ACTH and Cortisone in the Treatment of Bronchial Asthma

ACTH and Cortisone in the Treatment of Bronchial Asthma ETHAN ALLAN BROWN, M.D., M.R.C.S. (LOND.), L.R.C.P. (ENG.)*

IN ACTH and cortisone we have powerful weapons with which to effect remissions in patients suffering from certain types of asthma. In those whose bronchospasm is caused by atopy alone, the relief is quick and oomplete, and after cessation of treatment lasts until the next moderate or massive exposure to the causative allergens. In those in whom the asthma is due to chronic infection, remission is not as satisfactory and does not last as long, unless concomitant treatment with antimicrobial agents is given. Patients suffering from bronchospasm due to physical allergy may be markedly benefited, while those whose wheezing is caused reflexly or psychogenically may be helped to some degree. Little relief can be given the patient with obliterative fibroblastic or degenerative pulmonary disease, although appetite and weight may both increase, and subjective improvement may warrant a continuation of ACTH and cortisone therapy. Patients whose wheezing is associated with bronchial deformity, foreign body inhalation, bronchostenosis, tuberculosis, neoplastic or cardiac disease will, if anything, be worse following ACTH or cortisone ad,ministr,ation. In no part of the field of therapy is it so necessary to have an exact diagnosis of the cause of the wheezing, as well as the patient's general physical, medical and mental state, since the contraindications, although few, are of great importance. The drugs should not be used unless the physician has ruled out, among other disorders, the presence of tuberculosis, diabetes, peptic ulcer, hypertension, congestive heart failure, renal insufficiency, frank endocrinopathies, as Cushing's syndrome, and psychoses. There may be retardation of healing in patients with large lesions, as burns or wounds. The drugs have, however, both been used in patients suffering from one or more of these disorders, with no irreversible ill effects, and in several patients in our own series, marked improvement of the contraindicating illness. Und·er controlled conditions, and in matters of life and death, there are no absolute contraindications. * A ssociate Professor of Pediatrics, Tufts College Medical School; Physician-inChief, Allergy Section, Boston Floating Hospital, Boston.

Ethan A llan Brown In our own series of over 300 patients, approximately 225 were treated with cortisone given orally, with no more than 20 of these taking the drug by injection. In no patients has it been used by aerosol or intranasal techniques. With ACTH, approximately 10 or 12 patients have had intravenous therapy, and another dozen have had intramuscular therapy. By far the greater number, and especially in recent years, have been treated by injections of the gel preparation. In our short series, approximately 5 to 10 per cent were not helped. Some of those not relieved by cortisone taken orally, responded to ACTH given subcutaneously or intramuscularly. 'I'hose not relieved by ACTH have not been benefited by cortisone. ACTH would appear to hold the edge, but the economic factors, such as the cost of the injection material, the physician's fee (if any), the daily visits, as well as the inconvenience and discomfort (however slight) of hypodermic therapy, make oral cortisone the drug of choice for ambulatory patients. For those hospitalized, and incidentally taking or needing intravenous treatment, ACTH should be used. As regards brand names, although individual workers have their own enthusiasms, I cannot say that anyone preparation is superior to any of the others. PHARMACOLOGY

'rhe physiopharmacological interrelationships involved are extraordinarily complex, and our knowledge of them is far from complete. The fundamental physiologic concepts of only a few months ago are constantly being modified and revised by new discoveries. Although oversimplification may to some extent falsify the reader's focus, it may safely be postulated at the present time that either the higher brain centers, or the hypothalamic nuclei, or both, can directly or indirectly, by humoral path\vays, cause increased secretion of anterior (and some posterior) pituitary hormones, especially ACTH. Rising blood level titers of ACTH can act on the adrenal medulla, causing the production of epinephrine, which itself will act upon the hypothalamic nuclei and the anterior pituitary. Stress associated with exertion, infection, trauma and burns may likewise act upon the medulla by means of the sympathetic nervous system, to stimulate the production of epinephrine. On the other hand, ACTH acting upon the adrenal cortex causes a rise in blood levels of at least three groups of cortical steroids. The first of these, chiefly concerned with anti-inflammatory phenomena, namely 11-dehydro-17-hydroxycorticosterone (cortisone) and 17-hydroxycorticosterone (hydrocortisone), when present in quantities greater than those normally found in the blood stream, inhibit the production of ACTH by the anterior pituitary. The administration of ACTH is, therefore, a type of stimulating therapy (t'o the cortex), ,vhile cortisone therapy is a replacement type of treatment. 'rhe presence of ACTH also

