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Cromolyn Sodium (Disodium Cromoglycate) Prophylaxis
Symposium on Pediatric Allergy
Cromolyn Sodium (Disodium Cromoglycate) Prophylaxis
Constantine J. Falliers, M.D.*
New perspectives in clinical allergy and a more diversified view of asthma have resulted from the therapeutic research which introduced cromolyn sodium (USAN)-more widely known by its original designation as disodium cromoglycate-for the prophylactic management of allergic respiratory disease. 1 • 2 • 11 This rather unique compound is not related to any of the other major groups of antiallergic and antiasthma tic drugs, such as antihistamines, adrenergic amines, xanthines, and corticosteroids. It is a bis-chromone, a synthetic analogue of khellin, which is a botanical extract known since ancient times for its smooth muscle relaxing properties but of little practical use due to side effects.U By contrast, cromolyn sodium appears to be very well tolerated. Also, interestingly its therapeutic value is not due to a bronchodilator effect, for it has none. 9 When symptoms of acute asthma and evidence of airways obstruction are present, cromolyn therapy is useless. This is known not only from experimental studies, 2 • 9 but also from experiences during the 5 years cromolyn sodium was not available officially in the United States, but was obtained by many patients across the borders or overseas and taken without medical supervision. Inhalations were taken sporadically, only when symptoms were present, and sometimes capsules were swallowed instead (unpublished observations)! Thanks to the extraordinary range of safety of this drug, no side effects were noted but such trials were wasteful and frustrating and resulted in a hasty condemnation of cromolyn as ineffective. Even now, due to the multiplicity of choices available,t 2 serious problems can and do arise, unless physicians and their patients obtain and retain the required basic facts concerning each particular therapeutic modality. '''Associate Clinical Professor of Pediatrics, University of Colorado School of Medicine, Denver; Attending Allergist, National Jewish Hospital and Research Center, Denver, Colorado
Pediatric Clinics of North America- Vol. 22, No. 1, February 1975
141
142
CoNSTANTINE ]. FALLIERS
MODE OF ACTION The demonstration that cromolyn sodium prevented experimentally induced asthma• (predictably provoked in a sensitized individual by the elective inhalation of an allergenic extract) served as the initial impetus for extensive clinical and basic research with this product. At first, it was thought that cromolyn prophylaxis was effective only against allergic asthma, the type caused by the interaction of reaginic antibody (IgE) with an extrinsic allergen.H Subsequent data, however, have shown11 that a broader "stabilization" of hyperreactive airways takes place. Exercise-induced asthma, airways obstruction resulting from voluntary hyperventialtion, and possibly certain cases of pharmacologically induced bronchospasm were found to be inhibited by pretreatment with cromolyn sodium inhalationsY· 18· 20· 25 Delayed (Type III) reactions may also be preventedP For clinical use, a dry powder of this drug is contained in a gelatin capsule, with lactose as an inert propellant. Placed in a specially designed inhaler (turbo-inhaler or Spinhaler), the capsule is punctured by the movement of two concentric pins and then, with a deep inspiration, the flow of air causes it to spin and release the micronized drug, which flows into the lungs. Three to six inhalations usually empty the capsule. Lack of understanding, or poor inspiratory flow, can reduce or prevent topical deposition of this drug. Particle size analysis has shown that 1 to 2 mg of the amount enclosed in one capsule reaches the alveolar region. 9 The remainder is retained in the orapharynx and trachea, from whence it is propelled, swallowed, and eliminated via the gastrointestinal tract. No accumulation in the lung or elswhere has been noted. About 9 per cent of a single dose is systemically absorbed and then excreted rapidly (average plasma half-life for man is 90 minutes) via the urine and bile.U Maxium blockade of experimentally induced asthma was observed when a therapeutic dose was inhaled 10 minutes before bronchial challenge with an appropriate antigen} Other studies have shown protection whether inhalational pretreatment was given 20 minutes or immediately before exposure. 