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Injection Therapy for Asthma and Allergic Rhinitis
Injection Therapy for Asthma and Allergic Rhinitis WILLIAM C. DEAMER, M.D. b
Is injection therapy (hyposensitization) helpful for asthma and allergic rhinitis? How does one establish the diagnosis and then decide on injection therapy? What is the immunologic mechanism for its action? What is the duration of therapy and how lasting the benefit? What type of extract should be used, in what dosage and with what precautions? These and other questions regarding injection therapy for asthma and allergic rhinitis, both seasonal and perennial, are frequently asked by patient and physician alike. This article attempts to answer some of them from the viewpoint of one physician who practices and teaches pediatric allergy. Other allergists will doubtless disagree with some of the statements made, but certainly not with all of them and probably not with most of them. Aids in Diagnosis This article concerns itself primarily with comments on injection therapy for asthma and allergic rhinitis. First, however, it may be useful to mention some aids in establishing these diagnoses if they are in doubt or if one must depend on history alone to make the diagnosis, as is often the case. The child with asthma is likeiy to have a recurrent night cough and to cough or wheeze on exertion. These may be his chief symptoms, and frank asthma attacks may not be identifiable by history. If he does have a so-called "attack," it can be easily mistaken for bronchitis or pneumonia. Respiratory tract allergy is the great masquerader. In the guise of infection it may be labeled "colds," sinusitis, bronchitis, bronchopneumonia, pneumonia, pharyngitis, or croup. Rales, rhonchi, musical sounds, and prolonged expiration may all be associated with asthma, but may not all be present constantly. The presence of fine or medium "Professor of Pediatrics, University of California San Francisco Medical Center, San Francisco, California.
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rales together with fever often leads to a diagnosis of infection when in reality asthma alone is present. When the question of bronchitis or pneumonia versus asthma arises, it is helpful to ask whether symptoms of allergic rhinitis have been present. If so, asthma is favored, since lung allergy is often accompanied by the episodes of sneezing and rubbing of the nose with which it is frequently associated. "Sinusitis" in a patient who has prolonged or frequent "colds" associated with periodic sneezing and nasal itching is almost certainly of allergic rhinitis origin. Helpfulness of Injection Therapy for Asthma and Nasal Allergy Injection therapy can unquestionably be helpful in treating properly selected cases of respiratory tract allergy due to inhalant allergens. But often too much is expected of it. Injection therapy should be looked upon as an adjunct to avoidance of the allergen to the fullest extent possible, not as a substitute for it. It has no place in the treatment of food allergy and is usually contraindicated in the treatment of atopic dermatitis. The reasons for apparent failure of injection therapy include: (a) Failure to accompany injection therapy with optimal avoidance of environmental allergens. (b) Faulty selection of antigens in the treatment set; injection treatment based on skin tests of questionable accuracy or on history alone without skin tests, can be of only questionable value. (c) Undertreatment. Even though the antigens in the treatment set have been properly selected, the dose in which they are given may be insufficient to provoke a beneficial immunologic response. This possibility (as well as possibility b) should be considered when there is little or no local reaction at the site of injection, especially in the early months of treatment. ( d) Overtreatment with properly selected antigens. Too large a dose of antigens to which a patient is allergic will provoke a systemic (constitutional) reaction. Marked swelling at the injection site and its persistence for over 24 hours should raise the question of possible overdosage. ( e) Treating inhalant allergy while overlooking concomitant food allergy. The benefit which would otherwise be apparent from injection therapy for inhalant allergy may be completely masked by an unrecognized food sensitivity. Such an oversight is particularly likely if headache, abdominal discomfort or other components of the tension-fatigue syndrome 3 accompany the patient's respiratory symptoms. Once respiratory tract allergy has been recognized and before deciding on the need for injection therapy, the physician should decide whether it is due to inhalants (80 per cent), <> food (15 per cent), or <> The percentages indicated are the author's estimate of the approximate frequency of the chief offenders, as experienced at the Pediatric Allergy Clinic of the University of California-San Francisco Medical Center.
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~~--~----r-------------~~~ ~ l -_____________ ..J -
ATTACK
------===-
, ....
t:dJo House dust .... ,
~Feathers
, "-
/ / /
/
I. TRIGGER MOVERS
• • • • • •
"-,
...
I ~ H) Dog or cat "-
,
Tension Respiratory infection Fatigue Climate Exertion Odors or smoke
.... ....
~Kapok
....,
,
§IDPolien
...... J
~11I)Food
Figure 1. Causes of asthma: assumed vs. actual. While the analogy represented here is somewhat oversimplified, it makes the important point that what seems to cause an asthma attack is often only what triggers it; the actual cause being the frequently unrecognized bullet or bullets (i.e., items to which the patient is sensitive). Proof of this concept comes when, following removal of the bullets, the trigger-movers no longer bring on an attack. As shown, psychological factors (tension) and respiratory infection usually operate as trigger-movers. They are rarely "bullets". In other words, purely psychogenic asthma and true bacterial allergy as a cause of asthma are rare in childhood, but they do occur.
other factors such as bacterial allergy or psychogenic causes (5 per cent), or to combinations of these. After the first year, inhalants are increasingly more responsible for asthma than foods, and are usually the chief offenders. Infection and psychogenic factors often appear to be, but actually they are usually trigger factors rather than bullets, as viewed in the gun diagram (Fig. I)-i.e., secondary rather than primary factors. If he determines that inhalant factors play a major role, the physician must then decide whether, in addition to avoidance of the offending inhalants, injection therapy is indicated.
