgE blocking” antibodies were produced, as during successful immunotherapy an initial increase in specific IgE was followed by an IgE fall and compensatory rise in IgG(blocking antibody). Researchers then postulated that specific IgG4 antibodies where induced towards the offending allergen. An associated reduction in mucosal mast cell numbers and a decrease in antigen-induced eosinophil migration to the site of inflammation is noted during immunotherapy.

 

The latest “hot” hypothesis is that immunotherapy modulates the T-helper cells, causing switching from predominantly TH2 (IgE inducing) to predominantly TH1 (IgG inducing) subsets and as a result of this, allergen-specific IgE falls with successful immunotherapy.

 

Who will benefit from allergen immunotherapy?

Allergen immunotherapy should only be considered to treat type 1 IgE-mediated allergy that has been confirmed either by allergen skin prick testing (Bayer) or radio-allergosorbent testing (CAP RAST-Pharmacia).labspecrotate.gif - 18.64 K

 

Another equally important consideration is whether the patient is likely to be compliant and adhere to this regular treatment regime for 3-5 years. The ideal candidate is a severely allergic person who is unable to avoid the offending allergen in daily life and in who drug therapy has failed to control the allergy or in whom drug side-effects have become intolerable.

 

The patient must be carefully evaluated to determine whether the severity of the disease justifies this kind of treatment by balancing the relative benefits, risks, cost and inconvenience of immunotherapy vs drug therapy.

 

mite.jpg - 5.19 K
 

Immunotherapy has been most successfully used in South Africa to treat grass pollen allergic rhino-conjunctivitis, honey bee or wasp sting anaphylaxis and house-dust mite allergic perennial rhinitis

(Table:2.).

 

 

Table: 2. Who benefits from Allergen Immunotherapy

Preferably an isolated IgE mediated allergy manifesting as follows:

 

  • Grass pollen allergic rhino-conjunctivitis uncontrolled by medication.
  • Bee or wasp sting anaphylaxis and at risk for repeated stings.
  • House dust mite allergic perennial rhinitis uncontrolled by medication.

 

 

The fewer allergens used in immunotherapy, the better the result. Vaccine mixtures tend to be unstable and should not contain unrelated allergens. People with a single specific inhalant allergy derive most benefit from immunotherapy. However, if indicated, two inhalant allergens can be administered at the same time, at different injection sites.

 

Never use more than two allergens or mixtures of unrelated inhalant allergens at any one time. For House-dust mite allergy use the standardised Dermatophagoides pteronyssinus whole mite vaccines. Grass pollen allergy is treated using Bermuda grass pollen extracts or a stabilised mix of SA grass pollens depending on skin testing or RAST results.

 

Honey-bee venom immunotherapy which is highly effective, should only be considered in those patients experiencing significant systemic symptoms after a sting or for those people living in a remote part of the country who if stung, have no access to emergency medical care.
(see Table 3).
Use only Apis mellifera venom and not the whole body vaccine for bee venom immunotherapy. After successful bee venom immunotherapy, the patient will usually tolerate 100ug/ml pure bee venom which is equivalent to two stings.

 

Table: 3. Indications for bee venom immunotherapy

 Type of reaction to sting  

Immunotherapy

Severe systemic reaction (Respiratory, Cardiac collapse)  

Yes

Moderate systemic (angioedema, nausea, dizziness)  

Yes

Mild systemic (generalized urticaria and erythema)  

No

Large local reaction (erythema and itch at site of sting)  

No

 

The diagnosis of bee venom allergy must include a raised Venom-specific IgE

 

Immunotherapy should only be considered to treat animal dander allergy such as that to cats and dogs, when these animals cannot be avoided in the case of veterinarians and animal handlers.

 

 

Who should not receive immunotherapy?

The procedure is generally contra-indicated in patients over 50 years of age and those under 5 years of age. It should not be used in patients with coronary heart disease, hyperthyroidism, auto-immune disease or malignancy (Table:4.).

 

Table: 4.a. Contra-indications to Allergen Immunotherapy

    • Less than 5 years and greater than 50 years of age
  • Concurrent cardiac disease, malignant disease, hyperthyroidism, auto-immune disease.

 

Table: 4.b. “Relative” contra-indications to immunotherapy

  • The non-compliant patient, Pregnancy, Atopic Eczema, Food allergy, Chronic asthma, Mould allergy, Multiple unrelated inhalant allergies.

 

B-blockers should be stopped before commencing the procedure as they interfere with the action of adrenaline when used to treat anaphylaxis. The patient should also not be wheezing at the commencement of therapy. Relative contra-indications are; pregnancy, eczema, chronic uncontrolled asthma, food allergy and mould allergy (due to a lack of safe commercially available standardised extracts).

