Hyposensitization in asthma: a review - Europe PMC

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Journal of the Royal Society of Medicine Volume 74 January 1981

Hyposensitization in asthma: a review' J 0 Warner MD MRCP Brompton, St Mary's and St Charles Hospitals, London

The Talmud (AD 200) described an approach to the treatment of egg sensitivity with a preparation of egg white (Epstein 1935). This was conceivably the first attempt at hyposensitization, though the concept of injection therapy for the treatment of allergic disease was only introduced in the twentieth century. Dunbar (1903) attempted to develop an 'antitoxin' to pollen in various animals to produce passive immunity in humans, but results were inconclusive. Noon (1911) and subsequently Freeman (1911) similarly believed that pollen produced a toxin which caused disease and therefore applied an immunization technique to produce active immunity. They reported 'a distinct amelioration of symptoms' in 20 hayfever patients given grass pollen extract injections. Cooke et al. (1935) found that serum injections from ragweed hyposensitized patients reduced symptoms in untreated patients. They introduced the concept of serum blocking antibodies produced by hyposensitization. The induction of such antibodies has been widely documented; they are thought to be of immunoglobulin G class, but studies suggest that clinical improvement following hyposensitization is not necessarily 'due to this phenomenon (Lichtenstein et al. 1968). 'Immunotherapy' has been suggested as the most appropriate term for this treatment but until we understand the mechanism of action, 'hyposensitization' probably more accurately describes what, at best, the treatment achieves. There has been a vast investment in hyposensitization for the treatment of allergic disorders over the last 60 years following the early uncontrolled observations of Noon and Freeman, but its efficacy is still not established, particularly for asthma. Debate on the subject often generates more emotion than fact and study of the literature produces conflicting argument. At best it can improve symptoms though not induce complete cure, and, at worst, can cause death from anaphylaxis, or a severe exacerbation of the disease being treated. Lack of understanding of the pathogenesis of allergic disease may account for the failure to rationalize this therapy, but in asthma there is difficulty even in defining whether allergy actually causes disease. Treatment of asthma Asthma can be precipitated by many factors, often acting simultaneously, in a variety of combinations. Even in clearly allergic asthmatics, attacks may be produced by intercurrent infection, exercise, emotional disturbance, nonspecific irritant dusts or fumes and changes in humidity or temperature. Furthermore, some asthmatics do not have demonstrable allergies and clearly hyposensitization will have no role in these patients. Thus the allergist can play only a subsidiary role in the multidisciplinary approach to the management of asthma. Prevention of disease must be our major objective, and Matthew et al. (1977) have shown that this may be successful. Any other treatment can be considered only as palliative. Avoidance of precipitating factors is the cheapest and most ideal treatment, but life in an allergen-free, infection-free and exercise-free environment would be unbearable and impossible. Simple avoidance recommendations are worthwhile if a food or family pet is involved. House-mite elimination techniques have been recommended (Sarsfi-eld et al. 1974), but sometimes found wanting (British Tuberculosis Association 1968, Burr et al. 1976). Attention to the 1 Based on paper read to Section of Paediatrics and Section of Clinical Immunology & Allergy, 27 April 1979. Accepted 7 October 1980

0141-0768/81/010060-06/$01.00/0

(D 1981 The Royal Society of Medicine


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psychological aspects of the condition is essential whilst conventional drugs remain the cornerstone of treatment. Hyposensitization is at present the last therapeutic approach to consider. Definition of hyposensitization Hyposensitization consists of a graded series of increasing doses of allergen. The optimal dose, dose interval and duration of therapy are still chosen arbitarily, but the aim is usually to achieve the maximum dose which just fails to produce dangerous reaction. Administration is usually subcutaneous though there have been some advocates of local nasal (Taylor & Shivalkar 1972) or bronchial hyposensitization (McAllen 1961), but results from 'topical' therapy have been disappointing (McClean et al. 1979). We do not know which categories of patients are most likely to benefit from this treatment, or indeed which allergens are best employed. The purity, standardization and characterization of extracts is far from satisfactory. Adverse reactions still result in mortalities following the use, or more frequently misuse of hyposensitization, and asthma may be exacerbated by the treatment. Finally, we still do not know how hyposensitization actually works. Therefore my definition of hyposensitization is 'exposure of allergic subjects to increasing doses of essentially uncharacterized immunogenic substances, at varying intervals for an indeterminate period of time, in an attempt to reduce allergic reactions to these substances'.