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causes the medulla to excrete additional hormones, affecting electrolyte balance and, as well, a group of adrenal sex hormones. In brief, ACTH injection causes hypertrophy of the adrenal~cortex, and stimulates the excretion of cortisone and hydrocortisone, with depression of autogenous AC'"fH production and abolition of autoregulation of such ACTH secretions as may be controlled by blood stream levels of adrenal cortical steroids. The administration of cortisone suppresses adrenal cortical secretion (with involution of the adrenal cortex, excepting the zona glomerulosa), suppressing as well endogenous ACTH secretion, abolishing similarly, in the same sense, autoregulation of such ACTH secretions as may be controlled by blood stream levels of adrenal cortical steroids. All of these effects are reversible over a period of three to ten days after cessation of such hormone therapy. Cortisone, whether given directly or due to adrenal cortical stimulation, has a number of effects, variously classified as interendocrine, metabolic, immunologic, enzymologic, cytologic and neuromuscular. An understanding of some of these helps the physician to measure the mechanism of the pharmacological results, and in the prevention and treatment of side and toxic effects. As noted above, there is involution of the adrenal cortex and depression of ACTH production. The thyroid may also be depressed. Menstruation may be delayed or inhibited. One of the metabolic results, namely increased gluconeogenesis, may increase insulin requirements, necessitating additional insulin in diabetic patients. Hypoglycemia may therefore be expected in some normal patients following cessation of cortisone therapy. Metabolic effects include increased gluconeogenesis, with an increased deposition of liver glycogen, and an action opposed to that of insulin, associated with a lowered renal threshold for glucose. Fat is more readily absorbed and stored. Protein catabolism is increased, causing a rise in urinary nitrogen, uric acid and creatine. Sodium is retained, but chloride, potassium, calcium and phosphorus are excreted. Immunologically, tissue reactions to chemical irritants and antibody responses may be prevented or diminished. This may be due to steroid effects on leukocytes, resulting in an increase in the titer of some circulating globulins, or by antitoxic effects mediated by changes in the cell membranes, preventing the passage of toxins from allergic, chemical or bacterial sources. The steroids may also act on intracellular protective enzymatic systems, preventing cell damage by circulating toxins of any origin, as noted ~n the suppression of the tuberculin test. Cortisone may, therefore, in large doses, suppress the signs and symptoms of infectioIl, and not only diminish tissue potentialities for localizing infection,~ but increase susceptibility to septicemia because enzymatic hyaluronidase activity is diminished. In small doses, although the signs and symptoms

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of such disease as may be present may be suppressed, the albuminglobulin ratio returns to normal levels. Other enzymologic and neuromuscular effects need not concern us, excepting for the obvious increase in psychomotor activity, associated frequently with euphoria, and occasionally depression and psychotic reactions. Cytologically, peripheral eosinopenia and neutrophilia, and occasional lymphopenia with tissue eosinophilia have been observed. Reticulocytes are produced or released in greater numbers. There may be involution of lymphoid tissue, and inhibition of fibroplasia. Although these relationships may at first appear formidable, in actuality all are quite obvious and easily discovered or measured by the history, the physical examination, and several simple laboratory procedures. On the other hand, the problem may not be as complex as it appears at first blush. The beneficial results of cortisone therapy may be due chiefly to the enhanced gluconeogenesis seen following its administration. The conversion of nitrogen compounds to glycogen involves the breakdown of amino acids, with the formation of urea in the liver, and the conversion of the residue of the molecule, through intermediate compounds, to glucose. The enzymes which promote oxidative de-aminization of amino acids are present in the liver and kidney, and enzymes which promote transamination, or the transfer of the amino group to alpha keto-acids are present in many tissues. If cortisone influences gluconeogenesis by causing protein and amino acids to be removed from tissues, extracellular fluid in reserve areas is translocated to organs such as the liver, where deamination and transamination may take place, then other nitrogenous products, deleterious substances, such as allergens, leukotaxine, amIno acids of various types, histamine-like substances and other metabolites may also be mobilized and translocated from the sites of tissue damage to the liver, where they are converted to innocuous substances. It-may be that the damaged cells may not be able to assimilate such normal metabolites. Their removal by cortisone may enable the damaged cell to re-establish its integrity. (J. G. MacDonald~personal communication.) METHODS OF 'rREATMENT

It is generally taught that in asthma ACTH gel should be used in dosage of 60 to 80 mg. once daily for two to four days, with reduction in dosage by 10 mg. every other day to a final dose of 10 mg. daily. The interval can then be increased to an injection everyone to three days. Perhaps because the patients in our private practice are more severely affected, we have found it both desirable and necessary to start with an injection of 120 mg. (1.5 cc) of the gel for the first day, reducing the

