The best argument in favour of allergy testing is that once the offending allergen is identified, a specific treatment such as desensitization immunotherapy can be given to induce immune tolerance.
By Dr. Adrian Morris
Synonyms: Desensitization, Specific Immunotherapy (SIT), Hyposensitisation, Sublingual immunotherapy (SLIT), Allergy “shots” or Allergy vaccination.
Only two specific treatments are available to the allergic patient – allergen avoidance and allergen-specific Systemic ImmunoTherapy (SIT) given either orally or by injection. 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 desensitization. The use of allergen-specific subcutaneous injection immunotherapy spans 90 years. The procedure was pioneered by Noon at St Mary’s Hospital, London in 1911. Noon and Freeman successfully treated Hayfever sufferers by injecting them with pollen extracts. Immunotherapy has been enthusiastically adopted as the treatment of choice for allergic rhinitis and asthma in North America and Europe. In the UK, 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 systemic 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. Oral grass pollen immunotherapy has recently been given the “green light” by the CSM.
How does immunotherapy work at a cellular level?
The exact immuno-modulatory mechanism by which desensitization 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 (a 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 are 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 I IgE-mediated allergy that has been confirmed either by allergen skin prick testing (ALK Abello, Inmunotek or Loframa)) or radio-allergosorbent testing (RAST or ImmunoCAP). Another equally important consideration is whether the patient is likely to be compliant and adhere to this regular treatment regime for three years. The ideal candidate is a severely allergic person who is unable to avoid the offending allergen in daily life and in whom 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 versus drug therapy.
Numerous sublingual desensitization immunotherapy (SLIT) formulations for hay fever are available in the UK, in the form of ALK Abello’s product Grazax, a Timothy grass pollen oral extract, Oralvac (Allergy Therapeutics), LAIS drops (Lofarma) and Oraltek (Inmunotek). All are available in the UK and can be prescribed on the NHS. Immunotherapy has been most successfully used in the United Kingdom to treat grass pollen seasonal allergic rhino-conjunctivitis (hayfever) as well as Wasp and Bee sting and Horse anaphylaxis. Housedust mite, Cat and Birch Pollen allergic rhinitis can only be successfully treated with immunotherapy and products are available on prescription. Grazax an oral tablet form of grass pollen desensitization immunotherapy is now readily available on prescription in the the UK. These tablets should be commenced 2 months before and during the grass pollen season to achieve maximal benefit and treatment should span 3 years. ALK Abello will be rolling out their new House Dust Mite SLIT called Acarizax in late 2021 and then a Silver Birch tree pollen SLIT called Itulazax shortly thereafter.
The fewer allergens used in immunotherapy, the better the result. Vaccine mixtures tend to be unstable and should not contain mixtures of 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. For House-dust mite allergy use the standardised Dermatophagoides pteronyssinus whole mite vaccines. Grass pollen allergy is treated using a Phleum pratense (Timothy grass) extract while Birch Pollen allergy is treated with Silver Birch Pollen extract. The efficacy of prolonged use multiple-allergen mixed desensitising injections as administered in the USA for many years (so called “Allergy Shots”) is hotly contested by mainstream European allergists.
Wasp and Bee venom injection immunotherapy is highly effective, but 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. After successful wasp and bee venom immunotherapy, the patient will usually tolerate 100ug/ml pure venom, which is equivalent to two stings.
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. B-blocker medication should be stopped before commencing the procedure as they interfere with the action of adrenaline if 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 the United Kingdom.
Injection 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. 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. The 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. Dosage starts at 20SQ Units and usually increases to a maintenance dose of 100 000 SQ Units.
The injection dose is doubled weekly until a state of tolerance to the allergen is achieved, usually at 15 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 to 6-weekly for a period of 3 years to complete the immune modulating process. During the grass pollen season, we usually reduce the maintenance dose by 25%. If an injection is missed the next dose may need to be proportionally reduced. The patient should be observed for at least one hour 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. Changing from one injection vaccine manufacturer to another should be done with extreme caution and we usually recommend a temporary reduction in dosage over the transition period.