24 The effect usually lasts about 6 hours. Given after the inhalational challenge, cromolyn sodium had no effect. 2· 9 Standard bronchial inhalational challenges have been considered as a possible means fQr establishing the indications for and the effectiveness of cromolyn sodium. 21 The "Lability Index" of the asthmatic lung was proposed18 as another method for the selection of candidates likely to benefit from cromolyn sodium. Summarizing recent experimental data, a group of investigators concluded that exercise testing may provide a useful basis for the selection of patients to be treated with cromolyn sodium.24 When cromolyn sodium is inhaled, its protective action is limited to the bronchial airways. Application of the drug directly on the nasal mucosa has shown that it can also prevent or control allergic rhinitis.8 The possibility that ophthalmic, gastrointestinal, dermatologic, and other topical symptoms attributable to allergy can also be prevented or controlled with cromolyn sodium is currently being considered.9 • 15
CROMOLYN SODIUM (DISODIUM CROMOGLYCATE) PROPHYLAXIS
143
Extensive basic research has been conducted in order to explain and in turn to direct further the therapeutic uses of cromolyn sodium on allergic disorders and on reversible obstructive airway disease. The primary site of action seemed to be the prevention of the disruption of mast cells and of the release of histamine and other mediators, caused by reagins or reagin-like antibodies upon contact with the sensitized cells.2 • 9 • 11 Ten to 20 meg per ml of cromolyn sodium reduced the amount of histamine and of slow-reacting substances of anaphylaxis (SRS-A) released from human lungs, passively sensitized with reaginic serum and exposed to the specific antigen at 37o C. 9 Further research has provided both laboratory and clinical evidence that cromolyn sodium has several types of blocking activity. Mast cells are functionally involved in these processes and, consequently, it has been postulated that these cells and cromolyn sodium are important in a wide range of human diseases.2 • 11 In most instances, mast cell stability was achieved by this drug, even against the nonantigenic stimulus of phospholipase-A or snake venom.9 Cromolyn sodium lacks muscle relaxant, antimed.iator (antihistamine, antiserotonin, etc.), and anti-inflammatory (corticosteroid-like) properties. These negative observations left three main possibilities for explaining the antiallergic action of this comqpund: (1) interference with the sensitization process, (2) altered antigen-antibody interaction, and (3) suppression of the release of pharmacologic mediators of anaphylaxis. Two experimental models have lucidly demonstrated the precise mode of action of cromolyn sodium and, concomitantly, have expanded our knowledge about the function of mast cells in general. These approaches, one in vitro and one in vivo 2 have shown that: (a) cromolyn sodium does not inhibit passive sensitization of the tissue when present throughout the sensitization procedure; (b) no histamine is released when cromolyn sodium is introduced with the antigen at the first challenge; and (c) when cromolyn sodium is present at the first challenge, but subsequently removed prior to a second antigen challenge, no histamine is released and the tissue appears desensitized. Since the drug does not antagonize histamine, the experiments suggest that although antigen-antibody interaction does take place in the presence of cromolyn sodium, no adverse reaction occurs due to the stabilization ("desensitization") of the previously hyperreactive tissue (mast cells). The fact that blood eosinophilia is reduced under cromolyn therapy10 may likewise reflect the absence of allergic stimuli which ordinarily produce it. No immunologic interference of cromolyn sodium with defense mechanisms of the host has as yet been detected. 11 • 21 Neither has there been any evidence that the adenyl cyclase and cyclic 3',5'AMP system is in any way altered by cromolyn sodium. Seasonal increases in specific reaginic antibodies take place even though clinical symptoms may be controlled with cromolyn. 3 • 14· 16 The drug is not known to cross the placenta or the blood-brain barrier and no teratogenic effects have been noted in experimental animals given extraordinarily large amounts of cromolyn sodium throughout pregnancy. Expectant mothers, treated with cromolyn sodium during pregnancy, are known to have given birth to healthy infants. 11 • 21 The isolated reports of pulmonary infiltration and
144
CoNSTANTINE
J.