Preparations The drug market is flooded with allergen preparations for hyposensitization and most at present are either soluble, or adjuvant extracts with alum or tyrosine. The latter preparations are probably preferable because they require fewer injections and as they contain smaller quantities of allergen, adverse reactions occur less frequently (Norman & Lichtenstein 1978). The preparations are tested for irritancy, sterility, antigenicity and specificity but they still contain a mixture of complex molecules, many of which have no specific biological activity. There is a current drive for greater purification of allergen. Purified hymenoptera venom extracts are undoubtedly more efficacious than whole body extracts for sting allergies and the rationale for this development is quite clear (Hunt et al. 1978). However, whilst antigen E of ragweed contains 95% of the allergenicity and only 5% of the protein content of the crude extract (King & Norman 1962), it is probably not the substance released from pollen grains when they first settle on moist mucosal surfaces before the ensuing allergic reaction sweeps them away. Furthermore, allergenicity is not synonymous with immunogenicity. In other words, the capacity of the extract to produce a favourable response may not be related to its capacity to produce an allergic reaction. The future of hyposensitization lies with the development of modified allergens. Chemical modification of allergens by formalin, ultraviolet light or urea to produce 'allergoids', reduces their allergenic,properties but not their ability to induce an immunogenic response (Marsh et al. 1972). Trials of these preparations have been limited and as yet results are inconclusive (Norman 1980). Allergen conjugates with D-glutamic acid, D-lysine or isologous gammaglobulin described as tolerogens, in animal studies render B cells tolerant to specific allergens and thus switch off immunoglobulin E antibody production. The preliminary clinical trials with copolymer D-glutamic acid: D-lysine conjugates have been published and look promising (Bernstein 1980). Mechanisms of action A variety of immunological changes have been demonstrated in subjects receiving hyposensitization.- Immunoglobulin G or blocking antibodies have been most widely documented but correlation between increasing titres of this antibody and symptom improvement, is relatively poor (Lichtenstein et al. 1968). My own trial, which demonstrated favourable response to house-mite hyposensitization, was not associated with an increase in IgG antibodies (Warner et al. 1980). It has therefore been suggested that local blocking