Selection of Patients for Injection Treatment The inhalant allergens most frequently used for injection therapy are extracts of pollens, house dust, and molds. Epidermals are only occasionally included, since they can usually be successfully avoided by the patient. Avoidance is so much more logical and successful than injection therapy that there is no question about its being preferable. As a result, injection therapy is used only when avoidance is not possible, as in the case of pollen and molds, or can be achieved only incompletely, as with house dust. In mild cases of asthma and allergic rhinitis, avoidance alone may solve the problem adequately and injection therapy may not be required as, for example, when a cat, a dog, or a feather pillow is the only offender. More often the patient is also sensitive to such antigens as pollens, molds,
*
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or house dust which cannot be eliminated adequately. In such a case the patient will usually benefit from injection therapy in addition to environmental control. Pollens. Injection therapy is the main weapon against pollen asthma and hay fever, since the ideal treatment-removal of pollen from the air we breathe-is virtually impossible. While it is true that antihistamines and vasoconstrictors for allergic rhinitis and bronchodilating drugs for asthma are useful adjuncts, treatment with drugs usually cannot compare with the more lasting benefit to be obtained by injection therapy.7 The validity of this statement is best documented by the experience of the many pollen-sensitive hay fever and asthma patients who have had injection therapy. There is also documentation in the literature,7,l1,13,19 but this is lagging because of the statistical problems involved in dealing with a complex clinical situation replete with subjective evaluations. Full acceptance of the value of injection therapy by the medical profession has also been handicapped by incomplete understanding of how it works, despite recent progress.u This situation is not new in the practice of medicine; cortisone plays an important role in modem therapy despite the incomplete understanding of its mode of action. At one clinic where a statistical study failed to obtain evidence of the advantage of ragweed extract over a placebo in treating ragweedsensitive patients, 5 injection therapy with ragweed pollen continues to be recommended, in agreement with the prevailing view concerning its efficacy. Skin tests with appropriate controls, when properly performed, are reliable in revealing specific pollen sensitivity. Injection therapy with pollens is usually helpful in combating the symptoms (nasal, ocular, or pulmonary) which they cause. It is the opinion of the author and others 2 ,6 that injection therapy for hay fever diminishes the likelihood of future development of asthma. If pollen asthma has already occurred, injection therapy is usually of marked benefit, so much so that the parents often feel that the child has been "cured" of his disease.· • Molds. The comments on pollen are generally applicable to mold spore allergy as well. Molds vary in importance in different areas of the country. In my clinic, mold allergy appears to be less of a problem than elsewhere; tests and treatment are confined chiefly to Alternaria and Homodendrum. House Dust. Injection therapy with house dust extract should never be undertaken without preceding removal of the sources of house dust from at least the bedroom. 4 A child customarily spends about half of his life in this one room-ll or 12 out of every 24 hours. His bedroom is apt to be a major source of the house dust allergen, the chief sources of which originate from kapok and cotton linters or their contaminants. Feather pillows, woolen rugs, and hair pads are secondary sources. It is obviously inappropriate for a patient to receive injections of house dust while ignoring its sources in the mattress, box springs, pillow,
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upholstered furniture, or stuffed toys in his bedroom. Minimal precautions include the use of rubber or synthetic fiber in pillows and stuffed toys, rubber or urethane foam mattresses and box springs, or the covering of ordinary box springs and mattresses with durable allergen proof encasings.'" Woolen rugs, cowhair pads and upholstered furniture should also be removed, and the heating vent sealed off. Once such precautions have been taken, injection therapy with house dust has a good chance to be of benefit to the house dust-sensitive child; otherwise it would probably be much less effective. If the patient leaves his bedroom in the morning without having had to contend with a heavy exposure to house dust all night, injection therapy can usually raise his tolerance sufficiently that any other exposure to house dust can be handled successfully. Epidermals. Of chief concern are cat and dog danders and feather pillows. No child with respiratory tract allergy should sleep on a feather pillow. If not already sensitive to feathers, by doing so he invites sensitization. Seldom is there much argument in arranging disposition of a feather pillow, but this is not the case for a dog or cat. Though it is widely accepted that these pets are frequent causes of asthma, they remain a major obstacle in the treatment of childhood asthma. It is the unpleasant but necessary obligation of physicians to (1) determine whether the asthmatic child who has a dog or cat is sensitive to its dander and, if so, (2) to see that the animal is excluded from the house. Injection therapy is no substitute. Sensitivity to dander may be obvious fro~n the history or may be demonstrated by a properly controlled intradermal skin test with reliable testing material. Much of the epidermal testing material on the market is relatively inactive. The reliability of an intradermal extract of dog dander may be checked by using it on a known dog dander patient. People often go to great extremes to avoid parting with their pets. They will make the misleading claim that their own pets are blameless and only those of the neighbors provoke allergic symptoms. Recently the mother of one of the author's patients related how she had shaved all the hair off a poodle in the mistaken assumption that the hair rather than the dander was the offender. Matters were made worse rather than better, since the naked animal could now not only shed dander more readily, but refused to leave the house. Chihuahua dogs are sometimes obtained on the false assumption that they are not allergenic. The only advantage of a Chihuahua over a St. Bernard is that there is less of him; that little, however, is still dog. If injection therapy without removal of pollen is successful, why is the same not true of injection therapy for household pets? The answer lies in the intensity of exposure. Pollen, fortunately, tends to present itself in a small quantity at a time-amounts which can usually be handled '" Allergen-Proof Encasings, 4046 Superior Avenue, Cleveland, Ohio 44103.
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successfully after injection therapy. But if the patient cuts the grass, plays in a field of ragweed, or pitches hay, he may find himself unprotected under such heavy challenge. If the correspondingly heavy challenge of living continually with a pet to which he is sensitive is avoided, a patient can frequently tolerate exposure which occurs out of doors or in other homes. If this is not the case and even such limited exposure is a frequent problem to the patient, injection therapy with the epidermal concerned should be considered. Occasionally, facilities permit the keeping of a pet outside of the home at all times-day and night, summer and winter. This may prove a satisfactory arrangement, if it can actually be carried out and if intimate and prolonged contact with the animal out of doors is also avoided. All too often it is apparent from the start that such an arrangement is doomed to failure and should not even be attempted. As a result, injection therapy is usually limited by the author to instances of house dust, pollen, and mold sensitivity; only occasionally are epidermals included in the treatment set. The basic principle is to give precedence to the elimination of an allergen over hyposensitization with it. The Immunologic Mechanism of Injection Therapy The final answer on the mechanism of injection therapy has not been established, but it may involve the production of a beneficial antibody (blocking antibody) as well as the reduction of the harmful antibody (reagin) responsible for the symptoms. A specific blocking antibody results from the injection of an antigen,10 pollen for example, but not from natural exposure to it. This antibody can then combine with its specific pollen antigen, upon subsequent exposure to it, and thus prevent its union on sensitized cells with reagin. Furthermore, continued injection of the pollen antigen eventually results in decreased production of reagin-possibly through some sort of immunologic tolerance mechanism. 1, 15 Whether these two observations explain all or only part of the improvement resulting from properly given injection therapy remains to be determined. Meanwhile, it is important to remember that benefit from such therapy can and does occur,7, 11, 13, 10 despite our incomplete understanding of the mechanisms. Duration of Injection Therapy In the author's clinic, injection therapy is given initially twice a week for 8 weeks, followed by a maintenance dose once every 3 to 4 weeks. If the patient is doing well after 2lh to 3 years, it is then stopped. It may be continued, however, if troublesome symptoms remain or retesting shows the development of new pollen sensitivities. The younger the child, the greater the likelihood that additional sensitization will occur. If a child of 4 years of age has acquired sensitivity to certain pollens as a result of four seasons of exposure, it is reasonable to assume