FALLIERS
nasal congestion5 • 19 as possible side effects of cromolyn therapy will require further confirmation.
THERAPEUTIC APPLICATIONS AND IMPLICATIONS Without much doubt, the most common form of asthma in children, the intermittent paroxysmal attacks following occasional exposures to allergens or coinciding with infection, are not sufficient indications for cromolyn sodium prophylaxis. Ordinary preventive and symptomatic measures should suffice to control these. Cromolyn sodium and possibly other chromone compounds in the future, can be useful primarily in the following situations: A. Immediately before and during unavoidable exposure to allergenic substances known to have caused serious difficulty in the past and proven by diagnostic testing to be responsible for provoking attacks of asthma; B. During an entire period of high pollen and mold count, for patients who have proved sensitive to specific airborne allergens; C. When bronchial "lability" has been clearly demonstrated, whether by the Jones criteria of reactivity to isoproterenol vs. exercise/" or by the detection of exercise-induced bronchospasm alone,24 or, more selectively, when this hyperreactivity cannot be modified by extended symptomatic management and with appropriate environmental controls; and D. As adjunct therapy for patients with chronic perennial asthma, of multiple or undetermined etiology, who require continuous daily therapy with bronchodilators and corticosteroids. 7 • 11 • 22
The usual recommended dose is inhalation of the contents from one 20 mg capsule four times daily, but sometimes only 1 or 2 capsules per day can be equally effective. 14 Emphasis must again be placed on prophylaxis, or health maintenance. Obviously treatment is required to maintain health only when, without this therapeutic intervention, symptoms of disease are likely to persist or recur. Therefore, the entire concept of prophylactic therapy is based on the anticipatory judgment that asthmatic symptoms will not abate without constant pharmacologic prophylaxis. In patients belonging to category "D" above, the need for daily medication is unquestionable; generally, by the time cromolyn sodium treatment is considered, "steroid-dependence" will have been proven by repeated attempts to withdraw bronchodilators and steroids and by the ensuing severe exacerbations of asthma. The need for cromolyn sodium prophylaxis may be questioned by physicians as well as patients in situations A, B, and C above, especially in view of the cost involved and the inconvenience of the daily routine of daily inhalational therapy. Children and their parents should be given detailed instructions on the technique as well as the purpose of therapy. Unless there are psychological contraindictions, they should be told that definite improvement can be expected in barely over 50 per cent of the cases,<· 20 • 24 and total control of asthma in no more than 20 per cent14 • 20 of the children treated, even after several weeks of daily inhalations. In doubtful cases, certain empirical considerations may assist in determining whether extended prophylactic therapy with cromolyn sodium deserves a trial:
CROMOLYN SODIUM (DISODIUM CROMOGLYCATE) PROPHYLAXIS
145
Younger patients, with atopic asthma, still seem to obtain the best results from this treatment. Indeed, current studies 14 suggest that preschool children, between 3 and 6 years old, may show the highest percentage of improvement, both in terms of numbers and in terms of the completeness of symptomatic control. Patients prone to intermittent acute episodes of dyspnea and wheezing, but with relatively few symptoms in the intervals, are more likely to respond to cromolyn than those with chronic cough, expectoration, and persistent auscultatory findings. Older patients (not only adults, but also older adolescents) with asthma of the intrinsic type and with frequent respiratory infections are- despite some evidence to the contrary"-the least likely to benefit from cromolyn prophylaxis, and even if they do so, improvement may not be noted until after months of continuous daily therapy. 7 • 11• 23 Finally and most importantly, it must be remembered that cromolyn sodium is not indicated for the treatment of an acute attack of asthma or for status asthmaticus; if the patient is already on a daily treatment program, he could be advised to discontinue inhalations temporarily and to resume this prophylactic program when the attack has subsided.