 

It has been suggested that immunotherapy may modify the natural history of asthma but at present, in view of the danger of inducing severe or fatal bronchospasm, immunotherapy is not generally recommended for the treatment of asthma in South Africa (ALLSA).

 

 

Immunotherapy – the procedure.

The injections should be given in the presence of a doctor and resuscitation equipment must always be available with adrenaline 1:1000, 0,5ml drawn up ready for injection (Table:5.).

 

At each visit, the patient should be assessed for any intercurrent febrile illnesses, sudden increased exposure to the allergen or any delayed adverse reaction to the last injection. If there has been a problem, the next dose may need to be modified or omitted. The manufacturers dose schedule for each extract should be regarded as a guideline, and frequently will have to be modified in the light of events occurring during the course of treatment.

 

desens.jpg - 8.46 KThe injection of allergen extract is given subcutaneously into the outer portion of the upper arm once a week. Always use a one millilitre finely calibrated syringe and first draw back on the syringe so as to prevent intravenous injection. The injection dose is doubled weekly until a state of tolerance to the allergen is achieved, usually at 12 weeks.

 

Grass pollen immunotherapy should be commenced pre-seasonally to so as to reach the maintenance dose before the pollen season starts. Thereafter maintenance injections are given 4 – 6 weekly for a period of 3 – 5 years to complete the immune modulating process. If an injection is missed the next dose may need to be proportionally reduced.pollen.jpg - 9.43 K

 

The patient should be observed for at least 30 minutes after each injection to ensure an adverse reaction does not occur. All forms of sport, exercise, alcohol and hot baths should be avoided for 6 – 8 hours afterwards as the increased blood circulation could precipitate an anaphylactic reaction.

 

Contact with the relevant allergens immediately after the injection should be avoided as this may also trigger an adverse reaction.

 

Table: 5. Emergency Resuscitation equipment.

Essential

 

  • Adrenaline 1:1000 – Adults 0,5ml for im or subcut administration

– Children 0,01ml/kg (max.. 0,3ml) 

  • Antihistamine (Phenergan Adult – 50mg, Children- 1mg/kg/dose)
  • Hydrocortisone solution ( Solucortef. Adults-200mg, Children-5mg/kg/dose)
  • Oral airway
  • Medihaler epi MDI (6-20 puffs)
  • B2 agonist MDI (4 puffs)
Preferable

  • Endotracheal tube
  • Oxygen
  • IV plasma expander.

 

 

 

More about the allergen extracts.

Only allergen vaccines that have been standardised and fulfill reference IUIS/WHO guidelines should be used. Suitable vaccines are marketed in South Africa by Bayer pharmaceuticals as part of the Albay and Allpyral range, which include: Apis mellifera venom (honey bee), Bermuda grass pollen and SA grass pollen mix and Dermatophagoides species extracts (House-dust mite).

 

Vesta pharmaceuticals will soon be marketing the ALK range of vaccines once our local Medicines Control Council registers these products.

 

The major allergen content (MAC) of an extract can be determined by a variety of methods using polyclonal or monoclonal antibodies. The vials should be labeled declaring their potency in relevant units (iu/ml) and should contain no non-allergenic material. Specific grass pollen vaccine content may be tailored to the results of the patients skin or RAST tests.

 

In the case of bee venom immunotherapy, the vaccine should preferably contain the venom rather than the whole-body extract. The vaccines must be stored in a refrigerator at a temperature between 2degC and 8degC. They need to be shaken but not warmed before use. Allergen mixtures of unrelated allergens are not efficacious as they degrade easily and therefore should not be used.

 

Adverse reactions to immunotherapy

Most adverse reactions to immunotherapy are attributed to errors in dosage and timing. Special care should therefore be taken to ensure that the patient receives the correct dose at the correct time. Adverse reactions are most likely to occur during the initial induction phase of immunotherapy.

 

Non-specific reactions such as excessive tiredness and headache are quite often reported but of no clinical significance. However, dizziness, itching and repeated clearing of the throat often precede a systemic reaction. The routine use of “pre-med” antihistamines before immunotherapy should be discouraged as they will suppress an immediate adverse reaction but the patient may then go on to have a delayed systemic reaction later on (at home).

 

If a small local reactions (<5cm swelling) occurs (Table:6.), continue the schedule as normal. If a larger area of swelling (>5cm) occurs, then treat with an oral anti-histamine and maintain the same dose at the next injection.