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antibody, perhaps of immunoglobulin A class produced in bronchial or nasal secretions, may be more important (Platts-Mills et al. 1976). With prolonged treatment immunoglobulin E antibody levels gradually decline with an associated reduction in skin, nasal or bronchial response to the allergen (D'Souza et al. 1973, Aas 1971). Decrease in proliferative response of T cells to allergen and other changes in specific T cell numbers have also been described but not directly associated with clinical response (Neiburger et al. 1978). The only change which has been associated with a favourable clinical response is the loss of the late bronchial reaction which sometimes occurs four to six hours after a positive allergen bronchial provocation test (Warner et al. 1978). The underlying immunological explanation for this phenomenon remains a mystery. Complications With careful use and adequate precautions hyposensitization should not produce any major problems. Indeed, a recent study from France revealed only 0. % of reactions in nearly 20 000 patients and most of these were due to improper use of the preparations. Asthma, rhinitis and urticaria were the most frequent reactions, whilst anaphylactic shock occurred in two patients; neither was fatal and responded to treatment with adrenalin (Vervloet et al. 1980). It has been suggested that hyposensitization may cause late sequelae such as autoimmune disease or lymphoproliferative disorder, but a recent study showed no increase in such problems (Levinson et al. 1978). Occasionally, worsening of allergic disease has beeh associated with courses of hyposensitization, but it is impossible to determine whether this would have occurred even without such treatment. Certainly, controlled clinical trials have not highlighted this as a problem. Efficacy The efficacy of hyposensitization must be proved by scientifically designed controlled clinical trials rather than anecdotal reports, but it is very difficult to carry out a controlled study in asthma. There has been a deluge of publications but few trials selected patients satisfactorily or monitored the response to treatment objectively. Most of the best hyposensitization studies have been on patients with allergic rhinitis who may or may not also have suffered from asthma. Whilst such studies have demonstrated the usefulness of this treatment in ameliorating symptoms in the upper airway, extrapolation of results to asthma may be inappropriate. There remain relatively few trials from which to derive meaningful information on the value of hyposensitization in asthma (Table 1). Despite the problems, controlled trials were conducted more than 25 years ago (Frankland & Augustin 1954) and it is disappointing that there have been so few worthwhile studies since then. Pollen The weight of evidence suggests that pollen hyposensitization may be useful in patients with pollen-induced allergic rhinitis and possibly asthma. The most convincing trials have come from the USA using ragweed pollen extracts (Lowell & Franklin 1965, Lichtenstein et al. 1968, Sadan et al. 1969), though there have been studies showing no benefit from this therapy (Fontana et al. 1966). In the United Kingdom, however, there are at least 12 common grass pollens which are indistinguishable on aerobiology counts. Most pollen hyposensitization regimes in this country contain mixtures of the different grass pollens and there is little controlled trial evidence to support their use. The classical controlled trial of Frankland & Augustin (1954) used crude or purified extracts of only two pollens (Timothy and Cocksfoot), and a recent study suggested that better results may be achieved using a single grass pollen (Brown et al. 1979). Such extracts would have to be selected on the basis of appropriate allergen testing and the prevalent grass grown in the locality. Most regimes involve repeated pre-seasonal courses of injections, and often the first course is relatively ineffective. As the best results from hyposensitization have been achieved by prolonged courses, it would seem more rational to commence treatment immediately after the last pollen season and continue throughout the year.


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House dust and mite House dust and house dust mite therapy for asthma is even more controversial. They are the commonest allergens to produce positive skin tests in asthmatic patients (Hendrick et al. 1975). There is ample evidence that the house dust mite, Dermatophagoides pteronyssinus, is the major allergen which causes perennial exacerbations of asthma in the United Kingdom and Europe, though perhaps not in the USA (Warner 1978). In adult asthmatics the weight of evidence is very much against the value of house dust or house dust mite hyposensitization, with four of six controlled studies showing no therapeutic benefit compared with placebo. On the other hand, children respond differently, and three studies have convincingly demonstrated improvements on this treatment (Table 1). One other study in children compared house dust with house dust mite extracts and found the former more effective (Smith & Pizarro 1972), though the mite extract was probably too dilute. The difference between adult and childhood asthmatics is interesting and perhaps important. There is frequently a spontaneous improvement in asthma with age, and it is possible that children are especially suitable for hyposensitization which may in some way hasten immunological maturation. The children in these trials underwent stringent selection criteria for treatment; in two of the trials this included bronchial provocation tests to establish accurate allergy diagnosis. Animal danders There is little, if any, indication for hyposensitization to animal danders. The British practice of harbouring animals inside their living quarters should be discouraged for many reasons, but particularly in the homes of asthmatic patients, whether or not they have a demonstrable allergy to the animal. Certainly, hyposensitization should not be contemplated unless the offending allergen has been removed from the home for at least three months. Extreme sensitivity can cause problems and restrict particularly a child's social life when unable to visit the homes of friends who have pets. One controlled study employing a cat pelt antigen demonstrated a decreased sensitivity to cat dander in a small number of asthmatics, but the sensitivity was not completely eliminated (Taylor et al. 1978). Such therapy may, therefore, be considered in exceptional cases.