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that in the course of the next several years he may acquire additional pollen sensitivities which should be treated. A 14-year old adolescent, contrariwise, has been exposed to 14 pollen seasons and may have finished acquiring new pollen sensitization. If treatment is stopped for him, he may go several years or a lifetime without return of symptoms. Apart from such considerations, there is a great variation in the duration of benefit after injections are stopped. It will vary with differences in the intensity of exposure, as well as in individual immunologic responses to injection therapy, apart from such factors as duration of therapy and dosage. A child who is markedly sensitive to ragweed pollen (the most potent pollen allergen) may require treatment each year during childhood, whereas a child who is sensitive to a less potent pollen and residing in an area of less intense exposure than the ragweedsensitive patient, may do quite well for several years after a 3-year course of treatment. He may not require subsequent treatment at all. Type of Extract To Be Used The choice is between the standard aqueous type of extract, which has been used for many years, and a newer type of pyridine-extracted and alum-precipitated extract marketed as Allpyral. This, in contrast to aqueous extracts, is absorbed slowly and presumably results in a prolonged antigenic effect. It is generally agreed that aqueous extracts give good results, but there is not, as yet, full agreement that Allpyral extracts do SO.9, 12, 14, 16, 18 A theoretical benefit of Allpyral extracts is that fewer injections are required to reach a maintenance dose and, when this is reached, the interval between injections can be longer than with aqueous extracts. Generally, 15 to 16 injections are required to reach maintenance with aqueous extracts, in contrast to nine for Allpyral. The recommended interval between maintenance doses with Allpyral is usually about 6 weeks, in contrast to a usual 3-week interval with aqueous extractswhich, however, can often be stretched to 4 and then 5 weeks or longer in the second or third year of therapy. An exception may occur during periods of intense exposure, such as during the ragweed pollen season, when more frequent injections of aqueous extract at reduced dosage may be desirable. One disadvantage of Allpyral is that a reaction from overdosage is usually delayed and not as readily apparent compared to that of fluid extracts. This and the absence of the local reaction as a reliable guide increase the hazard that overtreatment will not be recognized. Presently the author prefers aqueous extracts for treatment. The Treatment Set The antigens in the treatment set are usually those to which the patient is exposed and clinically sensitive and which cannot be effectively avoided-viz., house dust, pollens, and molds. Epidermals
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(feathers, cats and dogs, etc.) can usually be eliminated adequately and are not normally included in the mixture of antigens. With pollens, the question arises of whether it is necessary to test and treat with individual varieties of a species, or whether antigenic similarity between varieties makes this unnecessary. The author is convinced that the latter is the case. For example, in his clinic a single test for oak sensitivity is made with a mixture of the most prevalent varieties of oak pollen rather than a test with each separately. A mixture of the three or four commonest sage pollens found on the west coast is used instead of testing numerous varieties of sage pollen individually. This approach was decided upon several years ago when, after a review of cases in which different varieties of sage pollen were reported to be different antigenically, it was found that the observation was based on careless skin testing and not on antigenic dissimilarities. It was further strengthened when we became aware of the difficulty encountered by experienced botanists in agreeing on varietal classification of specimens of sage growing in the field. The matter of antigenic similarity among different members of a single species is most important with grasses. One has the choice of testing to each variety of grass prevalent in one's area (some 36 in certain areas of the country) or with pooled members of subtribes of grasses (i.e., a mixture of brome grasses, a mixture of rye grasses, etc.) or with a single composite mixture of all the most prevalent grasses. We have had experience with all three methods in our clinic and are convinced that the last method gives satisfactory results in both testing and treatment. To test for grass pollen sensitivity, we use a mixture of the most common grass pollens in our area (including a double portion of Bermuda grass). This provides for an antigen common to all grasses as well as any which might occur only in certain grasses (see also p. 227). By thus grouping closely related tree, weed, and grass pollens we are able to accomplish in one visit and 28 tests what would otherwise require several visits and many more tests if we tested for individual pollens. These comments are not to be construed as favoring the use of mixtures of unrelated pollens in testing or treatment-such as would be found, for example, in a "spring mixture." In making a treatment set, pollens, house dust, and molds may be combined in one or, if too numerous, two treatment mixtures. The practice of also including other environmental antigens which give positive tests, such as tobacco smoke, kapok, feathers, human dander, wool and other epidermals, together with a stock bacterial vaccine, represents a shot-gun approach which cannot be supported. Pollen Dosage Proper pollen dosage is a matter of opinion as well as a matter of tolerance. While the individual patient's tolerance must always be the
r
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prime consideration, some allergists believe therapy should be pushed to the maximum tolerated dose. Most of them, including the author, do not go that far and favor a somewhat lower and therefore safer dose, but one large enough to cause an easily visible local reaction and an effective antigenic response (indicated by improvement in the patient's symptoms). The normal local reaction to subcutaneous injection of the antigen mixture produces slight swelling, redness and some itching which can last a few hours or up to 24 hours. If perennial treatment is used, the average maintenance dose of ragweed pollen is somewhere between 1500 and 3000 protein nitrogen units (PNU). Those who advocate a "maximum tolerated dose" inject up to five times these amounts. S The average starting dose varies from 5 to 10 PNU. In very sensitive patients, however, one may start with only 1 or 2 PNU and reach a maximum dose of only 200 or 300 PNUabout 0.5 m!. of a 1:1000 weight-by-volume extract. The size of the skin reaction, the speed with which it appears, and, to some extent, the history all help in the initial estimate of whether the patient is extremely sensitive and what sort of dosage schedule he should have. Subsequently, his response to the first few injections will help to clarify the matter. With continued treatment, the patient's tolerance usually increases. In the second year of therapy, the highly sensitive patient may tolerate a gradual increment of 50 to 100 per cent in his maintenance dosage, and benefit from it. The average patient may also benefit from a corresponding gradual increment in his maintenance dose. The dosages mentioned pertain to pollens of one antigenic species, such as ragweed, oak, or grass. When mixtures of pollens of several different species are incorporated in one vial, these doses may never be reached for a single species, since each one added dilutes the others. Despite this limitation, it is usually possible to incorporate amounts of the important reacting pollens, which, though less than ideal, are still adequate, in either one or two antigen mixtures. If two are required, they are best given separately (one in each upper arm), rather than mixed in a single syringe. Individualization of dosage from each vial, dependent on the size of the local reaction, is thus facilitated. Injections are given subcutaneously. Most treatment schedules currently in use resemble the following plan: Weak dilution (X): 0.05 ml. 0.10 ml. 0.20 m!. 0.40 m!. 0.60 mI. 0.80 m!. 1.00 mI.
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Medium dilution (lOX):
Strong dilution (100X):
0.10 0.20 0.40 0.60 0.80 1.00 0.10 0.20 0.30 0.40
C.
DEAMER
ml. ml. ml. ml. m!. m!. mI. m!. m!. m!. (maintenance dose)
Such a schedule can be criticized on two accounts: (1) Volumes of 0.05 ml. and 0.10 ml., representing only % of a drop to 1 Yz drops, are too small to be practical. Even minimal leakage at the site of injection could account for the loss of a significant part of the total dose, and an error of only 0.01 or 0.02 m!. in calibration or in filling the syringe could also represent a relatively significant error in dosage. (2) The dosage increments in such a schedule do not appear to be logical. The first four doses are each increments of 100 per cent, whereas the change from 0.8 to 1.0 ml. is an increment of only 25 per cent. The subsequent dose (0.1 m!. of lOX) is intentionally not an increase (since constitutional reactions are more likely when changing to a more concentrated extract), but the following dose (0.2 m!. of lOX) is an increment of 100 per cent. Let us now examine how a slight variation in the value of X influences such a schedule. If we assign an arbitrary value of 100 units to 1.0 m!. of dilution X, the sequence of units in the schedule is 80-100-100200. If, by intention or through loss of strength by aging, X is reduced to three-fourths strength (0.75 X), the sequence of units becomes 67-7575-150. It is difficult to reconcile progressing from 80 to 100 units in the first instance with the increase from 75 to 150 units in the second instance. The author has found the following schedule of approximately 50 per cent increments more logical, while still maintaining a desirable • uniformity: Weak dilution (X):
Medium dilution (lOX):
Strong dilution (100X):
0.15 0.22 0.32 0.48 0.70 1.00 0.15 0.22 0.32 0.48 0.70 1.00 0.15 0.22 0.30 0.40
m!. m!. m!. m!. m!. m!. m!. mI. m!. m!. m!. m!. m!. ml. ml. ml. (maintenance dose)
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When the size and duration of the local reaction indicate a high degree of sensitivity, this schedule can be modified so that no increase in dosage occurs when changing from one concentration to the next. One m!. of lOX, for example, would then be followed by 0.1 m!. of 100X. Doing so will lessen the likelihood of a constitutional reaction, which might otherwise occur because of more rapid absorption of the smaller volume or because of slight errors in measurement of dosage or in dilution.