Sublingual Immunotherapy – the procedure
Grazax oral tablet and Oraltek drops desensitization immunotherapy is now available for adults in the UK as a treatment for grass pollen induced hayfever and allergic rhino-conjunctivitis. This oral treatment is called Sublingual Immunotherapy or SLIT. Each tablet contains an extract of Timothy Grass (Phleum Pratense) 75000SQ-T. The procedure is very safe and far less likely than injection immunotherapy to cause any adverse reaction (SLIT side-effects include headache and oral itching). The first dose must be administered under the supervision of a medical doctor (with 20-30 minutes observation), and all subsequent doses can safely be taken at home. The treatment involves taking one tablet daily and allowing it to dissolve under the tongue over one minute before swallowing. Treatment should commence 2 months before the grass pollen season and continued throughout the grass pollen season for maximal benefit. Some people experience irritating itching of the tongue and mouth during treatment. The dose can be temporarily reduced (halved) until this settles, or an antihistamine can be taken 30 minutes before each dose. Very seldom, certain individuals experience ongoing oral itching with each dose and have to stop the treatment. The treatment is stopped in the autumn/winter and then recommence 2 months prior to each subsequent grass pollen season. The only drawback is cost – each tablets cost over £4 or £110 per month for 3 years!
More about the allergen extracts.
Only allergen vaccines that have been standardised and fulfil reference IUIS/WHO guidelines should be used. Grazax an oral tablet specific for treating grass pollen allergy is now available on prescription in the UK. This sublingual form of immunotherapy (SLIT) is much safer than injection immunotherapy. Other suitable injection vaccines are marketed in the United Kingdom by ALK Abello as part of the Alutard SQ range, which include: Wasp Venom, Bee Venom, House dust mite and a Grass pollen mix. Silver Birch tree pollen, Cat and Dog Dander’s and Dermatophagoides species extracts (House-dust mite) are also available in sublingual form from Inmunotek and Lofarma. Allergy Therapeutics pharmaceuticals also market the Oralvac of Tree and Grass Pollen injectable extracts. 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 labelled 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 injection vaccines must be stored in a refrigerator at a temperature between 2degC and 8degC and need to be discarded after 6 months. They need to be shaken but not warmed before use. Allergen mixtures of unrelated allergens as used in the USA are not efficacious as they degrade easily and therefore should not be used.
Adverse reactions to injection immunotherapy
Most adverse reactions to injection immunotherapy such as Alutard SQ and Pollinex 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 precedes 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 reaction (less than 5cm diameter of swelling) occurs, continue the schedule as normal. If a larger area of swelling (greater than 5cm) occurs, then treat with an oral anti-histamine and maintain the same dose at the next injection. A mild systemic reaction is indicated by intense itching, erythema, rhinitis, localized angioedema and is treated by antihistamines and a stepwise reduction of the next dose. A more severe systemic reaction includes; laryngeal oedema and respiratory distress and is promptly treated with intra-muscular adrenaline 1:1000 0,5ml solution. The adrenaline injection may need to be repeated 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 desensitization immunotherapy program should possibly be abandoned. Sublingual immunotherapy is much safer and has a good side effect profile, at worst causing oral itching and some swelling of the tongue.
Outcome & benefits of successful immunotherapy.
The success of injection 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. Grass and Birch Pollen allergic patients seem to derive benefit for at least 6 years after completion of the full course of immunotherapy. In Housedust mite allergy the duration of clinical response may be shorter and injection 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 injection 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 will achieve 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.
Sublingual Immunotherapy (SLIT) is now available on prescription in the UK and marketed as Grazax by ALK Abello and Oraltek (Inmunotek), Oralvac (Allergy Therapeutics) and LAIS (Lofarma).. This treatment involves taking a tablet or drops containing the grass pollen allergen under the tongue on a daily basis to induce immune tolerance. SLIT negates the need for distressing injections and the one hour wait after each injection in the allergy clinic. These tablet can safely be administered at home. Results from extensive clinical studies on SLIT have been very encouraging but patient commitment is essential and the tablets must be taken every day to derive maximal benefit.
Better methods for standardizing allergen extracts may pave the way for the inclusion of asthma as recognised treatment entity in Britain. As the major allergens are sequenced at a protein and DNA level, the more likely those 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 success via other routes such as intranasal and rectally. These alternate routes would make immunotherapy much easier to administer and there is a great deal of research interest in the area. However, these practices are still under review and need to be extensively evaluated before they can be recommended for wider use. Initial studies of Peanut oral desensitisation immunotherapy have been very successful and should become commercially available soon. Research is being conducted into developing a desensitising “patch” containing which is applied to the skin to slowly induce tolerance and desensitise to specific environmental and food allergens (not available yet).
Caution about EPD
This webpage relates to Allergen Specific Immunotherapy (SIT and SLIT) which should not be confused with Enzyme Potentiated Desensitization (EPD). This is an entirely different procedure which employs an enzyme (B-glucuronidase) mixed with numerous allergens and then applied to the skin. This practice was reviewed in a study published in the British Medical Journal which found no therapeutic effect and concluded that EPD as an allergy treatment should not be recommended (Radcliffe M.J. et al, BMJ; 2003: 327: 251).