 

Table: 6. Adverse reactions to immunotherapy

Type of reaction

 

Action plan

  • Small local reaction (<5cm swelling)
  • continue schedule as normal
  • Larger local reaction (>5cm swelling)
  • give oral anti-histamine and maintain same dose for next injection.
  • Mild systemic reaction (itchy eyes, nose, throat or skin, dizziness).
  • give oral or intramuscular anti-histamine and reduce next dose to previously tolerated dose.
  • Severe systemic reaction (laryngeal oedema, hypotension and respiratory distress).
  • give adrenaline 1:1000 0,5ml subcut., 20 puffs with Medihaler epi, commence resuscitation and cancel any further immunotherapy injections.

 

A mild systemic reaction is indicated by intense itching, erythema, rhinitis, localized angioedema and is treated by antihistamines and reducing the next dose. A more severe systemic reaction includes; laryngeal oedema and respiratory distress and is promptly treated with subcutaneous adrenaline 1:1000 0,5ml solution and inhaled adrenaline (up to 20 puffs with a Medihaler epi).

 

The adrenaline injection may need to be repeated intravenously after 5 minutes if no improvement occurs. Oxygen and intravenous fluids may need to be administered with intravenous hydrocortisone 200mg and antihistamines in the case of generalised anaphylaxis.

 

A tourniquet can be applied to the limb above the site of allergen injection and a further injection of adrenaline given to the allergen injection site will delay further absorption of allergen. If these severe reactions occur, the immunotherapy program should be abandoned.

 

 

Outcome & benefits of successful immunotherapy.

The success of immunotherapy is dependent on the patient receiving regular injections of the highest tolerated dose of the biologically standardised vaccine for at least 3 years. Only limited knowledge exists about the optimal duration of immunotherapy and the duration of the therapeutic response achieved.

 

Pollen allergic patients seem to derive benefit for at least 6 years after completion of the full course of immunotherapy. In house dust mite allergy the duration of clinical response may be shorter and immunotherapy may need to be re-commenced at a later stage.

 

Between 7 and 17% of bee-venom allergic people will relapse 1-2 years after completion of successful immunotherapy. Because of this small risk of relapse, it may be advisable for patients to carry emergency antihistamines or adrenaline after completing their immunotherapy.

 

Successful immunotherapy will reduce the severity of an allergic disorder, improve the quality of life of allergy sufferer and diminish the risk and cost of pharmacotherapy. The ideal end point to signify successful immunotherapy is a negative skin prick test or a fall in allergen specific IgE to negligible levels. However, only a minority of patients Archives this end point despite the procedure producing a good clinical and symptomatic response. In Europe, immunotherapy is a popular adjunct to anti-allergy pharmacotherapy and is often used to augment asthma treatment.

 

 

The future

Better methods for standardizing allergen extracts may pave the way for the inclusion of asthma as recognised treatment entity in South Africa. As the major allergens are sequenced at a protein and DNA level, the more likely that highly purified semi-synthetic vaccines will come onto the market and be safer to administer. The most important aspect of successful immunotherapy is the careful selection of the potential candidate. Immunotherapy has been administered with limited success via other routes such as intranasally and sublingually, these practices are still controversial and need to be further evaluated.

Practice Point.

 

The patient should receive verbal and written information about immunotherapy, including a description of efficacy, possible complications, practical details of the duration of treatment, observation, costs and who is to administer the injections.

Practice Point.

 

“Immunotherapy and pharmacotherapy should be integrated components in the treatment strategy for allergic diseases in order to gain the best result” – European Association of Allergy and Clinical Immunology Position Paper, 1993.

Suggested Reading

  • Malling H-J, Weeke B. EAACI Immunotherapy Position Paper, Allergy 1993; 48: 9-35
  • BSACI Position Paper on Immunotherapy, Clin Exp Allergy 1993; 23: 1-44.
  • Noon L. Prophylactic inoculation against hayfever, Lancet 1911; 1:1572.
  • CSM Update, Desensitising vaccines BMJ 1986; 293: 948.
  • Potter PC. Immunotherapy – 80 years later. S Afr Med J; 1992; 81: 393.
  • Weinberg EG. Allergen Immunotherapy. In: Potter PC, Lee S. Eds. ALLSA Handbook of Practical Allergy. Cape Town, 1994
  • Ramsay M. Guidelines on the correct use of specific immunotherapy. CME 1994;12:9:1235-1237.
  • Malling H-J. Immunotherapy in Europe. Clin Exp Allergy. 1994; 24:515-521.
  • Varney VA., Gaga M., Frew AJ., et al. Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by anti-allergic drugs. Br Med J 1991; 302: 265-9.