BACTERIAL ALLERGY
In the author's opinion, bacterial allergy is not encountered as frequently in children as is sometimes claimed. Instances in which it is presumed to exist often prove to be cases in which respiratory tract allergy masquerades as infection and in which the existence of infection can be questioned. However, a small number of asthmatic patients, usually under age 3, present no evidence-by skin test, diet manipulation. or history-of inhalant or food allergy, yet wheeze after almost every upper respiratory tract infection. Fever is usually more prominent than it is in ordinary asthma, while sneezing and nasal itching are absent. The infectious nature of the problem may be evidenced by a similar illness in intimate contacts. Evidence that the "cold" is not acting in the usual manner as a trigger (secondary factor), but has moved over to the "bullet" (primary allergen) side of the diagram (Fig. 1), is suggested by the absence of other primary allergens. The history suggests that the patient is responding to some components of the infection just as other asthmatics do to pollen or house dust. Such patients are often infants with a history of repeated attacks of bronchiolitis, bronchitis, pneumonia or "croup." Older children are less likely candidates. We have treated a limited number of such patients with a mixture of equal parts of ordinary stock and acellular respiratory vaccines with sufficient success to believe it has a place in hyposensitization therapy. We start with a 1:100,000 dilution and with increments of 50 per cent arrive at a final maintenance dilution of 1:50 or 1:10. The dosage schedule is thus similar to that for pollens-except that it can usually be terminated after 9 to 12 months. The guidelines for choosing patients who receive vaccine therapy are difficult to define and call for considerable clinical judgment. Skin tests with bacterial vaccines are of no help. The danger is ever present that vaccine therapy will be used in lieu of more logical measures which have been overlooked. Precautions With Injection Therapy Injection therapy can be expected to fail when given in (a) insufficient dosage, (b) overdosage, (c) a shotgun manner without prior skin testing or based on skin tests of doubtful accuracy or doubtful
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significance, (d) treatment of a food allergy mistaken for inhalant allergy, and (e) patients without employing appropriate environmental control measures. When asthma is accompanied by an active atopic dermatitis, great caution must be observed in giving injection therapy, as it is likely to Hare the dermatitis, even when very small doses of antigen are used. Why tolerance of injection therapy is so limited in these cases, as compared with respiratory tract allergy, is not understood, but it is a well-known clinical observation. It may be necessary to reduce the starting dose to 'lioo of what would otherwise be used, and the standard top dose may never be reached. Unless the asthma is the greater of the two problems, it is best to forego injection therapy in such patients.
SUMMARY Injection therapy in properly selected cases, when properly administered, has an important place in the treatment of many patients with respiratory tract allergy. It should always be accompanied by maximal efforts toward avoidance of the allergens concerned.
REFERENCES 1. Connell, J. T., and Sherman, W. B.: Skin sensitizing antibody titre. III. Relationship to intracutaneous skin test, to the tolerance of injections of antigens and to the effects of prolonged treatment with antigen. J. Allergy, 35:169, 1964. 2. Criep, L. H.: The importance of allergy in the practice of pediatrics. Penn. Med. J., 46:816, 1943. 3. Crook, W. G., Harrison, W. W., Crawford, S. E., and Emerson, B. S.: Systemic manifestations due to allergy (sometimes referred to as allergic toxemia and the allergic tension-fatigue syndrome). Pediatrics, 27:790, 1961. 4. Deamer, W. C.: Allergy in childhood. Advances in Ped., 11:147, 1960. 5. Fontana, V. J., Holt, E. L., and Mainland, D.: A study of the effectiveness of hyposensitization therapy in ragweed hay fever in children. J.A.M.A., 195:985, 1966. 6. Glaser, J.: Allergy in Childhood. Springfield, Ill., Charles C Thomas, 1956, p. 282. 7. Johnstone, D. E.: Comparative value of hyposensitization and symptomatic therapy in pollenosis in children. N.Y. State J. Med., 60: 1448, 1960. 8. Levin, S. J.: Hyposensitizing (immunizing) inoculations in hay fever and asthma. PEDIAT. CLIN. N. AMER., 6:698, 1959. 9. Lichtenstein, L. N., Norman, P. S., and Winkonwerder, W. L.: Antibody response following immunotherapy in ragweed hayfever: Allpyral vs. whole ragweed extract. 24th Annual Meeting, Amer. Acad. Allergy, Boston, February 7, 1968. 10. Loveless, M. H.: The presence of two antibodies related to the same antigen in the serum of treated hay fever patients. J. Immunol., 38:25, 1940. 11. Lowell, F. C., and Franklin, W. A.: A double blind study of treatment of allergic rhinitis with aqueous allergenic extracts. J. Allergy, 34:165, 1963. lla. Lowell, F. C., and Franklin, W. A.: A double-blind study of the effectiveness and specificity of injection therapy in ragweed hayfever. New Eng. J. Med., 273: 675,1965. 12. Maunsell, K.: Rise in blocking antibodies in patients with pyridine-extracted alum-
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precipitated pollen allergen. 24th Annual Meeting, Amer. Acad. Allergy, Boston, February 7, 1968. Norman, P. E., Winkenwerder, W. L., and Lichtenstein, L. M.: Immunotherapy of hayfever with ragweed antigen E: Comparison with whole pollen extract and placebos. J. Allergy, 42:93, 1968. Reisman, R. E., and Arbesman, C. E.: Clinical effectiveness of two ragweed preparations. 21st Annual Meeting, Amer. Acad. Allergy, Bar Harbor, February 1965. Sherman, W. B., and Connell, J. T.: Changes in skin sensitizing antibody following 2 to 4 years of injection. 22nd Annual Meeting, Amer. Acad. Allergy, New York, February 23, 1966. Sherman, W. B.: Hypersensitivity. Philadelphia, W. B. Saunders Co., 1968, p. 177. Sprecace, C. A., Pomper, S. C., Sherman, W. B., Lemlich, A., and Ziffer, H.: The effect of antigen injection on skin reactivity to antigens. J. Allergy, 38:9, 1966. Tuft, L., Spiegelman, J., and Friedman, H.: Serologic response to alum-precipitated pyridine (Allpyrol) ragweed pollen extracts. 24th Annual Meeting, Amer. Acad. Allergy, Boston, February 7, 1968. Van der Veer, A.: Hayfever. In Cooke, R. A., ed.: Allergy in Theory and Practice. Philadelphia, W. B. Saunders Co., 1947, Chapter 10, Section III. Waldbott, C. L.: The treatment of chronic intractable asthma with pollen extracts. Ann. Int. Med., 7:508, 1953. Walzer, M.: Round table discussion on allergy. J. Pediat., 21:137, 1942.
