Pediatric Annals

Corticosteroids for Allergic Disorders in Children

Sheldon C Siegel, MD

Abstract

Although it has been more than 30 years since it was established that the corticosteroids were effective in the management of allergic disorders, considerable controversy and uncertainty as to their proper usage for these diseases still remain. Nevertheless, major progress has been made in our understanding of their physiopharmacologic properties. Progress, too, has been made in the development of new corticosteroid compounds and in methods to minimize their adverse effects. In this article I plan to review some of these advances and present my views on some of the debatable issues surrounding the use of corticosteroids for the management of the allergic child.

GENERAL ACTIONS

The corticosteroids have many profound and varying effects on a number of important physiologic and metabolic systems in man. Understanding these functions is essential if the best possible therapeutic effectiveness is to be obtained with a minimum of undesirable consequences. These effects will be only briefly mentioned here, but readers can find greater detail in a number of excellent reviews and texts.1"8

Recently, the mechanism by which the corticosteroids are able to produce so many diverse specific actions in different tissues has been elucidated. On entry into the cells, the hormones are bound to specific cytoplasmic receptors to form activated complexes. These complexes are then translocated to the nucleus, where they are bound to the target-cell genome. The target cell then responds by increased ribonucleic acid (RNA) synthesis, producing messenger RNA (mRNA). The mRNAs are exported to the cytoplasm, where specific protein synthesis takes place. Although this synthesis occurs within minutes, the clinical effects of the corticosteroid activity usually do not become apparent for several hours. This delay has been attributed to the time required for synthesis of sufficient enzyme protein to mediate the effect of hormones.

The major actions of these agents can be divided into their (1) glucocorticoid, (2) mineralocorticoid, and (3) anti-inflammatory and antiallergic effects. The glucocorticoid effect of Cortisol and its synthetic analogues increase hepatic glucose by stimulating gluconeogenesis; at the same time the transport of amino acids into muscle is inhibited and new-protein synthesis is reduced (anabolic effect). The naturally occurring corticosteroids Cortisol and cortisone have mineralocorticoid effects (sodium retention and increased excretion of potassium), while the synthetic preparations are largely devoid of this action. All these compounds have been shown to induce a negative calcium balance and oppose the action of vitamin D on the intestine. Thus, osteoporosis and osteomalacia may result. Fat metabolism and its distribution are also altered. The lipolytic action of the catecholamines is potentiated in the arms and legs, while lipogenesis increases in the fat tissue of the abdomen and dorsal fat pad, giving rise to some of the characteristic Cushingoid features. The excitability of the brain cortex is also increased, and there are diverse effects on the lymphocytes, granulocytes, erythrocytes, and thrombocytes.

ANTIINFLAMMATORY AND ANTIALLERGIC EFFECTS

The corticosteroids' ability to suppress the inflammatory response is well known, and this is one of the more likely explanations for their antiallergic properties. However, even here the relative roles of the various actions of these agents remain obscure. Their betterknown anti-inflammatory characteristics include (1) maintenance of the integrity of the microcirculation by blocking the increased permeability of the endothelium of the capillaries and through vasoconstriction of both arterioles and venules; (2) stabilization of cell and lysosomal membranes, thus reducing the release or elaboration of mediators of inflammation; and (3) suppression of the cellular response through interference with marginization and sticking of leukocytes to the vascular endothelium and by inhibiting neutrophil and monocytic Chemotaxis. Pharmacologic doses of the corticosteroids also induce a peripheral neutrophil leukocytosis, eosinopenia, monocytopenia, and…

Although it has been more than 30 years since it was established that the corticosteroids were effective in the management of allergic disorders, considerable controversy and uncertainty as to their proper usage for these diseases still remain. Nevertheless, major progress has been made in our understanding of their physiopharmacologic properties. Progress, too, has been made in the development of new corticosteroid compounds and in methods to minimize their adverse effects. In this article I plan to review some of these advances and present my views on some of the debatable issues surrounding the use of corticosteroids for the management of the allergic child.

