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ROLE OF ALLERGY TESTING AND IMMUNOTHERAPY IN THE MANAGEMENTOF RESPIRATORY ALLERGIC DISEASES
DM TRIPATHI*
*Hon. Allergologist, Bombay Hospital, Mumbai 400 020.
The central point of allergy diagnosis remains the skin testing even-to-day, when the test results can be better guaranteed and differentiated through modern process like provocation test or RAST. In the diagnosis of allergic conditions such as bronchial asthma, allergic rhinitis in which allergy may be a pathogenic factor has been substantially facilitated by allergy skin testing. Skin testing demonstrates the presence of IgE directed against the specific allergen tested. Although, there are a variety of in-vivo and in-vitro methods for assessing the presence of specific IgE antibodies, the skin testing is preferred because it is simple, inexpensive, specific and results are immediately available. Allergy skin tests correlate well with clinical history, provocative challenge and in-vitro allergy assays such as RAST, modified RAST, QUIDEL, allergen screens, histamine release and immunocap system.
The advancements in medical and biological sciences have unravelled the mysteries of various diseases and a control over them has been achieved. But, the medical science is still in its infancy to understand a host of allergic disorders. The interesting feature of allergic manifestation is that in most cases, the casual material is not pathogenic and is important for the maintenance and perpetuation of vegetation, which is extremely essential.
Since Charles Blackley in the year 1973 published his proof that pollen grains cause hay fever, an array of scientists spread all over the world got interested in studying the nature of allergenic reactions with special reference to offending substances responsible for manifestations of such symptoms. The airborne pollen allergen is found to be the main responsible agent for manifestation of seasonal hay fever (allergic rhinitis) and seasonal asthma. In perennial allergic rhinitis or asthma the main offending agents are : house dust, dust mites and certain moulds.
The first step in the diagnosis of any disease is an appropriate level of suspicion. Whenever a patient presents with respiratory symptoms such as congestion, excessive secretion, sneezing, coughing, wheezing, burning or itching, the possibility that ‘allergy’ may be a factor kept in mind.
Our new understanding of the classic allergic diseases (allergic rhinitis, allergic asthma, eczema, etc) has underlined their multifactorial pathogenesis and wide clinical spectrum. However, all have one important pathway in common i.e. release of chemical mediators from mast cells and circulating basophils. The immunoglobulin E exhibits unique specificity i.e. affinity and avidity for binding to sites of the surface of basophils and mast cells. In allergic patients repeated exposure to an allergen results in production of specific IgE antibodies. The allergen is a protein molecule which has some allergenic determinants that binds to allergen specific IgE attached to mast cells. The coupling of allergen and specific IgE stimulates the mast cells to release histamine and vaso-amines producing symptoms.
The central point of diagnosis and treatment remains the detection of specific IgE. The diagnosis of allergic rhinitis, allergic asthma and eczema is result of demonstration of presence of allergen specific IgE, while treatment of the diseases in involves the blocking of allergen specific IgE by antigen dose.
Diagnosis of allergic disorders
When comparing the various methods used to diagnose allergy, in vivo and in vitro, it is necessary to take into consideration their specificity, safety, technical simplicity, the objectivity of the criteria, the rapidity of the diagnosis and reproducibility of results. The management of patient with respiratory diseases is highly dependent on the accuracy of aetiological diagnosis and interpretation of test results in terms of clinical relevance. Hence, all the factors as specific and non-specific findings must be taken into consideration.
The diagnosis of allergic diseases is made primarily by performing a detailed history and physical examination. It is almost necessary to confirm the presence of specific IgE antibodies directed towards inhalants or foods implicated in the history.
METHODS OF ALLERGY TESTING
A. In vitro testing
In the past, allergy as a diagnostic classification has been used loosely leading to diagnostic and therapeutic dilemmas. Now the role of IgE has led to the development of new tools by means of which diagnosis and treatment can be more predictable and rational. In vitro method involves the measurement of serum IgE by using various techniques such as Radio allergens sorbent test (RAST), modified RAST, PRIST or enzyme linked assay (ELISA), Pharmacia CAP system. These tests are less sensitive in comparison to skin prick test. Skin prick test is often positive when RAST tests are negative. Hence, allergy skin testing (prick testing), when possible, is the preferred method in comparison with various in vitro tests because it is more sensitive and specific, simpler to use and less expensive (Ten et al, 1995).