Two recent references appeared too late to be included in the manuscript and have been added in proof: Brown, F. R., and Wolfe, H. I.: Observation on animal dander hyposensitization. Ann. Allergy, 26:305, 1968. Johnstone, D. E., and Dutton, A.: Value of hyposensitization for bronchial asthma. Pediatrics, 42:793, 1968. Department of Pediatrics University of California School of Medicine San Francisco, California 94122
Is injection therapy (hyposensitization) helpful for asthma and allergic rhinitis? How does one establish the diagnosis and then decide on injection therapy? What is the immunologic mechanism for its action? What is the duration of therapy and how lasting the benefit? What type of extract should be used, in what dosage and with what precautions? These and other questions regarding injection therapy for asthma and allergic rhinitis, both seasonal and perennial, are frequently asked by patient and physician alike. This article attempts to answer some of them from the viewpoint of one physician who practices and teaches pediatric allergy. Other allergists will doubtless disagree with some of the statements made, but certainly not with all of them and probably not with most of them. Aids in Diagnosis This article concerns itself primarily with comments on injection therapy for asthma and allergic rhinitis. First, however, it may be useful to mention some aids in establishing these diagnoses if they are in doubt or if one must depend on history alone to make the diagnosis, as is often the case. The child with asthma is likeiy to have a recurrent night cough and to cough or wheeze on exertion. These may be his chief symptoms, and frank asthma attacks may not be identifiable by history. If he does have a so-called "attack," it can be easily mistaken for bronchitis or pneumonia. Respiratory tract allergy is the great masquerader. In the guise of infection it may be labeled "colds," sinusitis, bronchitis, bronchopneumonia, pneumonia, pharyngitis, or croup. Rales, rhonchi, musical sounds, and prolonged expiration may all be associated with asthma, but may not all be present constantly. The presence of fine or medium "Professor of Pediatrics, University of California San Francisco Medical Center, San Francisco, California.
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rales together with fever often leads to a diagnosis of infection when in reality asthma alone is present. When the question of bronchitis or pneumonia versus asthma arises, it is helpful to ask whether symptoms of allergic rhinitis have been present. If so, asthma is favored, since lung allergy is often accompanied by the episodes of sneezing and rubbing of the nose with which it is frequently associated. "Sinusitis" in a patient who has prolonged or frequent "colds" associated with periodic sneezing and nasal itching is almost certainly of allergic rhinitis origin. Helpfulness of Injection Therapy for Asthma and Nasal Allergy Injection therapy can unquestionably be helpful in treating properly selected cases of respiratory tract allergy due to inhalant allergens. But often too much is expected of it. Injection therapy should be looked upon as an adjunct to avoidance of the allergen to the fullest extent possible, not as a substitute for it. It has no place in the treatment of food allergy and is usually contraindicated in the treatment of atopic dermatitis. The reasons for apparent failure of injection therapy include: (a) Failure to accompany injection therapy with optimal avoidance of environmental allergens. (b) Faulty selection of antigens in the treatment set; injection treatment based on skin tests of questionable accuracy or on history alone without skin tests, can be of only questionable value. (c) Undertreatment. Even though the antigens in the treatment set have been properly selected, the dose in which they are given may be insufficient to provoke a beneficial immunologic response. This possibility (as well as possibility b) should be considered when there is little or no local reaction at the site of injection, especially in the early months of treatment. ( d) Overtreatment with properly selected antigens. Too large a dose of antigens to which a patient is allergic will provoke a systemic (constitutional) reaction. Marked swelling at the injection site and its persistence for over 24 hours should raise the question of possible overdosage. ( e) Treating inhalant allergy while overlooking concomitant food allergy. The benefit which would otherwise be apparent from injection therapy for inhalant allergy may be completely masked by an unrecognized food sensitivity. Such an oversight is particularly likely if headache, abdominal discomfort or other components of the tension-fatigue syndrome 3 accompany the patient's respiratory symptoms. Once respiratory tract allergy has been recognized and before deciding on the need for injection therapy, the physician should decide whether it is due to inhalants (80 per cent), <> food (15 per cent), or <> The percentages indicated are the author's estimate of the approximate frequency of the chief offenders, as experienced at the Pediatric Allergy Clinic of the University of California-San Francisco Medical Center.
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~~--~----r-------------~~~ ~ l -_____________ ..J -
ATTACK
------===-
, ....
t:dJo House dust .... ,
~Feathers
, "-
/ / /
/
I. TRIGGER MOVERS
• • • • • •
"-,
...
I ~ H) Dog or cat "-
,
Tension Respiratory infection Fatigue Climate Exertion Odors or smoke
.... ....
~Kapok
....,
,
§IDPolien
...... J
~11I)Food
Figure 1. Causes of asthma: assumed vs. actual. While the analogy represented here is somewhat oversimplified, it makes the important point that what seems to cause an asthma attack is often only what triggers it; the actual cause being the frequently unrecognized bullet or bullets (i.e., items to which the patient is sensitive). Proof of this concept comes when, following removal of the bullets, the trigger-movers no longer bring on an attack. As shown, psychological factors (tension) and respiratory infection usually operate as trigger-movers. They are rarely "bullets". In other words, purely psychogenic asthma and true bacterial allergy as a cause of asthma are rare in childhood, but they do occur.
other factors such as bacterial allergy or psychogenic causes (5 per cent), or to combinations of these. After the first year, inhalants are increasingly more responsible for asthma than foods, and are usually the chief offenders. Infection and psychogenic factors often appear to be, but actually they are usually trigger factors rather than bullets, as viewed in the gun diagram (Fig. I)-i.e., secondary rather than primary factors. If he determines that inhalant factors play a major role, the physician must then decide whether, in addition to avoidance of the offending inhalants, injection therapy is indicated.