GENERAL ACTIONS

The corticosteroids have many profound and varying effects on a number of important physiologic and metabolic systems in man. Understanding these functions is essential if the best possible therapeutic effectiveness is to be obtained with a minimum of undesirable consequences. These effects will be only briefly mentioned here, but readers can find greater detail in a number of excellent reviews and texts.1"8

Recently, the mechanism by which the corticosteroids are able to produce so many diverse specific actions in different tissues has been elucidated. On entry into the cells, the hormones are bound to specific cytoplasmic receptors to form activated complexes. These complexes are then translocated to the nucleus, where they are bound to the target-cell genome. The target cell then responds by increased ribonucleic acid (RNA) synthesis, producing messenger RNA (mRNA). The mRNAs are exported to the cytoplasm, where specific protein synthesis takes place. Although this synthesis occurs within minutes, the clinical effects of the corticosteroid activity usually do not become apparent for several hours. This delay has been attributed to the time required for synthesis of sufficient enzyme protein to mediate the effect of hormones.

The major actions of these agents can be divided into their (1) glucocorticoid, (2) mineralocorticoid, and (3) anti-inflammatory and antiallergic effects. The glucocorticoid effect of Cortisol and its synthetic analogues increase hepatic glucose by stimulating gluconeogenesis; at the same time the transport of amino acids into muscle is inhibited and new-protein synthesis is reduced (anabolic effect). The naturally occurring corticosteroids Cortisol and cortisone have mineralocorticoid effects (sodium retention and increased excretion of potassium), while the synthetic preparations are largely devoid of this action. All these compounds have been shown to induce a negative calcium balance and oppose the action of vitamin D on the intestine. Thus, osteoporosis and osteomalacia may result. Fat metabolism and its distribution are also altered. The lipolytic action of the catecholamines is potentiated in the arms and legs, while lipogenesis increases in the fat tissue of the abdomen and dorsal fat pad, giving rise to some of the characteristic Cushingoid features. The excitability of the brain cortex is also increased, and there are diverse effects on the lymphocytes, granulocytes, erythrocytes, and thrombocytes.

ANTIINFLAMMATORY AND ANTIALLERGIC EFFECTS

The corticosteroids' ability to suppress the inflammatory response is well known, and this is one of the more likely explanations for their antiallergic properties. However, even here the relative roles of the various actions of these agents remain obscure. Their betterknown anti-inflammatory characteristics include (1) maintenance of the integrity of the microcirculation by blocking the increased permeability of the endothelium of the capillaries and through vasoconstriction of both arterioles and venules; (2) stabilization of cell and lysosomal membranes, thus reducing the release or elaboration of mediators of inflammation; and (3) suppression of the cellular response through interference with marginization and sticking of leukocytes to the vascular endothelium and by inhibiting neutrophil and monocytic Chemotaxis. Pharmacologic doses of the corticosteroids also induce a peripheral neutrophil leukocytosis, eosinopenia, monocytopenia, and lymphocytopenia. The lymphocytopenia in man probably occurs as a result of redistribution from the peripheral blood to some other body pool, such as the bone marrow. It has also been postulated that the corticosteroids exert their inhibitory effects on the inflammatory response by directly influencing fibroblastic activity.

In addition to the above, the suppressive action of these drugs on antibody formation has been considered as contributing to their antiallergic properties. Even with modest doses of prednisone (15-20 mg. per day) administered for 15 days, serum immunoglobulin levels of IgG and IgE have been significantly decreased in patients. Decreases in serum IgG have been attributed to increased catabolism. Recently, Saxon et al.9 found that they were related to cell-cell interactions. These authors demonstrated diminished B-cell responsiveness and removal of suppressor T-cell activity while helper T-cell function remained intact.

The usual dose of corticosteroids required to treat most patients with atopic disorders does not appear to affect materially the concentrations of circulating antibodies, nor does it seem to affect a person's ability to respond to a specific antigen. Corticosteroids also do not interfere with the immediate-type skin test and the subsequent development of wheal and flare responses.10 Thus, it would appear unlikely that the suppressive effects on antibody formation by these agents plays any role in producing their beneficial effects in the atopic disorders.