SUMMARY In summary, successful therapeutic application of cromolyn sodium prophylaxis depends on a correct etiologic diagnosis of asthma and on the ability to predict the clinical behavior of a patient, by means of extended clinical observations and appropriate tests. Adequate preparation of each patient with intensive bronchodilator and, when necessary, corticosteroid therapy for "normalization" of pulmonary function are essential. Furthermore, the existential significance of respiratory regulatory processes13 must be kept in mind and the idea of prophylaxis convincingly presented to the family. Throughout the course of treatment and especially during the first few weeks, the physician and the patient, or the parents, must remain in close contact for individualized therapeutic guidance and for an accurate evaluation of the results of treatment.
REFERENCE 1. Altounyan, R. E. C.: Inhibition of experimental asthma by a new compound-disodium cromoglycate-"Intal." Acta Allerg., 12:487, 1967. 2. Altounyan, R. E. C., Orr, T. S. C. and Cox, J. S. G.: Biological and pharmacological basis of disodium cromoglycate therapy. In Serafini, U. eta!. (eds.): New Concepts in Allergy and Clinical Immunology. Excerpta Medica Internat'l. Congress Series No. 232. Amsterdam, Excerpta Medica, 1971, pp. 377-384. 3. Berg, T., and Johansson, S. G. 0.: In vitro diagnosis of atopic allergy. IV. Seasonal variations of I gE antibodies in children allergic to pollens- A study of non treated children and of children treated with inhalations of disodium cromoglycate. Int. Arch. Allerg., 41 :452, 1971. 4. Bernstein, I. L., et a!.: A controlled study of cromolyn sodium sponsored by the Drug Committee of the American Academy of Allergy. J. Allerg. Clin. Immunol., 50:235, 1972. 5. Block, S. H.: Nasal congestion as a side effect of cromolyn sodium. ]. Allerg. Clin. Immunol., 53:243, 1974. 6. Blummenthal, M. N., Schoenwetter, W. F., MacDonald, F. M., and McHugh, R. B.: Cromolyn in extrinsic and intrinsic asthma. J. All erg. Clin. Immunol., 52:105, 1973. 7. Chai, H., Molk, L., Falliers, C. ]., and Miklich, D.: Steroid-sparing effects of disodium cromoglycate (DSC) in children with severe chronic asthma. In Serafini, U., et a!.
146
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
CONSTANTINE ]. FALLIERS
(eds.): New Concepts in Allergy and Clinical Immunology. Exerpta Medica Internat'l. Congress Series No. 232. Amsterdam, Excerpta Medica, 1971, pp. 385-391. Chalk, N.: A double-blind crossover trial of disodium cromoglycate powder in perennial allergic rhinitis. Med. J. Austral., 1:491, 1973. Cox, J. S. G.: Disodium cromoglycate: Mode of action and its possible relevance to the clinical use of the drug. Brit. J. Dis. Chest., 65:189, 1971. Easton, J. G.: Effect of cromolyn sodium (disodium cromoglycate) on the peripheral eosinophilia of asthmatic children. Ann. Allerg., 31:134, 1973. Falliers, C. J.: Cromolyn sodium (disodium cromoglycate). Editorial. J. Allerg., 47:298, 1971. Falliers, C. J.: Comparative assessment of prophylactic inhalational treatment of asthma. Presentation at the 123rd Annual Convention, AMA, Chicago, June 24, 1974, p. 49. Falliers, C. J.: Respiration as interface between self and non-self. In Breck, A. D. and Yourgrau, W. (eds.): Proceed. Internat'l. Colloquium: Biology, History and Natural Philosophy. New York, Plenum Press, 1972, pp. 111-121. Falliers, C. J.: Development of reaginic antibodies in pre-school children, treated with cromolyn for asthma. Study in progress. Frost, M.: Cromoglycate in aphthous stomatitis. Lancet, 2:389, 1973. Holmgren, A., Olsson, A. G., Svanborg, N., and Wide, L.: The effect of disodium cromoglycate on airway conductance and on serum cortisol and serum reagins in asthma. Acta Allerg., 27:27-40, 1972. Howell, J. B., and Altounyan, R. E. C.: A double-blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma. Brit. Med. J., 3:177, 1967. Jones, R. S., and Blackhall, M. 1.: Role of disodium cromoglycate in the treatment of childhood asthma. Arch. Dis. Child., 45:49, 1970. Loebel, H., Machtey, I., and Eldror, M. Y.: Pulmonary infiltrates with eosinophilia in an asthmatic patient treated with disodium cromoglycate. Lancet, 