Selection of Patients for Injection Treatment The inhalant allergens most frequently used for injection therapy are extracts of pollens, house dust, and molds. Epidermals are only occasionally included, since they can usually be successfully avoided by the patient. Avoidance is so much more logical and successful than injection therapy that there is no question about its being preferable. As a result, injection therapy is used only when avoidance is not possible, as in the case of pollen and molds, or can be achieved only incompletely, as with house dust. In mild cases of asthma and allergic rhinitis, avoidance alone may solve the problem adequately and injection therapy may not be required as, for example, when a cat, a dog, or a feather pillow is the only offender. More often the patient is also sensitive to such antigens as pollens, molds,
*
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or house dust which cannot be eliminated adequately. In such a case the patient will usually benefit from injection therapy in addition to environmental control. Pollens. Injection therapy is the main weapon against pollen asthma and hay fever, since the ideal treatment-removal of pollen from the air we breathe-is virtually impossible. While it is true that antihistamines and vasoconstrictors for allergic rhinitis and bronchodilating drugs for asthma are useful adjuncts, treatment with drugs usually cannot compare with the more lasting benefit to be obtained by injection therapy.7 The validity of this statement is best documented by the experience of the many pollen-sensitive hay fever and asthma patients who have had injection therapy. There is also documentation in the literature,7,l1,13,19 but this is lagging because of the statistical problems involved in dealing with a complex clinical situation replete with subjective evaluations. Full acceptance of the value of injection therapy by the medical profession has also been handicapped by incomplete understanding of how it works, despite recent progress.u This situation is not new in the practice of medicine; cortisone plays an important role in modem therapy despite the incomplete understanding of its mode of action. At one clinic where a statistical study failed to obtain evidence of the advantage of ragweed extract over a placebo in treating ragweedsensitive patients, 5 injection therapy with ragweed pollen continues to be recommended, in agreement with the prevailing view concerning its efficacy. Skin tests with appropriate controls, when properly performed, are reliable in revealing specific pollen sensitivity. Injection therapy with pollens is usually helpful in combating the symptoms (nasal, ocular, or pulmonary) which they cause. It is the opinion of the author and others 2 ,6 that injection therapy for hay fever diminishes the likelihood of future development of asthma. If pollen asthma has already occurred, injection therapy is usually of marked benefit, so much so that the parents often feel that the child has been "cured" of his disease.· • Molds. The comments on pollen are generally applicable to mold spore allergy as well. Molds vary in importance in different areas of the country. In my clinic, mold allergy appears to be less of a problem than elsewhere; tests and treatment are confined chiefly to Alternaria and Homodendrum. House Dust. Injection therapy with house dust extract should never be undertaken without preceding removal of the sources of house dust from at least the bedroom. 4 A child customarily spends about half of his life in this one room-ll or 12 out of every 24 hours. His bedroom is apt to be a major source of the house dust allergen, the chief sources of which originate from kapok and cotton linters or their contaminants. Feather pillows, woolen rugs, and hair pads are secondary sources. It is obviously inappropriate for a patient to receive injections of house dust while ignoring its sources in the mattress, box springs, pillow,
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upholstered furniture, or stuffed toys in his bedroom. Minimal precautions include the use of rubber or synthetic fiber in pillows and stuffed toys, rubber or urethane foam mattresses and box springs, or the covering of ordinary box springs and mattresses with durable allergen proof encasings.'" Woolen rugs, cowhair pads and upholstered furniture should also be removed, and the heating vent sealed off. Once such precautions have been taken, injection therapy with house dust has a good chance to be of benefit to the house dust-sensitive child; otherwise it would probably be much less effective. If the patient leaves his bedroom in the morning without having had to contend with a heavy exposure to house dust all night, injection therapy can usually raise his tolerance sufficiently that any other exposure to house dust can be handled successfully. Epidermals. Of chief concern are cat and dog danders and feather pillows. No child with respiratory tract allergy should sleep on a feather pillow. If not already sensitive to feathers, by doing so he invites sensitization. Seldom is there much argument in arranging disposition of a feather pillow, but this is not the case for a dog or cat. Though it is widely accepted that these pets are frequent causes of asthma, they remain a major obstacle in the treatment of childhood asthma. It is the unpleasant but necessary obligation of physicians to (1) determine whether the asthmatic child who has a dog or cat is sensitive to its dander and, if so, (2) to see that the animal is excluded from the house. Injection therapy is no substitute. Sensitivity to dander may be obvious fro~n the history or may be demonstrated by a properly controlled intradermal skin test with reliable testing material. Much of the epidermal testing material on the market is relatively inactive. The reliability of an intradermal extract of dog dander may be checked by using it on a known dog dander patient. People often go to great extremes to avoid parting with their pets. They will make the misleading claim that their own pets are blameless and only those of the neighbors provoke allergic symptoms. Recently the mother of one of the author's patients related how she had shaved all the hair off a poodle in the mistaken assumption that the hair rather than the dander was the offender. Matters were made worse rather than better, since the naked animal could now not only shed dander more readily, but refused to leave the house. Chihuahua dogs are sometimes obtained on the false assumption that they are not allergenic. The only advantage of a Chihuahua over a St. Bernard is that there is less of him; that little, however, is still dog. If injection therapy without removal of pollen is successful, why is the same not true of injection therapy for household pets? The answer lies in the intensity of exposure. Pollen, fortunately, tends to present itself in a small quantity at a time-amounts which can usually be handled '" Allergen-Proof Encasings, 4046 Superior Avenue, Cleveland, Ohio 44103.
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successfully after injection therapy. But if the patient cuts the grass, plays in a field of ragweed, or pitches hay, he may find himself unprotected under such heavy challenge. If the correspondingly heavy challenge of living continually with a pet to which he is sensitive is avoided, a patient can frequently tolerate exposure which occurs out of doors or in other homes. If this is not the case and even such limited exposure is a frequent problem to the patient, injection therapy with the epidermal concerned should be considered. Occasionally, facilities permit the keeping of a pet outside of the home at all times-day and night, summer and winter. This may prove a satisfactory arrangement, if it can actually be carried out and if intimate and prolonged contact with the animal out of doors is also avoided. All too often it is apparent from the start that such an arrangement is doomed to failure and should not even be attempted. As a result, injection therapy is usually limited by the author to instances of house dust, pollen, and mold sensitivity; only occasionally are epidermals included in the treatment set. The basic principle is to give precedence to the elimination of an allergen over hyposensitization with it. The Immunologic Mechanism of Injection Therapy The final answer on the mechanism of injection therapy has not been established, but it may involve the production of a beneficial antibody (blocking antibody) as well as the reduction of the harmful antibody (reagin) responsible for the symptoms. A specific blocking antibody results from the injection of an antigen,10 pollen for example, but not from natural exposure to it. This antibody can then combine with its specific pollen antigen, upon subsequent exposure to it, and thus prevent its union on sensitized cells with reagin. Furthermore, continued injection of the pollen antigen eventually results in decreased production of reagin-possibly through some sort of immunologic tolerance mechanism. 1, 15 Whether these two observations explain all or only part of the improvement resulting from properly given injection therapy remains to be determined. Meanwhile, it is important to remember that benefit from such therapy can and does occur,7, 11, 13, 10 despite our incomplete understanding of the mechanisms. Duration of Injection Therapy In the author's clinic, injection therapy is given initially twice a week for 8 weeks, followed by a maintenance dose once every 3 to 4 weeks. If the patient is doing well after 2lh to 3 years, it is then stopped. It may be continued, however, if troublesome symptoms remain or retesting shows the development of new pollen sensitivities. The younger the child, the greater the likelihood that additional sensitization will occur. If a child of 4 years of age has acquired sensitivity to certain pollens as a result of four seasons of exposure, it is reasonable to assume