The corticosteroids possess several other properties that should influence the intensity of an immediate type-I allergic reaction. These include:

1. Inhibition of synthesis or release of various mediators (histamine, slow-reacting substance of anaphylaxis [SRS-AJ, prostaglandins, vasoactive kinins, and probably others;

2. Potentiating and synergistic effects on adrenergic responses by stimulating adenyl cyclase and thus increasing the level and action of cyclic adenosine monophosphate and also by decreasing the synthesis or action of cyclic guanosine monophosphate (the corticosteroids, in addition, also have the ability to restore /3-adrenergic- receptor responsiveness in patients who have become resistant to adrenergic drugs);11

3. Relaxation of smooth muscle by counteracting contraction responses to acetylcholine and histamine by direct action.

Although the role of immune complexes (type III) and cell-mediated immunologic injury (type !Y) in atopic disorders remains unclear, the corticosteroids have profound suppressive effects on both types of injury. Their beneficial effects in type III have been attributed to decreased vascular permeability, decreased neutrophil Chemotaxis, and lysosome stabilization. In type IV the suppressive effects are probably due to the corticosteroids' actions on cytotoxic lymphocytes and their inhibition of macrophage function.

THERAPEUTIC INDICATIONS

The corticosteroids produce profound symptomatic relief in almost all of the atopic disorders. However, because of their serious undesirable side effects, especially when administered in high doses for prolonged periods, in the prescribing of these drugs their beneficial effects must always be weighed against their potential adverse consequences. I use these six indications as a guide for their systemic administration:

1. Corticosteroids should be administered promptly for the management of severe, acute allergic reactions in cases where their use might be lifesaving - e.g., status asthmaticus, anaphylaxis, exfoliative dermatitis.

2. They should be used for reducing the morbidity and duration of self-limiting episodes of allergic reactions - e.g., seasonal pollen asthma, contact dermatitis, serumsickness- like reactions.

3. They are indicated for the temporary relief of severe, chronically ill allergic patients - e.g., those with exacerbations of asthma or atopic dermatitis. (Usually a three-day burst of suppressive doses will suffice.)

4. Corticosteroids may be helpful in the long-term management of patients with severe chronic allergic disease who are incapacitated and remain unresponsive to other measures.

5. Prophylactic treatment with corticosteroids during any type of stress should be given to prevent potential adrenal insufficiency in patients who previously have received corticosteroids.

6. On a short-term basis they may be useful diagnostically for differentiating asthma from other chronic obstructive pulmonary diseases, since the obstruction in asthma characteristically is reversible.

CHOICE OF PREPARATION

The derivatives of cortisone and hydrocortisone were synthesized in an effort to dissociate the antiallergic and anti-inflammatory properties of these agents from their harmful effects. A great advance was made with the development of prednisone and prednisolone, which were relatively free of mineralocorticoid activity. Over the years, additional alterations in their structure have resulted in compounds with increased biologic and antiallergic activity. Although these newer synthetic analogues are also relatively devoid of effects on sodium and potassium, their increased antiallergic properties in general unfortunately parallel their other undesirable side effects. Accordingly, I prefer prednisone or prednisolone for systemic therapy, since they are less costly and have a suitable biologic half-life for alternate-day therapy. Certain of the newer synthetic compunds have a tendency to produce selected side effects when administered in equivalent pharmacologic doses (Table 1). For example, dexamethasone has a greater effect in stimulating the appetite, whereas triamcinolone tends to have little or no effect on appetite. On the other hand, triamcinolone has a greater propensity to produce muscle myopathy than the other corticosteroids. In addition, these agents have quite different plasma and biologic half-lives.

Table

TABLE 1RELATIVE ANTI-INFLAMMATORY POTENCIES, SIDE EFFECTS, AND BIOLOGIC HALF-LIVES OF CORTICOSTEROID PREPARATIONS

TABLE 1

RELATIVE ANTI-INFLAMMATORY POTENCIES, SIDE EFFECTS, AND BIOLOGIC HALF-LIVES OF CORTICOSTEROID PREPARATIONS

The corticosteroids with longer biologic half-lives are more likely to produce Cushingoid side effects because of their continuous stimulation of peripheral tissues. This fact should be kept in mind when one is choosing compounds for a particular treatment regimen. Thus, for replacement therapy, the twice-daily administration of Cortisol, with an eight-to-1 2-hour biologic half-life, simulates normal daily secretion of the endogenous hormone. For alternate-day therapy, hormones that have a 12-to-3 6-hour biologic half-life allow for persistence of anti-inflammatory activity for the first half of the day "off" and recovery of hypothalamic-pituitary-adrenal axis (and other suppressed functions) until the next dose is administered, on the following morning.