The major advantages of in vitro testing includes lack of risk of systemic reactions, lack of dependence on skin reactivity modified by drugs, diseases or age of the patients. The disadvantages of in vitro testing include the limited allergen selection; reduced sensitivity as compared with skin testing; lack of immediately available results and increased expenses due to added technical help.
B. In vivo testing
Amongst the in vivo testing, the skin testing covers three modes of testing - prick test, intradermal test and patch test.
Prick testing
Advantages of prick tests are:
1. It can be performed with glycerinated stable extracts, and the concentrations usually employed, correlates better with clinical sensivity.
2. Compatible with testing more allergens per session, less expensive and doesn’t give rise to systemic reactions.
3. It is more rapid, associated with less discomfort.
The test procedure consists of cleaning the skin with isopropyl or ethyl alcohol. The skin is marked with a ballpoint so as to identify and locate the site of each test. The volar side of forearm is recommended (Rance et al, 2000) for testing site and modified prick test technique (Tripathi, 1994) is preferably used. A single drop of each test solution is placed with the help of an applicator. A sterile lancet is then placed through the drop of an allergen solution at acute angle to the skin and a shadow lift is made. The lancet is raised for a second before the skin is released. This is repeated for each drop of allergen solution. After each prick, lancet is carefully wiped with dry cotton or wool.
After the skin test is performed, the drop of allergen solution is wiped after 15 minutes. The results are assessed by relating wheal area to that induced by histamine (0.1% w/v). Dermographic reactions are excluded by using a negative control (50% glycerosaline solution). Histamine reactions are read after 10 minutes while allergen test reactions are read after 15 to 20 minutes. The size of wheal and flare reactions are recorded in millimetres with mean of the largest and midpoint orthogonal diameters.
Intradermal testing
In the presence of a negative prick test results intradermal test may be useful in including or excluding allergens suggested the patient’s history. However, it must be appreciated that positive intradermal test results are commonly encountered in an asymptomatic population (Shulan et al, 1985). In intradermal testing unglycerinated aqueous allergen extracts are used which are unstable. Intradermal test is recommended in those subjects where prick test is negative.
Many studies have demonstrated that intradermal testing gives more false positive reactions and these reactions do not correlate with history, provocation test, histamine release test, etc. Since intradermal testing demonstrates poor specificity, it involves the risk of general allergic reactions, and is painful for the patient. Hence, it is not used frequently in allergological investigations.
Provocation testing
Direct administration of the allergen to respiratory mucosa (nasal, bronchial) with later observation of target organ is an adjunct to skin testing. In this testing high dilution of standardised allergen is introduced in to the nose, bronchi or eye. The test is risky and demands all the precautionary measures at hand and is inconvenient for the patient, hence is not recommended for regular use.
CONTRAINDICATION OF SKIN TESTING
During pregnancy skin test should be avoided as a precautionary step. Skin tests are not advisable in patients suffering from severe bronchospasm or having fever and in patients with dermographism.
European Academy of Allergology and Clinical Immunology (1988) has recommended that the following medications have to be avoided before any type of skin testing:
A. Antihistamines - both short acting and long acting.
B. The new antihistamines such as Astemizole, Terfenadine and Loratidine should be avoided for 6 weeks or more.
C. Tricyclic antidepressants such as Doxepin, Chlorpromazine, Hydroxyzine hydrochloride (for at least 5 days before testing).
D. Corticosteroids in small quantity do not influence the test results.
THE MANAGEMENT OF RESPIRATORY ALLERGIC DISEASES
Allergen immunotherapy enjoyed wide spread use since it was first introduced in 1911.
The dramatic changes in health-care delivery in the past decade have brought a renewed focus on the value of and indication for many therapies. Among these is allergen specific immunotherapy (SIT) - using no. of allergens for respiratory allergic diseases (Patterson, 1998).
To achieve a safe and effective maintenance dose, patient must receive full series course (2-3 years) of injections.