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that in the course of the next several years he may acquire additional pollen sensitivities which should be treated. A 14-year old adolescent, contrariwise, has been exposed to 14 pollen seasons and may have finished acquiring new pollen sensitization. If treatment is stopped for him, he may go several years or a lifetime without return of symptoms. Apart from such considerations, there is a great variation in the duration of benefit after injections are stopped. It will vary with differences in the intensity of exposure, as well as in individual immunologic responses to injection therapy, apart from such factors as duration of therapy and dosage. A child who is markedly sensitive to ragweed pollen (the most potent pollen allergen) may require treatment each year during childhood, whereas a child who is sensitive to a less potent pollen and residing in an area of less intense exposure than the ragweedsensitive patient, may do quite well for several years after a 3-year course of treatment. He may not require subsequent treatment at all. Type of Extract To Be Used The choice is between the standard aqueous type of extract, which has been used for many years, and a newer type of pyridine-extracted and alum-precipitated extract marketed as Allpyral. This, in contrast to aqueous extracts, is absorbed slowly and presumably results in a prolonged antigenic effect. It is generally agreed that aqueous extracts give good results, but there is not, as yet, full agreement that Allpyral extracts do SO.9, 12, 14, 16, 18 A theoretical benefit of Allpyral extracts is that fewer injections are required to reach a maintenance dose and, when this is reached, the interval between injections can be longer than with aqueous extracts. Generally, 15 to 16 injections are required to reach maintenance with aqueous extracts, in contrast to nine for Allpyral. The recommended interval between maintenance doses with Allpyral is usually about 6 weeks, in contrast to a usual 3-week interval with aqueous extractswhich, however, can often be stretched to 4 and then 5 weeks or longer in the second or third year of therapy. An exception may occur during periods of intense exposure, such as during the ragweed pollen season, when more frequent injections of aqueous extract at reduced dosage may be desirable. One disadvantage of Allpyral is that a reaction from overdosage is usually delayed and not as readily apparent compared to that of fluid extracts. This and the absence of the local reaction as a reliable guide increase the hazard that overtreatment will not be recognized. Presently the author prefers aqueous extracts for treatment. The Treatment Set The antigens in the treatment set are usually those to which the patient is exposed and clinically sensitive and which cannot be effectively avoided-viz., house dust, pollens, and molds. Epidermals
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(feathers, cats and dogs, etc.) can usually be eliminated adequately and are not normally included in the mixture of antigens. With pollens, the question arises of whether it is necessary to test and treat with individual varieties of a species, or whether antigenic similarity between varieties makes this unnecessary. The author is convinced that the latter is the case. For example, in his clinic a single test for oak sensitivity is made with a mixture of the most prevalent varieties of oak pollen rather than a test with each separately. A mixture of the three or four commonest sage pollens found on the west coast is used instead of testing numerous varieties of sage pollen individually. This approach was decided upon several years ago when, after a review of cases in which different varieties of sage pollen were reported to be different antigenically, it was found that the observation was based on careless skin testing and not on antigenic dissimilarities. It was further strengthened when we became aware of the difficulty encountered by experienced botanists in agreeing on varietal classification of specimens of sage growing in the field. The matter of antigenic similarity among different members of a single species is most important with grasses. One has the choice of testing to each variety of grass prevalent in one's area (some 36 in certain areas of the country) or with pooled members of subtribes of grasses (i.e., a mixture of brome grasses, a mixture of rye grasses, etc.) or with a single composite mixture of all the most prevalent grasses. We have had experience with all three methods in our clinic and are convinced that the last method gives satisfactory results in both testing and treatment. To test for grass pollen sensitivity, we use a mixture of the most common grass pollens in our area (including a double portion of Bermuda grass). This provides for an antigen common to all grasses as well as any which might occur only in certain grasses (see also p. 227). By thus grouping closely related tree, weed, and grass pollens we are able to accomplish in one visit and 28 tests what would otherwise require several visits and many more tests if we tested for individual pollens. These comments are not to be construed as favoring the use of mixtures of unrelated pollens in testing or treatment-such as would be found, for example, in a "spring mixture." In making a treatment set, pollens, house dust, and molds may be combined in one or, if too numerous, two treatment mixtures. The practice of also including other environmental antigens which give positive tests, such as tobacco smoke, kapok, feathers, human dander, wool and other epidermals, together with a stock bacterial vaccine, represents a shot-gun approach which cannot be supported. Pollen Dosage Proper pollen dosage is a matter of opinion as well as a matter of tolerance. While the individual patient's tolerance must always be the
r
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251
prime consideration, some allergists believe therapy should be pushed to the maximum tolerated dose. Most of them, including the author, do not go that far and favor a somewhat lower and therefore safer dose, but one large enough to cause an easily visible local reaction and an effective antigenic response (indicated by improvement in the patient's symptoms). The normal local reaction to subcutaneous injection of the antigen mixture produces slight swelling, redness and some itching which can last a few hours or up to 24 hours. If perennial treatment is used, the average maintenance dose of ragweed pollen is somewhere between 1500 and 3000 protein nitrogen units (PNU). Those who advocate a "maximum tolerated dose" inject up to five times these amounts. S The average starting dose varies from 5 to 10 PNU. In very sensitive patients, however, one may start with only 1 or 2 PNU and reach a maximum dose of only 200 or 300 PNUabout 0.5 m!. of a 1:1000 weight-by-volume extract. The size of the skin reaction, the speed with which it appears, and, to some extent, the history all help in the initial estimate of whether the patient is extremely sensitive and what sort of dosage schedule he should have. Subsequently, his response to the first few injections will help to clarify the matter. With continued treatment, the patient's tolerance usually increases. In the second year of therapy, the highly sensitive patient may tolerate a gradual increment of 50 to 100 per cent in his maintenance dosage, and benefit from it. The average patient may also benefit from a corresponding gradual increment in his maintenance dose. The dosages mentioned pertain to pollens of one antigenic species, such as ragweed, oak, or grass. When mixtures of pollens of several different species are incorporated in one vial, these doses may never be reached for a single species, since each one added dilutes the others. Despite this limitation, it is usually possible to incorporate amounts of the important reacting pollens, which, though less than ideal, are still adequate, in either one or two antigen mixtures. If two are required, they are best given separately (one in each upper arm), rather than mixed in a single syringe. Individualization of dosage from each vial, dependent on the size of the local reaction, is thus facilitated. Injections are given subcutaneously. Most treatment schedules currently in use resemble the following plan: Weak dilution (X): 0.05 ml. 0.10 ml. 0.20 m!. 0.40 m!. 0.60 mI. 0.80 m!. 1.00 mI.
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Medium dilution (lOX):
Strong dilution (100X):
0.10 0.20 0.40 0.60 0.80 1.00 0.10 0.20 0.30 0.40
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DEAMER
ml. ml. ml. ml. m!. m!. mI. m!. m!. m!. (maintenance dose)
Such a schedule can be criticized on two accounts: (1) Volumes of 0.05 ml. and 0.10 ml., representing only % of a drop to 1 Yz drops, are too small to be practical. Even minimal leakage at the site of injection could account for the loss of a significant part of the total dose, and an error of only 0.01 or 0.02 m!. in calibration or in filling the syringe could also represent a relatively significant error in dosage. (2) The dosage increments in such a schedule do not appear to be logical. The first four doses are each increments of 100 per cent, whereas the change from 0.8 to 1.0 ml. is an increment of only 25 per cent. The subsequent dose (0.1 m!. of lOX) is intentionally not an increase (since constitutional reactions are more likely when changing to a more concentrated extract), but the following dose (0.2 m!. of lOX) is an increment of 100 per cent. Let us now examine how a slight variation in the value of X influences such a schedule. If we assign an arbitrary value of 100 units to 1.0 m!. of dilution X, the sequence of units in the schedule is 80-100-100200. If, by intention or through loss of strength by aging, X is reduced to three-fourths strength (0.75 X), the sequence of units becomes 67-7575-150. It is difficult to reconcile progressing from 80 to 100 units in the first instance with the increase from 75 to 150 units in the second instance. The author has found the following schedule of approximately 50 per cent increments more logical, while still maintaining a desirable • uniformity: Weak dilution (X):
Medium dilution (lOX):
Strong dilution (100X):
0.15 0.22 0.32 0.48 0.70 1.00 0.15 0.22 0.32 0.48 0.70 1.00 0.15 0.22 0.30 0.40
m!. m!. m!. m!. m!. m!. m!. mI. m!. m!. m!. m!. m!. ml. ml. ml. (maintenance dose)
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When the size and duration of the local reaction indicate a high degree of sensitivity, this schedule can be modified so that no increase in dosage occurs when changing from one concentration to the next. One m!. of lOX, for example, would then be followed by 0.1 m!. of 100X. Doing so will lessen the likelihood of a constitutional reaction, which might otherwise occur because of more rapid absorption of the smaller volume or because of slight errors in measurement of dosage or in dilution.