LIQUID PREPARATIONS

Though most children who are unable to swallow pills will accept a crushed tablet when it is administered with jelly, a marshmallow, or chocolate syrup, at times it is necessary to administer a fluid preparation. Unfortunately, there is not a commercially available fluid product of either prednisone or prednisolone. For short-term usage one may have to resort to using either hydrocortisone, triamcinolone, dexamethasone, or betamethasone (all of which are available in a liquid form). It should be reemphasized, however, that because most of these agents have long biologic half-lives they should not be used for long-term alternate-day therapy.

PARENTERAL PREPARATIONS

When high tissue levels of corticosteroids are required rapidly, a water-soluble conjugated ester preparation (e.g., Solu-Cortef, Solu-Medrol) may be given intravenously over a period of one to several minutes. Because of incompatibility reactions, chloramphenicol, tetracyclines, vancomycin, B-complex vitamin preparations, and ephedrine hydrochloride should not be mixed with corticosteroids in the same intravenous solutions. When no emergency exists and when the patient is unable to take oral preparations, the administration of the phosphate or hemisuccinate conjugates by the intramuscular route will also provide high, sustained blood levels within an hour.12 Acetate derivatives, on the other hand, are slowly absorbed over a longer period of time and generally produce lower circulating concentrations.

TOPICAL PREPARATIONS

The corticosteroids have revolutionized the topical treatment of the allergic dermatoses. Not only are they the most effective topical medicament, but they have the additional advantage in that their activity is largely local. Thus, the serious complications noted with systemic administration of this agent can he largely avoided. Nevertheless, all topical corticosteroid preparations are absorbed to some extent when applied to the skin and under certain circumstances can lead to serious side effects. For example, if corticosteroids are applied under an occlusive dressing, such as Saran Wrap, absorption can be enhanced a hundredfold. (Complications will be treated in more detail below.)

There are now more than 200 different topical dermatologie corticosteroid preparations on the market. They are available in varying concentrations and in different types of vehicles as sprays, lotions, gels, creams, and ointments. Often they are combined with many other active dermatologie agents, including tars, antibacterials, antifungals, antiseborrheics, analegsics, and other preparations.

Many new topical corticosteroid preparations have been synthesized in recent years that have much greater anti-inflammatory activity than hydrocortisone and potentially could give rise to more complications if improperly used. Although these newer formulations can be used advantageously, good dermatologie principles dictate that the correct strength and formulation be used for the particular dermatologie condition and the specific area of the body affected. Ointments are usually more effective for dry, scaly lesions, and creams are more acceptable cosmetically. In hairy areas, a solution or liquefying vehicle, such as a gel, may permit better skin contact than a cream or ointment.

Generally, one should use the more potent topical steroids initially for recalcitrant lesions or to obtain a brisk response. Once suppression has been achieved, these agents should be replaced with less potent corticosteroid preparations. Special precautions should be taken in applying high-potency fluorinated preparations to the face, scrotum, penis, groin, and perianal regions, where they are more readily absorbed and where they are more likely to produce undesirable effects. In addition to potency and location, such other factors as solubility, vehicle, method of application, and cost should be considered in the selection of an appropriate corticosteroid product. Costs, relative potencies, type of vehicle, and brand names of some of the available topical corticosteroid preparations are indicated in Table 2.

OPHTHALMOLOGIC PREPARATIONS

The corticosteroids have been reported to be effective in treating a wide range of ocular disorders. The route of administration depends more on the affected site than on the nature of the disease process. Pediatricians, however, are most likely to employ topical ointments and solutions in treating their patients. As with the dermatologie preparations, a wide variety of products are available, varying in potency, vehicle, incidence of side effects, etc. When one is evaluating preparations for a particular patient, consideration should be given to the entity being treated, whether ocular penetration is necessary, and whether the patient is predisposed to developing glaucoma. Some evidence has been presented that hydroxy mesterone (medrysone) 1 per cent (HMS Liquifilm ophthalmic suspension) ophthalmic drops are less likely to produce a rise in intraocular pressure and, thus, less likely to induce glaucoma than other preparations.14

DOSAGE

The dose of the corticosteroids must always be individualized. It should be governed as much by the severity of the reaction as by the size of the patient. As a general rule I have used either prednisone or prednisolone, 2 mg./kg. body weight in divided doses, as an initial suppressive dose. The amount given generally should not be less than 20 mg., and it should not exceed 60-80 mg. per day. Once the desired effects have been attained, the dose should be tapered to the smallest amount needed to suppress the allergic symptoms. If only a three-day burst is necessary to bring the allergic reaction under control, the hormones may be abruptly discontinued.