2:1032, 1972. McClean, W. L., Lozano, J., Hannaway, P., Sakowitz, S., and Mueller, H. L.: Cromolyn treatment of asthmatic children. Am. J. Dis. Child., 125:332, 1973. Pepys, J., and Frankland, A. W.: Disodium Cromoglycate in Allergic Airways Disease. London, Butterworth & Co., Ltd., 1970. Read, J., and Rebuck, A. S.: Steroid-sparing effect of disodium cromoglycate ("lntal") in chronic asthma. Med. J. Austral., 1:566, 1969. Silverman, M., Connolly, N. M., Balfour-Lynn, L., and Godfrey, S.: Long-term trial of disodium cromoglycate and isoprenaline in children with asthma. Brit. Med. J., 3:378381, 1972. Silverman, M., and Andrea, T.: Time course of effect of disodium cromoglycate on exercise-induced asthma. Arch. Dis. Child., 47:419-422, 1972. Toogood, J. H., Lefcoe, N. M., Buck, C., and McCourtie, D. R.: A clinical index of disability due to chronic asthma tested during a trial of cromolyn sodium treatment. Chest, 63:881-888, 1973.
Allergy and Asthma Clinic, P.C. 155 Cook Street Denver, Colorado 80206
Cromolyn Sodium (Disodium Cromoglycate) Prophylaxis
Constantine J. Falliers, M.D.*
New perspectives in clinical allergy and a more diversified view of asthma have resulted from the therapeutic research which introduced cromolyn sodium (USAN)-more widely known by its original designation as disodium cromoglycate-for the prophylactic management of allergic respiratory disease. 1 • 2 • 11 This rather unique compound is not related to any of the other major groups of antiallergic and antiasthma tic drugs, such as antihistamines, adrenergic amines, xanthines, and corticosteroids. It is a bis-chromone, a synthetic analogue of khellin, which is a botanical extract known since ancient times for its smooth muscle relaxing properties but of little practical use due to side effects.U By contrast, cromolyn sodium appears to be very well tolerated. Also, interestingly its therapeutic value is not due to a bronchodilator effect, for it has none. 9 When symptoms of acute asthma and evidence of airways obstruction are present, cromolyn therapy is useless. This is known not only from experimental studies, 2 • 9 but also from experiences during the 5 years cromolyn sodium was not available officially in the United States, but was obtained by many patients across the borders or overseas and taken without medical supervision. Inhalations were taken sporadically, only when symptoms were present, and sometimes capsules were swallowed instead (unpublished observations)! Thanks to the extraordinary range of safety of this drug, no side effects were noted but such trials were wasteful and frustrating and resulted in a hasty condemnation of cromolyn as ineffective. Even now, due to the multiplicity of choices available,t 2 serious problems can and do arise, unless physicians and their patients obtain and retain the required basic facts concerning each particular therapeutic modality. '''Associate Clinical Professor of Pediatrics, University of Colorado School of Medicine, Denver; Attending Allergist, National Jewish Hospital and Research Center, Denver, Colorado
Pediatric Clinics of North America- Vol. 22, No. 1, February 1975
141
142
CoNSTANTINE ]. FALLIERS
MODE OF ACTION The demonstration that cromolyn sodium prevented experimentally induced asthma• (predictably provoked in a sensitized individual by the elective inhalation of an allergenic extract) served as the initial impetus for extensive clinical and basic research with this product. At first, it was thought that cromolyn prophylaxis was effective only against allergic asthma, the type caused by the interaction of reaginic antibody (IgE) with an extrinsic allergen.H Subsequent data, however, have shown11 that a broader "stabilization" of hyperreactive airways takes place. Exercise-induced asthma, airways obstruction resulting from voluntary hyperventialtion, and possibly certain cases of pharmacologically induced bronchospasm were found to be inhibited by pretreatment with cromolyn sodium inhalationsY· 18· 20· 25 Delayed (Type III) reactions may also be preventedP For clinical use, a dry powder of this drug is contained in a gelatin capsule, with lactose as an inert propellant. Placed in a specially designed inhaler (turbo-inhaler or Spinhaler), the capsule is punctured by the movement of two concentric pins and then, with a deep inspiration, the flow of air causes it to spin and release the micronized drug, which flows into the lungs. Three to six inhalations usually empty the capsule. Lack of understanding, or poor inspiratory flow, can reduce or prevent topical deposition of this drug. Particle size analysis has shown that 1 to 2 mg of the amount enclosed in one capsule reaches the alveolar region. 