BACTERIAL ALLERGY
In the author's opinion, bacterial allergy is not encountered as frequently in children as is sometimes claimed. Instances in which it is presumed to exist often prove to be cases in which respiratory tract allergy masquerades as infection and in which the existence of infection can be questioned. However, a small number of asthmatic patients, usually under age 3, present no evidence-by skin test, diet manipulation. or history-of inhalant or food allergy, yet wheeze after almost every upper respiratory tract infection. Fever is usually more prominent than it is in ordinary asthma, while sneezing and nasal itching are absent. The infectious nature of the problem may be evidenced by a similar illness in intimate contacts. Evidence that the "cold" is not acting in the usual manner as a trigger (secondary factor), but has moved over to the "bullet" (primary allergen) side of the diagram (Fig. 1), is suggested by the absence of other primary allergens. The history suggests that the patient is responding to some components of the infection just as other asthmatics do to pollen or house dust. Such patients are often infants with a history of repeated attacks of bronchiolitis, bronchitis, pneumonia or "croup." Older children are less likely candidates. We have treated a limited number of such patients with a mixture of equal parts of ordinary stock and acellular respiratory vaccines with sufficient success to believe it has a place in hyposensitization therapy. We start with a 1:100,000 dilution and with increments of 50 per cent arrive at a final maintenance dilution of 1:50 or 1:10. The dosage schedule is thus similar to that for pollens-except that it can usually be terminated after 9 to 12 months. The guidelines for choosing patients who receive vaccine therapy are difficult to define and call for considerable clinical judgment. Skin tests with bacterial vaccines are of no help. The danger is ever present that vaccine therapy will be used in lieu of more logical measures which have been overlooked. Precautions With Injection Therapy Injection therapy can be expected to fail when given in (a) insufficient dosage, (b) overdosage, (c) a shotgun manner without prior skin testing or based on skin tests of doubtful accuracy or doubtful
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significance, (d) treatment of a food allergy mistaken for inhalant allergy, and (e) patients without employing appropriate environmental control measures. When asthma is accompanied by an active atopic dermatitis, great caution must be observed in giving injection therapy, as it is likely to Hare the dermatitis, even when very small doses of antigen are used. Why tolerance of injection therapy is so limited in these cases, as compared with respiratory tract allergy, is not understood, but it is a well-known clinical observation. It may be necessary to reduce the starting dose to 'lioo of what would otherwise be used, and the standard top dose may never be reached. Unless the asthma is the greater of the two problems, it is best to forego injection therapy in such patients.
SUMMARY Injection therapy in properly selected cases, when properly administered, has an important place in the treatment of many patients with respiratory tract allergy. It should always be accompanied by maximal efforts toward avoidance of the allergens concerned.
REFERENCES 1. Connell, J. T., and Sherman, W. B.: Skin sensitizing antibody titre. III. Relationship to intracutaneous skin test, to the tolerance of injections of antigens and to the effects of prolonged treatment with antigen. J. Allergy, 35:169, 1964. 2. Criep, L. H.: The importance of allergy in the practice of pediatrics. Penn. Med. J., 46:816, 1943. 3. Crook, W. G., Harrison, W. W., Crawford, S. E., and Emerson, B. S.: Systemic manifestations due to allergy (sometimes referred to as allergic toxemia and the allergic tension-fatigue syndrome). Pediatrics, 27:790, 1961. 4. Deamer, W. C.: Allergy in childhood. Advances in Ped., 11:147, 1960. 5. Fontana, V. J., Holt, E. L., and Mainland, D.: A study of the effectiveness of hyposensitization therapy in ragweed hay fever in children. J.A.M.A., 195:985, 1966. 6. Glaser, J.: Allergy in Childhood. Springfield, Ill., Charles C Thomas, 1956, p. 282. 7. Johnstone, D. E.: Comparative value of hyposensitization and symptomatic therapy in pollenosis in children. N.Y. State J. Med., 60: 1448, 1960. 8. Levin, S. J.: Hyposensitizing (immunizing) inoculations in hay fever and asthma. PEDIAT. CLIN. N. AMER., 6:698, 1959. 9. Lichtenstein, L. N., Norman, P. S., and Winkonwerder, W. L.: Antibody response following immunotherapy in ragweed hayfever: Allpyral vs. whole ragweed extract. 24th Annual Meeting, Amer. Acad. Allergy, Boston, February 7, 1968. 10. Loveless, M. H.: The presence of two antibodies related to the same antigen in the serum of treated hay fever patients. J. Immunol., 38:25, 1940. 11. Lowell, F. C., and Franklin, W. A.: A double blind study of treatment of allergic rhinitis with aqueous allergenic extracts. J. Allergy, 34:165, 1963. lla. Lowell, F. C., and Franklin, W. A.: A double-blind study of the effectiveness and specificity of injection therapy in ragweed hayfever. New Eng. J. Med., 273: 675,1965. 12. Maunsell, K.: Rise in blocking antibodies in patients with pyridine-extracted alum-
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13. 14. 15. 16. 17. 18. 19. 20. 21.
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precipitated pollen allergen. 24th Annual Meeting, Amer. Acad. Allergy, Boston, February 7, 1968. Norman, P. E., Winkenwerder, W. L., and Lichtenstein, L. M.: Immunotherapy of hayfever with ragweed antigen E: Comparison with whole pollen extract and placebos. J. Allergy, 42:93, 1968. Reisman, R. E., and Arbesman, C. E.: Clinical effectiveness of two ragweed preparations. 21st Annual Meeting, Amer. Acad. Allergy, Bar Harbor, February 1965. Sherman, W. B., and Connell, J. T.: Changes in skin sensitizing antibody following 2 to 4 years of injection. 22nd Annual Meeting, Amer. Acad. Allergy, New York, February 23, 1966. Sherman, W. B.: Hypersensitivity. Philadelphia, W. B. Saunders Co., 1968, p. 177. Sprecace, C. A., Pomper, S. C., Sherman, W. B., Lemlich, A., and Ziffer, H.: The effect of antigen injection on skin reactivity to antigens. J. Allergy, 38:9, 1966. Tuft, L., Spiegelman, J., and Friedman, H.: Serologic response to alum-precipitated pyridine (Allpyrol) ragweed pollen extracts. 24th Annual Meeting, Amer. Acad. Allergy, Boston, February 7, 1968. Van der Veer, A.: Hayfever. In Cooke, R. A., ed.: Allergy in Theory and Practice. Philadelphia, W. B. Saunders Co., 1947, Chapter 10, Section III. Waldbott, C. L.: The treatment of chronic intractable asthma with pollen extracts. Ann. Int. Med., 7:508, 1953. Walzer, M.: Round table discussion on allergy. J. Pediat., 21:137, 1942.
Two recent references appeared too late to be included in the manuscript and have been added in proof: Brown, F. R., and Wolfe, H. I.: Observation on animal dander hyposensitization. Ann. Allergy, 26:305, 1968. Johnstone, D. E., and Dutton, A.: Value of hyposensitization for bronchial asthma. Pediatrics, 42:793, 1968. Department of Pediatrics University of California School of Medicine San Francisco, California 94122