Table

TABLE 2RELATIVE COST AND POTENCY OF TOPICAL CORTICOSTEROIDS

TABLE 2

RELATIVE COST AND POTENCY OF TOPICAL CORTICOSTEROIDS

The doses of corticosteroids required for intensive short-term treatment of more lifethreatening allergic emergencies, such as status asthmaticus, are less clearly defined. The range of doses recommended has ranged from 25 mg. of prednisone to as much as 2,500 mg. of hydrocortisone per day. Based on doses of corticosteroids necessary to attain plasma Cortisol levels normally produced in response to stress (concentrations exceeding 150 µd/100 ml.), Dwyer15 and Collins16 and their co-workers suggest using doses of 4-8 mg. of hydrocortisone per kg. body weight followed by repeated doses of 4 mg./kg. body weight every two to three hours. Although some recent reports17'18 suggest there may be no major advantage in using massive doses of corticosteroids, I prefer to use large doses for the treatment of status asthmaticus. My reasoning is that it is better to err on the side of giving too much than too little for this lifethreatening illness. Empirically, I initially use 7 mg./kg. of a water-soluble hydrocortisone ester or its equivalent pharmacologic dose of other synthetic preparations. For maintenance therapy, 7 mg./kg./24 hours is given in divided doses every six hours. If the asthma comes under good control and if the corticosteroids have been administered for less than five days, they may be withdrawn abruptly without tapering.

GENERAL PRINCIPLES OF THERAPY

Several general principles should be followed if complications from corticosteroid therapy are to be avoided or at least kept to a minimum (see box).

Foremost among them is that these agents should be avoided whenever possible. Corticosteroids should not be substituted indiscriminately for allergic management with conventional medications, but, rather, reserved primarily for the indications specified above.

There is general agreement that the incidence of adverse reactions directly relates to the amount and duration of therapy. Accordingly, another general principle of therapy is to use the smallest therapeutically effective dose over the shortest period of time. A constant effort should be made to decrease or discontinue the dose. Furthermore, the therapeutic aim should be to keep the patient comfortable enough to pursue daily activities, not necessarily to make him symptom-free. A decision should be made in advance on the specific signs, symptoms, or laboratory tests that will be used to determine whether a beneficial response has occurred.

Once the decision has been made to use corticosteroids, absolute cooperation of the family and close supervision of the child become mandatory. It is my practice to inform the parents or an older child of some of the potential hazards of these agents. I believe an awareness of the untoward reactions that may result from corticosteroid therapy can be a deterrent to their promiscuous use - and, at the same time, will alert all members of the family to the necessity of giving the affected child additional corticosteroids to prevent adrenal insufficiency during any form of stress, such as surgery.

Certain diseases or circumstances are more likely to predispose the patient to a particular complication. For example, diabetes may be aggravated or a preexisting diabetes unmasked. Osteoporosis is rarely encountered in children during corticosteroid therapy, in contrast to the experience with adult patients. When it is present, however, it is a serious contraindication to prolonged corticosteroid therapy.

Caution should also be exercised in administering these agents to patients with ulcers, hypertension and cardiovascular disease, psychologic disorders, tuberculosis, or other chronic infections. When possible, corticosteroids should be avoided during pregnancy. Children receiving corticosteroids should not receive live viral vaccines.

Finally, an obvious general principle to be followed in using corticosteroids is that the physician prescribing these agents be aware of all of the potential complications that may arise and be alert to signs or symptoms of them in his patients.

COMPLICATIONS

Untoward reactions to corticosteroid use may vary from the inconsequential to completely unacceptable complications, including some that are life-threatening. Tolerable side effects - those that do not ordinarily preclude continuation of corticosteroid therapy - are listed in Table 3. The major unacceptable reactions that have been reported are shown in Table 4. Many of the adverse effects shown in Table 4 can be reduced if corticosteroid therapy can be discontinued, but some of them (such as subcapsular cataracts) are usually irreversible.