1. Patient must receive full course of SIT initial therapy for 6-8 months and later maintenance therapy for 3-5 years.
2. Administration should be proper.
3. Patient should be under observation for 20 minutes to monitor allergic reactions if any.
Indication for immunotherapy
The treatment of allergic diseases is based on allergen avoidance, pharmacotheraphy allergen immunotherapy and patient education. Physician should know the local and regional aerobiology and be aware of local potential allergens in the patient’s environment. Selection of clinically relevant allergens for therapy is totally based on knowledge of aerobiology.
Immunotherapy is effective in IgE mediated allergic conditions. Allergen immunotherapy is very common treatment in many parts of the world and is effective under optimal conditions including a demonstrated IgE mediated disease, a high quality extract, an optimal allergen dose and a correct indication. It is indicated in severe pollinosis and seasonal or perennial allergic rhinitis or asthma (Jean Bousquet et al, 1998).
Allergen immunotherapy is contraindicated in the management of patients with chronic bronchitis, non-IgE mediated allergic rhinitis and non-IgE mediated asthma. Allergen immunotherapy during pregnancy is also contraindicated. However, an already commenced immunotherapy, perhaps with reduced dose, may be advisable to continue if pregnancy occurs. TYPE OF IMMUNOTHERAPY
The immunotherapy protocols are based on immunizing a patient with a series of injections, once or twice a week with gradually increasing doses starting so low as to avoid any risk or untoward reaction.
A. Conventional immunotherapy : The basic concept of conventional immunotherapy to start with an arbitrary low dose by an arbitrary schedule to end with an arbitrary high doses the so-called "maximum tolerable dose".
B. Optimal dose immunotherapy : The optimal dose approach is governed by the concept that patient varies in sensitivity. Therefore, sensitivity of the patient to tested antigen can be ascertained by use of serial dilution titration (end point titration). The highly sensitive patients are given much smaller antigen dose, which is relatively close to top effective dose.
Although, allergen immunotherapy can be started at any time, however, in order to achieve desired effects the following methods have been recommended (Tripathi, 1992).
1. Preseasonal method : Preseasonal therapy is specially employed for pollinosis. The therapy is started 3-6 months before the pollen season. Increasing doses are given until the maximum tolerated doses are attained; the treatment is discontinued during the season and resumed the following year on the same date. For compliance of this method, it is very essential to know prevalence at atmospheric allergens.
2. Perennial method : Perennial therapy may be begun at any time. Top well tolerable dose is continued at 2 to 3 weeks interval throughout the year with some reduction in dose during the season. The perennial treatment is composed of two phases:-The maintenance dose varies considerably from patient to patient. Some patients may tolerate large dose while sensitive patients are required to be tailored individual dose considering seasonal prevalence of allergens. The dose is reduced during pollen season, during injection and when the preceding injection has caused marked local or systemic allergic reaction.
a. Initial treatment : This phase is also called as safety phase. Increasing injection doses are given of different concentration, starting with lowest concentration till top tolerable dose is reached of maximum concentration.
b. Maintenance therapy : The maintenance dose is critical for efficacy of immunotherapy. Initially it was proposed (EAACI, 1991) to give high dose to patient but owing to severe reactions, other investigators follow the concept of so called "skin titration". Bousquet et al, (1998) proposed to use an optimal maintenance dose. The ideal Maintenance dose is that which provides maximum long-term efficacy without adverse reaction. After a maintenance dose of immunotherapy is achieved the gap between two boosters may be 2 to 6 weeks depending on the dose and apparent response.
ALLERGEN EXTRACTS AND ROUTE OF ADMINISTRATION
Allergen extract
Allergen extracts are complex mixture of allergens. Some of them are heat labile and some heat stable. Extracts without stabilizer rapidly lose their potency. The loss is less with concentrated extracts and most pronounced with diluted extracts. Glycerol is most effective stabilizer for aqueous extracts. Allergen extracts may be administer as aqueous, depot or modified extracts:
1. Aqueous extracts : Since the beginning of allergen immunotherapy, aqueous allergen extracts have been subjected to validate its efficacy. As aqueous extracts are rapidly absorbed, from the site of injections, reaction, if any, appear within 20 to 30 minutes. The major disadvantage with aqueous extract is that therapeutic effectiveness requires multiple injections over a prolonged period of time.