Other allergens Bacterial vaccines have been widely advocated by some authorities as infection sometimes precipitates asthmatic episodes, but there is good evidence, at least in children, that viruses rather than bacteria are involved (Horn & Gregg 1973). There is, therefore, no justification for bacterial vaccine and several well controlled trials have shown no benefit compared with placebo (Table 1). Only one trial reported a positive result but the benefit in this was minimal (Barr et al. 1965). This treatment may be dangerous and is used to produce autoimmune disease in animals (Christian et al. 1965). Many asthmatics are sensitive to a wide variety of allergens, but the use of mixed vaccines based on skin test responses must be condemned. A few studies have suggested that mixed therapy may produce beneficial responses (Johnstone & Dutton 1968), but such therapy produces an unacceptably high frequency of adverse reactions (A Mithal, personal communication). Furthermore skin tests are frequently misleading for accurate allergy diagnosis (Aas 1974). The best results from trials have been achieved using single allergen preparations. The use of mould extracts must await adequate trials and there is currently no justification for food hyposensitization. Indications Hyposensitization should be reserved for those allergic factors which cannot be eliminated and that can be demonstrated to play a major role in producing asthma. Accurate allergy diagnosis must precede treatment and should be based on a combination of clinical history with skin and bronchial provocation tests, or possibly IgE antibody measurements. The reliability of any of the above tests must be examined by study but it is clear that skin tests

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Table 1. Controlled trials of hyposensitization in asthma Outcome of trial Allergen

Favourable

Unfavourable

Pollens

Frankland & Augustin 1954 Johnstone 1957 p Lowell & Franklin 1965 Lichtenstein et al. 1968 Sadan et al. 1969 p Barr et al. 1965

Fontana et al. 1966 p

Bacteria

Animal dander House dust and mite

Taylor et al. 1978 Aas 1971 p Smith 1971 D'Souza et al. 1973 Taylor et al. 1974 p Warner et al. 1978 p

Frankland et al. 1955 Johnstone 1959 p Aas et al. 1963 p

British Tuberculosis Association 1968 Gaddie et al. 1976 Newton et al. 1978 British Thoracic Association 1979

, Trials of patients with 'hayfever', some of whom had asthma p Trials of children alone

alone are inadequate, giving both false positive and negative responses (Aas 1974). Patients with asthma controlled on simple and safer conventional therapy should not be considered for hyposensitization. Finally, it must be emphasized that hyposensitization can produce 'an amelioration of symptoms' but not complete cure, and may not avoid the requirement for other anti-asthma therapy. References Aas K (1971) Acta Paediatrica Scandinavica 60, 264-268 Aas K (1974) The Bronchial Provocation Test. Charles C Thomas, Springfield, Illinois Aas K, Berdal P, Henriksen S D & Gardborg 0 (1963) Acta Paediatrica Scandinavica 52, 338-344 Barr S E, Brown K, Fuchs M, Orvis H, Connor A, Murray F J & Seltzer A (1965) Journal of Allergy 36, 47-61 Bernstein I L (1980) Journal of Allergy and Clinical Immunology 65, 165 British Thoracic Association (1979) British Journal of Diseases of the Chest 73, 260-270 British Tuberculosis Association (1968) British Medical Journal iii, 774-777 Brown H M, Thantrey N & Jackson F (1979) Clinical Allergy 9, 465-472 Burr M L, St Leger A S & Neale E (1976) Lancet i, 333-335 Christian C L, Dessinone A R & Abruzzo J L (1965) Journal of Experimental Medicine 121, 309-321 Cooke R A, Barnard J H, Hebold S & Stuli A (1935) Journal of Experimental Medicine 62, 733-750 D'Souza M F, Pepys J, Wells I D, Tai E, Palmer F, Overell B G, McGrath I T & Megston M (1973) Clinical Allergy 3, 177-193 Dunbar W P (1903) Zur Ursache und specifischen Heilung des Heufiebers. R Oldenbourg, Munich Epstein 1 (1935) The Babylonian Talmud. Soncino, London Fontana V J, Holt L E & Mainland D (1966) Journal of the American Medical Association 195, 985-992 Frankland A W & Augustin R (1954) Lancet i, 1055-1057 Frankland A W, Hughes W H & Gorrill R H (1955) British Medical Journal iv, 941-944 Freeman J (1911) Lancet ii, 814-817 Gaddie J, Skinner C & Palmer K N V (1976) British Medical Journal ii, 561-563 Hendrick D J, Davies R J, D'Souza M F & Pepys J (1975) Thorax 30, 2-8 Horn M E C & Gregg 1 (1973) Chest 63, Suppl; pp 44 48 Hunt K J, Valentine M D, Sobutka R K, Benton A W, Amodio F J & Lichtenstein L M (1978) New England Journal of