Table

TABLE 3COMPLICATIONS OF CORTICOSTEROID THERAPY: TOLERABLE SIDE EFFECTS

TABLE 3

COMPLICATIONS OF CORTICOSTEROID THERAPY: TOLERABLE SIDE EFFECTS

SPECIFIC MEASURES TO MINIMIZE COMPLICATIONS

Several specific ways of circumventing, minimizing, or countering adverse side effects of corticosteroid therapy have been proposed (Table 5).19 All of these methods are helpful in preventing or minimizing the adverse side effects of long-term suppressive corticosteroid therapy, with the exception of the routine use of supplementary antacids, prophylactic antibiotics, and periodic stimulation of the adrenals with exogenous adrenocorticotropic hormone (ACTH). The three most effective measures are the use of corticosteroid-sparing agents, alternate-day therapy, and topical administration to the respiratory tract.

Corticosteroid-sparing agents. Otpimal use of the j8-adrenergic and xanthine agents should be an absolute prerequisite before and during the administration of the corticosteroids for the management of asthma. Other drugs have also been shown to have a corticosteroidsparing effect. The macrolide antibiotics (erythromycin estuiate, oleandomycin, and triactyloleandomycin), possibly through alteration of liver function, thereby affecting the metabolism of theophylline or augmentation of the glucococorticoid suppression of lymphocyte proliferation,20 have been demonstrated to reduce the requirements for corticosteroids. However, because of the potential hepatotoxic effects of these antibiotics, they should be used with caution and their prolonged usage limited to patients in whom a profound corticosteroid-sparing effect has been demonstrated.

Many short-term studies, such as the one by Chai and his associates,21 indicate that cromolyn sodium permits the reduction or withdrawal of the corticosteroids in children dependent on steroids. The extent of the reduction in dosage has varied greatly in the different studies. Most authors report they halved the dose in about 50 per cent of their patients. Pseudorheumatism has been observed with too rapid a withdrawal of corticosteroids. The pediatrician must remember that it may take several months or a year after the hormones have been discontinued for the hypothalamic-pituitary-adrenal axis to fully recover its function. Accordingly, any stressful illness - including severe exacerbations of asthma - that occurs within a year after these drugs have been discontinued must be treated promptly with corticosteroids if possible adrenal insufficiency is to be avoided.

Intermittent therapy. The concept of intermittent therapy for the management of the nephrotic syndrome was first suggested by Lange and his associates22 in 1951 as a means of lessening undesirable side effects of the corticosteroids. Their technique consisted of administering large doses of corticosteroids for three successive days, and then eliminating corticosteroids completely for the next four days. Several years ago we23 adopted this method for the management of allergic disorders in children and investigated adrenal suppressiveness before and at varying times after introduction of the hormone therapy. Although this regimen of therapy was found to be clinically effective, it also resulted in some impairment of adrenal responsiveness to ACTH. Furthermore, it demonstrated that the degree of adrenal suppression was doserelated - the larger the dose of prednisone, the greater the impairment of adrenal responsiveness.

In 1963, Harter et al.24 introduced another regimen of intermittent therapy, an alternate-day single-dose method. This technique has been employed successfully in a variety of clinical disorders requiring high doses of corticosteroids for prolonged periods of time and has been shown to diminish side effects and produce less pituitary-adrenal suppression. We25 and others have also demonstrated that corticosteroid-induced growth suppression can also be minimized with alternate-day prednisone therapy in most children requiring corticosteroids for prolonged periods. In using this method of therapy it is imperative that only corticosteroids with relatively short biologic half-lives be given - such agents as prednisone, prednisolone, or methylprednisolone - and that they be administered early in the morning.

This method appears to be preferable to continuous corticosteroid treatment, although it has not been shown conclusively that fewer adverse effects result.

Topical administration. Because complications from corticosteroids are largely dependent on dose and duration of therapy, it has been suggested that the amount of drug necessary to control symptoms in patients with allergic rhinitis and asthma could be reduced materially by topical administration of the corticosteroids directly to the mucous membranes of the respiratory tract. As a result, it was reasoned that the incidence of undesirable side effects would drop. Early attempts to utilize corticosteroid aerosols never gained wide acceptance, however, because of variable effectiveness and systemic absorption of the agents used.