2. Depot extracts : In an attempt to reduce the problem associated with aqueous extract, allergen extracts have been modified to reduce absorption rate. As these extracts have slow absorption rate, the reactions, if any, are delayed. The depot extracts are as efficacious as aqueous extracts and they are equally risky. The real advantage of depot extracts is that they require fewer injections than needed for aqueous extracts.ROUTE OF ADMINISTRATION
a. Alum precipitated extract : These are aqueous extracts absorbed on aluminium hydroxide carrier to slow the release of antigen. The main disadvantage of these extracts are (i) increased incidence of local reactions and (ii) incorrect allergen dose with poorly mixed suspension.
b. Modified extracts : New extracts have been developed with a view to reduce the allergenicity and retain the immunogenicity such as allergoides, pyridine extracted allergens, etc. These allergen extracts are not commercially available at present.
Subcutaneous route
Subcutaneous route of allergen administration is most widely used and were documented. Controlled studies demonstrated that subcutaneous allergen immunotherapy is effective for patients with skin hypersensitivity, allergic rhinitis, conjunctivitis and allergic asthma (Bousquet et al, 1998). Immunotherapy is effective treatment for many pollen species and house dust mite species in the treatment of asthma and rhinitis.
Despite the established efficacy of subcutaneous injections of causal allergens, the therapy did not gain popularity due to risk of systemic reactions which may be life threatening. The initial treatment (build-up phase) requires 30-40 injections each of which involves time and cost to the patient.
Local and nasal
In order to minimize the untoward reactions, local or nasal administrations of allergen extracts have been tried by spraying specified dose of extracts into nasal cavity at specified time interval. Though, the efficacy has been reported; the side effects like nasal pruritus, congestion and sneezing are intolerable to many patients and hence this routine for allergen immunotherapy is not yet recommended.
Oral or sublingual
Oral immunotherapy has been reported to be safe and effective by European workers. As oral immunotherapy requires further evidences, it is not recommended for general use at present.
EFFICACY AND SAFETY OF SUBCUTANEOUS IMMUNOTHERAPY
Controlled studies of the conventional immunotherapy for certain antigens have demonstrated a modest level of efficacy in majority of treated individuals. Many scoring systems have been proposed to assess the efficacy such as patient’s self-assessment and physician’s assessment for symptoms score. This method, is however, laborious and time consuming. Efficacy of immunotherapy could be assessed in combination with patient’s self evaluation, physician’s clinical evaluation of symptom score and in-vivo and in-vitro tests such as skin tests, allergen and histamine provocation test before or during the treatment period.
The way in which immunotherapy works was initially thought to be through a reduction in skin reactivity, but when it was observed that cutaneous reactivity to allergen was not obliterated, the term immunotherapy which does not imply a mechanism was adopted.
Various immunological changes produced by immunotherapy have been documented including a decrease in IgE antibody titres after prolonged therapy; an increase in allergen specific T suppressor cells and a decrease in histamine releasing factor are the major one. The blocking antibody mechanism has been the major theory of how immunotherapy acts. This antibody was ultimately recognized as IgG antibody.
Allergic side effects may be possibly avoided but risk of such reaction is always present. Adverse effects to allergenic extract can range from mild local reactions to severe generalized reactions. Local reactions are normally limited to swelling and irritation. Systemic reactions, which may be immediate or delayed, include cough, sneezing, urticarial rashes, bronchospasm, laryngeal oedema, generalised anaphylaxis and shock.
Most serious reactions occur due to error in selection of dosage and inexperienced hands. Norman (1989) pointed out that there is essentially no other important safety problem with allergen immunotherapy except careful selection of optimal tolerable dose in a given individual. Lockey et al (1987) also pointed out that most of the life threatening reactions are due to error in dose.
Hence following precautionary measures are recommended in order to minimise untoward reactions:
1. The starting dose of allergen extract must be individualised for each patient based on history and skin test results. Highly sensitive patients with marked skin test reactivity should be started with higher initial dilutions.
2. Interruption in dose schedule should be modified. If there is gap of 3 to 6 weeks, the same dose to be repeated. For long interval dose to be reduced.