9 The remainder is retained in the orapharynx and trachea, from whence it is propelled, swallowed, and eliminated via the gastrointestinal tract. No accumulation in the lung or elswhere has been noted. About 9 per cent of a single dose is systemically absorbed and then excreted rapidly (average plasma half-life for man is 90 minutes) via the urine and bile.U Maxium blockade of experimentally induced asthma was observed when a therapeutic dose was inhaled 10 minutes before bronchial challenge with an appropriate antigen} Other studies have shown protection whether inhalational pretreatment was given 20 minutes or immediately before exposure. 24 The effect usually lasts about 6 hours. Given after the inhalational challenge, cromolyn sodium had no effect. 2· 9 Standard bronchial inhalational challenges have been considered as a possible means fQr establishing the indications for and the effectiveness of cromolyn sodium. 21 The "Lability Index" of the asthmatic lung was proposed18 as another method for the selection of candidates likely to benefit from cromolyn sodium. Summarizing recent experimental data, a group of investigators concluded that exercise testing may provide a useful basis for the selection of patients to be treated with cromolyn sodium.24 When cromolyn sodium is inhaled, its protective action is limited to the bronchial airways. Application of the drug directly on the nasal mucosa has shown that it can also prevent or control allergic rhinitis.8 The possibility that ophthalmic, gastrointestinal, dermatologic, and other topical symptoms attributable to allergy can also be prevented or controlled with cromolyn sodium is currently being considered.9 • 15
CROMOLYN SODIUM (DISODIUM CROMOGLYCATE) PROPHYLAXIS
143
Extensive basic research has been conducted in order to explain and in turn to direct further the therapeutic uses of cromolyn sodium on allergic disorders and on reversible obstructive airway disease. The primary site of action seemed to be the prevention of the disruption of mast cells and of the release of histamine and other mediators, caused by reagins or reagin-like antibodies upon contact with the sensitized cells.2 • 9 • 11 Ten to 20 meg per ml of cromolyn sodium reduced the amount of histamine and of slow-reacting substances of anaphylaxis (SRS-A) released from human lungs, passively sensitized with reaginic serum and exposed to the specific antigen at 37o C. 9 Further research has provided both laboratory and clinical evidence that cromolyn sodium has several types of blocking activity. Mast cells are functionally involved in these processes and, consequently, it has been postulated that these cells and cromolyn sodium are important in a wide range of human diseases.2 • 11 In most instances, mast cell stability was achieved by this drug, even against the nonantigenic stimulus of phospholipase-A or snake venom.9 Cromolyn sodium lacks muscle relaxant, antimed.iator (antihistamine, antiserotonin, etc.), and anti-inflammatory (corticosteroid-like) properties. These negative observations left three main possibilities for explaining the antiallergic action of this comqpund: (1) interference with the sensitization process, (2) altered antigen-antibody interaction, and (3) suppression of the release of pharmacologic mediators of anaphylaxis. Two experimental models have lucidly demonstrated the precise mode of action of cromolyn sodium and, concomitantly, have expanded our knowledge about the function of mast cells in general. These approaches, one in vitro and one in vivo 2 have shown that: (a) cromolyn sodium does not inhibit passive sensitization of the tissue when present throughout