Medicine 299, 257-261 Johnstone D E (1957) American Journal of Diseases of Children 94, 1-5 Johnstone D E (1959) Pediatrics 24, 427-433 Johnstone D E & Dutton A (1968) Pediatrics 42, 793-802 King T P & Norman P S (1962) Biochemistry 1, 709-720


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Levinson Al, Summers R J, Lawley T J, Evans R & Frank M M (1978) Journal ofAllergy and Clinical Immunology 62, 109-114 Lichtenstein L M, Norman P S & Winkenwerder W L (1968) American Journal of Medicine 44, 514-524 Lowell F C & Franklin W (1965) New England Journal of Medicine 273, 675-679 McAllen M K (1961) Thorax 16, 30-35 McClean J A, Matthews K P, Bayne N K, Brayton P R & Solomon W R (1979) Journal of Allergy and Clinical Immunology 63, 166 Marsh D G, Lichtenstein L M & Norman P S (1972) Immunology 22, 1013-1028 Matthew D J, Taylor B, Norman A P, Turner M W & Soothill J F (1977) Lancet i, 321-324 Neiburger R G, Neiburger J B & Dockhorn R J (1978) Journal of Allergy and Clinical Immunology 61, 88-92 Newton D A G, Maberley D J & Wilson R (1978) British Journal of Diseases of the Chest 72, 21-28 Noon L (1911) Lancet i, 1572-1573 Norman P S (1980) Journal of Allergy and Clinical Immunology 65, 87-96 Norman P S & Lichtenstein L M (1978) Journal of Allergy and Clinical Immunology 61, 384-389 Platts-Mills T A E, Von Maur R G, Ishizaka K, Norman P S & Lichtenstein L M (1976) Journal of Clinical Investigation 57, 1041-1050 Sadan N, Rhyne M B, Meilits E D, Goldstein E 0, Levy D A & Lichtenstein L M (1969) New England Journal of Medicine 280, 623-627 Sarsfield J K, Gowland G, Toy R & Norman A L E (1974) Archives of Disease in Childhood 49, 716-721 Smith A P (1971) British Medical Journal iv, 204-206 Smith J M & Pizarro Y A (1972) Clinical Allergy 2, 281-283 Taylor B, Sanders S S & Norman A P (1974) Clinical Allergy 4, 35-40 Taylor G & Shivalkar P R (1972) Clinical Allergy 2, 125-136 Taylor W V, Ohman J L & Lowell F C (1978) Journal of Allergy and Clinical Immunology 61, 283-287 Vervioet D, Khairaliah E, Arnaud A & Charpin J (1980) Clinical Allergy 10, 59-64 Warner J 0 (1978) British Journal of Diseases of the Chest 72, 79-87 Warner J 0, Price J F, Soothill J F & Hey E N (1978) Lancet ii, 912-915 Warner J 0, Price J F, Helms P, Turner M W, Platts-Mill T, Soothill J F & Hey E N (1980) Allergologia et Immunopathologia 8, 351