3. In very sensitive patients, it would be beneficial to give an antihistaminic dose about an hour before injection.
4. It is mandatory that patient waits in the doctor’s office or waiting room for 20 to 30 minutes after injection.
5. The site of injection has to be inspected before the patient leaves the office.
6. The schedule dose should be modified under the following circumstances:COST EFFECTIVE
a. A reaction to previous injection.
b. Respiratory tract infection.
c. When a new batch of allergen extract is used.
d. Following a large local reaction.
Allergen immunotherapy is indicated for patients who have demonstrable evidence of specific IgE antibodies to clinically relevant allergens. For the past 90 years immunotherapy has been used to treat allergic diseases caused by the inhalant allergens. There is good evidence that immunotherapy with inhalant allergens used to treat seasonal or perennial allergic rhinitis and asthma is clinically effective. Although, the symptoms of allergen induced rhinitis and asthma can be effectively controlled by available pharmacotherapy, this requires regular prophylaxis, usually with more than one agent in a multiple daily dosage regimen. The cost of these medications is substantial. Thus, appropriate use of allergen immunotherapy (allergen vaccine) is not only efficacious but cost effective. Immunotherapy and allergen avoidance are the only treatments that may affect the natural course of allergic disease.
IMMUNOTHERAPY FAILURE
Approximately 5 to 10 per cent patients in a practice with true inhalant allergy do not respond to immunotherapy with significant clinical improvement in their symptoms (Keenan, 1989). When a patient has less ideal control of his or her allergic symptoms by immunotherapy, one should assume that an error may have been made in the initial interpretation of test results that could be related to variations in the strength of quality of the testing solutions. It would be advantageous to repeat the test before prescribing for immunotherapy at least with those allergens, which have been selected for immunotherapy mixture.
Co-existing chemical exposure that could exacerbate the patient’s symptoms to inhalant allergen should also be considered a reason for ineffective immunotherapy. Some patients with allergic rhinitis show a marked increase in their allergic complaints due to exposure to chemical fertilizers, weed sprays and insect repellents.
Inspite of every attempt to educate, a smaller number of patients obtain less than ideal response to immunotherapy because of non-compliance. As soon as these patients notice some improvement in symptoms, they skip injections and more over, they do not take responsibility for their illness and they often blame the physician for their lack of satisfactory response to immunotherapy.
REFERENCES
1.Bousquet J, Lockey R, Malling HJ. WHO panel members. Allergen immunotherapy : The therapeutic vaccine for allergic diseases - A WHO position paper. J Allergy Clin Immunol 1998; 102 (4) : 558-61.
2.Lockey, et al. Fatality from immunotherapy. J Allergy Clin Immunol 1987; 79 : 660-77.
3.Keenan JP. Management of problems and immunotherapy failures : In Otolaryngic Allergy and Immunology. WB Saunders Co. Philadelphia. 1989.
4.Norman PS. Safety of allergen immunotherapy. J Allergy Clin Immunol 1989; 84 (4) : 438.
5.Bousquet J, Maasch H, Martinot B, Hejjaoui A, Wahl R, Michel FB. Double blind placebo-controlled immunotherapy with mixed grass pollen allergoids. II comparison between parameters assessing the efficacy of immunotherapy. J Allergy Clinic Immunol 1988; 82 : 439-46.
6.Patterson R. The role of immunotherapy in respiratory allergic diseases. J Allergy Clin Immunol 1998; 101 : L403-4.
7.Tripathi DM. Role of Aerobiology in treatment of allergic patients. Current trends in life sciences 1994; 20 : 291-300.
8.Rance F, Dartau G, Abbal M. Mustard allergy in children. Allergy 2000; Ss : 446-500.
9.Tripathi DM. Principles of successful immunotherapy. Bom Hosp J 1992; 34 (4) : 71-9.
10.European Academy of Allergology and Clinical immunology. Immunotherapy position paper. 1988; 43.
11.Shulan KJ, Weiter JM, Koontz F, Richardson HB. Contamination of intradermal skin test syringes. J Allergy and Clinical Imm 1985; 76 : 226-7.
12.Ten RM, Klen JS, Frigas E. Allergy skin testing. Mayo Clinic Proc 1995; 70 : 785-86.
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