Recently, several new corticosteroids have become available that have a high index of topical activity and yet produce only minimal systemic effects - beclomethasone dipropionate (BD), betamethasone valerate, triamcinolone acetonide, and flunisolide. Only BD is available commercially in this country for the treatment of asthma. Originally it was thought that these preparations produced few systemic effects because they were poorly absorbed. Now it appears that BD is absorbed but is metabolized rapidly to inactive metabolites.

Table

TABLE 4COMPLICATIONS OF CORTICOSTEROID THERAPY: UNACCEPTABLE SIDE EFFECTS

TABLE 4

COMPLICATIONS OF CORTICOSTEROID THERAPY: UNACCEPTABLE SIDE EFFECTS

Table

TABLE 5SPECIFIC MEASURES TO MINIMIZE COMPLICATIONS OF CORTICOSTEROID THERAPY

TABLE 5

SPECIFIC MEASURES TO MINIMIZE COMPLICATIONS OF CORTICOSTEROID THERAPY

Our own investigations with BD have confirmed earlier reports27,28 of its effectiveness in steroid-dependent asthma and in severe chronic non- steroid-dependent asthmatic children. We also found no evidence of suppression of the pituitary-adrenal gland or other serious adverse effects from the aerosol. Although the optimal therapeutic dose has not been established, good results have been obtained with two inhalations (50 /Ag. of BD per actuation) four times a day for a total dose of 400 µ-g./day. The dose can be varied according to the clinical response; however, since an increased incidence of candidiasis and abnormal metyrapone responses have been noted29 with doses exceeding 400 µ-g./ day, it is probably best not to exceed this dose in children until further studies have been performed.

The side effects from BD aerosol that we have observed have been primarily local effects - dryness, sore throats, and mild hoarseness. In our cases, clinically detectable oropharyngeal candidiasis has occurred infrequently, and this is the most significant complication that we have encountered. Since this infection has been easily treated orally with nystatin, it usually has not been necessary to interrupt BD aerosol therapy.

BD aerosols are not indicated for acute attacks of wheezing or for episodes of status asthmaticus. As with cromolyn sodium therapy, if possible adrenal insufficiency is to be avoided in patients who have previously been on long-term corticosteroid therapy, it is mandatory that they be given supplemental systemic corticosteroids during an exacerbation of asthma (or other forms of stress).

Aerosol corticosteroids are also ineffectual for preventing exercise-induced bronchospasm and in young children who cannot master the technique of inhaling the aerosol. Pending further studies, they are also contraindicated for patients with a history of tuberculosis or those with a positive tuberculosis skin test.

Until more is known of the long-term adverse effects of topical corticosteroid aerosols, their use should be restricted to steroiddependent patients or to asthmatics unresponsive to bronchodilators and cromolyn sodium. Furthermore, they should be administered with the same precautions used in prescribing oral corticosteroids.

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27. Klein, R., Waldman, D., Kershner, H" et al. Treatment of chronic childhood asthma with beclomethasone dipropionate aerosols. I. A double-blind crossover trial in non-steroid-dependent patients. Pediatrics 60 (1977), 7.

28. Kershner, H., Klein, R., Waldman, D., et al. Treatment of chronic childhood asthma with beclomethasone dipropionate aerosoles. II. Effect on pituitary-adrenal function after substitution for oral corticosteroids. Pediatrics 62 (1978), 189.

29. Wyatt, R., Washek, J-, Weinberger, M., et al. Effects of beclomethasone and alternate-day prednisone on children with asthma. N. Engl. /. Med. 299 (1978), 1387.

TABLE 1

RELATIVE ANTI-INFLAMMATORY POTENCIES, SIDE EFFECTS, AND BIOLOGIC HALF-LIVES OF CORTICOSTEROID PREPARATIONS

TABLE 2

RELATIVE COST AND POTENCY OF TOPICAL CORTICOSTEROIDS

TABLE 3

COMPLICATIONS OF CORTICOSTEROID THERAPY: TOLERABLE SIDE EFFECTS

TABLE 4

COMPLICATIONS OF CORTICOSTEROID THERAPY: UNACCEPTABLE SIDE EFFECTS

TABLE 5

SPECIFIC MEASURES TO MINIMIZE COMPLICATIONS OF CORTICOSTEROID THERAPY

10.3928/0090-4481-19790901-09

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