the sensitization procedure; (b) no histamine is released when cromolyn sodium is introduced with the antigen at the first challenge; and (c) when cromolyn sodium is present at the first challenge, but subsequently removed prior to a second antigen challenge, no histamine is released and the tissue appears desensitized. Since the drug does not antagonize histamine, the experiments suggest that although antigen-antibody interaction does take place in the presence of cromolyn sodium, no adverse reaction occurs due to the stabilization ("desensitization") of the previously hyperreactive tissue (mast cells). The fact that blood eosinophilia is reduced under cromolyn therapy10 may likewise reflect the absence of allergic stimuli which ordinarily produce it. No immunologic interference of cromolyn sodium with defense mechanisms of the host has as yet been detected. 11 • 21 Neither has there been any evidence that the adenyl cyclase and cyclic 3',5'AMP system is in any way altered by cromolyn sodium. Seasonal increases in specific reaginic antibodies take place even though clinical symptoms may be controlled with cromolyn. 3 • 14· 16 The drug is not known to cross the placenta or the blood-brain barrier and no teratogenic effects have been noted in experimental animals given extraordinarily large amounts of cromolyn sodium throughout pregnancy. Expectant mothers, treated with cromolyn sodium during pregnancy, are known to have given birth to healthy infants. 11 • 21 The isolated reports of pulmonary infiltration and
144
CoNSTANTINE
J.
FALLIERS
nasal congestion5 • 19 as possible side effects of cromolyn therapy will require further confirmation.
THERAPEUTIC APPLICATIONS AND IMPLICATIONS Without much doubt, the most common form of asthma in children, the intermittent paroxysmal attacks following occasional exposures to allergens or coinciding with infection, are not sufficient indications for cromolyn sodium prophylaxis. Ordinary preventive and symptomatic measures should suffice to control these. Cromolyn sodium and possibly other chromone compounds in the future, can be useful primarily in the following situations: A. Immediately before and during unavoidable exposure to allergenic substances known to have caused serious difficulty in the past and proven by diagnostic testing to be responsible for provoking attacks of asthma; B. During an entire period of high pollen and mold count, for patients who have proved sensitive to specific airborne allergens; C. When bronchial "lability" has been clearly demonstrated, whether by the Jones criteria of reactivity to isoproterenol vs. exercise/" or by the detection of exercise-induced bronchospasm alone,24 or, more selectively, when this hyperreactivity cannot be modified by extended symptomatic management and with appropriate environmental controls; and D. As adjunct therapy for patients with chronic perennial asthma, of multiple or undetermined etiology, who require continuous daily therapy with bronchodilators and corticosteroids. 7 • 11 • 22
The usual recommended dose is inhalation of the contents from one 20 mg capsule four times daily, but sometimes only 1 or 2 capsules per day can be equally effective. 14 Emphasis must again be placed on prophylaxis, or health maintenance. Obviously treatment is required to maintain health only when, without this therapeutic intervention, symptoms of disease are likely to persist or recur. Therefore, the entire concept of prophylactic therapy is based on the anticipatory judgment that asthmatic symptoms will not abate without constant pharmacologic prophylaxis. In patients belonging to category "D" above, the need for daily medication is unquestionable; generally, by the time cromolyn sodium treatment is considered, "steroid-dependence" will have been proven by repeated attempts to withdraw bronchodilators and steroids and by the ensuing severe exacerbations of asthma. The need for cromolyn sodium prophylaxis may be questioned by physicians as well as patients in situations A, B, and C above, especially in view of the cost involved and the inconvenience of the daily routine of daily inhalational therapy. Children and their parents should be given detailed instructions on the technique as well as the purpose of therapy. Unless there are psychological contraindictions, they should be told that definite improvement can be expected in barely over 50 per cent of the cases,<· 20 • 24 and total control of asthma in no more than 20 per cent14 • 20 of the children treated, even after several weeks of daily inhalations. In doubtful cases, certain empirical considerations may assist in determining whether extended prophylactic therapy with cromolyn sodium deserves a trial:
CROMOLYN SODIUM (DISODIUM CROMOGLYCATE) PROPHYLAXIS
145
Younger patients, with atopic asthma, still seem to obtain the best results from this treatment. Indeed, current studies 14 suggest that preschool children, between 3 and 6 years old, may show the highest percentage of improvement, both in terms of numbers and in terms of the completeness of symptomatic control. Patients prone to intermittent acute episodes of dyspnea and wheezing, but with relatively few symptoms in the intervals, are more likely to respond to cromolyn than those with chronic cough, expectoration, and persistent auscultatory findings. Older patients (not only adults, but also older adolescents) with asthma of the intrinsic type and with frequent respiratory infections are- despite some evidence to the contrary"-the least likely to benefit from cromolyn prophylaxis, and even if they do so, improvement may not be noted until after months of continuous daily therapy. 7 • 11• 23 Finally and most importantly, it must be remembered that cromolyn sodium is not indicated for the treatment of an acute attack of asthma or for status asthmaticus; if the patient is already on a daily treatment program, he could be advised to discontinue inhalations temporarily and to resume this prophylactic program when the attack has subsided.
SUMMARY In summary, successful therapeutic application of cromolyn sodium prophylaxis depends on a correct etiologic diagnosis of asthma and on the ability to predict the clinical behavior of a patient, by means of extended clinical observations and appropriate tests. Adequate preparation of each patient with intensive bronchodilator and, when necessary, corticosteroid therapy for "normalization" of pulmonary function are essential. Furthermore, the existential significance of respiratory regulatory processes13 must be kept in mind and the idea of prophylaxis convincingly presented to the family. Throughout the course of treatment and especially during the first few weeks, the physician and the patient, or the parents, must remain in close contact for individualized therapeutic guidance and for an accurate evaluation of the results of treatment.
REFERENCE 1. Altounyan, R. E. C.: Inhibition of experimental asthma by a new compound-disodium cromoglycate-"Intal." Acta Allerg., 12:487, 1967. 2. Altounyan, R. E. C., Orr, T. S. C. and Cox, J. S. G.: Biological and pharmacological basis of disodium cromoglycate therapy. In Serafini, U. eta!. (eds.): New Concepts in Allergy and Clinical Immunology. Excerpta Medica Internat'l. Congress Series No. 232. Amsterdam, Excerpta Medica, 1971, pp. 377-384. 3. Berg, T., and Johansson, S. G. 0.: In vitro diagnosis of atopic allergy. IV. Seasonal variations of I gE antibodies in children allergic to pollens- A study of non treated children and of children treated with inhalations of disodium cromoglycate. Int. Arch. Allerg., 41 :452, 1971. 4. Bernstein, I. L., et a!.: A controlled study of cromolyn sodium sponsored by the Drug Committee of the American Academy of Allergy. J. Allerg. Clin. Immunol., 50:235, 1972. 5. Block, S. H.: Nasal congestion as a side effect of cromolyn sodium. ]. Allerg. Clin. Immunol., 53:243, 1974. 6. Blummenthal, M. N., Schoenwetter, W. F., MacDonald, F. M., and McHugh, R. B.: Cromolyn in extrinsic and intrinsic asthma. J. All erg. Clin. Immunol., 52:105, 1973. 7. Chai, H., Molk, L., Falliers, C. ]., and Miklich, D.: Steroid-sparing effects of disodium cromoglycate (DSC) in children with severe chronic asthma. In Serafini, U., et a!.
146
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
CONSTANTINE ]. FALLIERS
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