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dose by 10 or 20 mg. daily, depending upon the patient's response. Maintenance doses consist of 20 mg. twice or three times weekly. With aqueous ACTH, administered intravenously, the dose varies from 10 to 30 mg. given slowly over a period of eight to twenty-four hours. For intramuscular use, the aqueous preparation can be injected in doses of 20 to 40 mg. every six hours. The interval can then be increased to every eight, twelve or twenty-four hours, and with continued remission the dose may be reduced to as low as 20 mg. once daily, and in rare patients, every other day. With cortisone orally, the patient initiates treatment with 50 mg. (2 tablets) every four hours until relieved. The interval is then increased to six, eight and twelve hours for the same dose. The amount taken is then diminished to 25 mg. (1 tablet) every eight or twelve hours. The average patient requires t50 to 75 mg. daily. Rarely, doses of 25 mg. or 100 mg. are neeessary. Occasional patients are resistant, and show no response to a daily total intake of 400 mg. continued for six to eight days. These same patients may respond to intramuscular daily doses in the magnitude of 200 mg. given every eight to twelve hours. We have had no experience vvith intravenous cortisone, although in doses of 100 mg. of a specially made up solution it has been given over a period of eight hours. Nor have we used cortisone by aerosol, for which the recommended dose is 5 mg. in physiological saline, given hourly for 10 doses, the total daily intake being of the magnitude of 50 mg. All patients are given a low sodium diet, and receive additional potassium orally, the enteric-coated iodide tablet (Enkide Brewer), 500 mg., one or two, three times daily after meals. The diet is simply described and easy to follow. It causes no hardship. The patient is permitted all ra\v, home cooked or frozen vegetables (none canned), and all fresh or frozen fruits and juices. He may have fresh meat, and fresh water fish, but no ham, prepared or canned meats. The diet includes one egg daily. All cheese is forbidden, excepting unsalted cottage cheese. Only sweet butter is permitted, as is milk. No salt is used in cooking or at the table. No salt substitutes are prescribed. ALLERGIC SIDE REACTIONS AND TOXIC EFFECTS

If patients are carefully selected, observed, and given the basic laboratory studi~s, and treated with the minimal effective dosage, side reactions should be few, and rarely seen. They do, however, occur, and unless the physician recognizes them for what they are, dangerous complications (or fatalities 1) may ensue. Allergic reactions seen following ACTH therapy are manifestations of specific or nOI1specific sensitivity to the proteins contained. In an allergic population, approximately 2 per cent are affected by urticaria and angioneurotic edema, anaphylactic reactions and shock, and in some

Ethan A llan Brown cases, bronchial asthma. rrhe major "side effects" seen, in order of importance, are euphoria, occult edema, acne, hirsutism, overt edema, glycosuria, potassium deficiency, ACTH resistance, hypertension, hyperglycemia, mental depression, secondary infection, thrombophlebitis, psychotic reactions, peptic ulcer, heart failure, hypothyroidism, perforation of peptic ulcer, and residual diabetic states. Other "side effects" infrequently seen, especially with large doses, are Cushing-like signs and symptoms, including mottled pigmentation, menstrual irregularity, moon facies, striae, increased libido, abnormal distribution of fat, and osteoporosis. lJncommon reactions may include purpurae, ecchymoses, hematuria and melena. Convulsions have been seen in patients with lupus erythematosus. Cardiac enlargement may occur, as due to salt and water retention. Very rarely patients may present hypercholesteremia, status epilepticus, ascorbic acid deficiency, adrenocortical failure, hemorrhagic diatheses, transient encephalopathy, and increased intracranial pressure. 'I'hese latter may be due to toxicity, exaggerated physiological responses, or intolerance. 'I'he allergic side and toxic reactions following cortisone therapy can best be given by systems. In the skin: hirsutism, and also loss of hair; acneiform eruptions, cutaneous striae, keratosis pilaris, diffuse brown pigmentation, melanotic deposition, moon facies, buffalo distribution of fat, cutaneous hemorrhages, purpuric lesions, hemorrhagic diatheses, ecchymoses, epistaxis, retardation of wound healing, painful nodules, and urticaria. In the lungs, bronchial asthma has been seen. In the glands of internal seeretion, there may be focal adenomatoid accumulation of basophil cells in the pituitary, functional regression of adrenocortical activity with atrophy of the fascicular and reticular layers, diabetogenic effects, depressed thyroid function, with decreased basal metabolic rate, depressed gonadal function with suppression of spermatogenosis, and in females, reduction in the size of the ovaries, with decrease in sexual drive and potency, and amenorrhea. Electrolyte balance may be disturbed, with retention of sodium chloride and excretion of potassium, preGipitating congestive heart failure and muscular weakness. In the cardiovascular system, mild hypertension and occasional hypotension may be seen. The patient may demonstrate edema, ascites, pleural effusion, anasarca, electrocardiographic changes, hypercholesteremia, and increase in serum phospholipids, with an increase as well in circulating heparin-like material, with prolongation of clotting time, thrombophlebitis, pulmonary infarct, and fatalities. Occasionally, clotting time may be reduced. In the musculoskeletal system, there may be weakness and exhaustion, osteoporosis, spontaneous fractures, compression fractures of the vertebrae, delayed healing of fractures and other disturbances. Psychotic and psychological reactions are described, as well as dependence upon the drug, and collapse following its withdrawal.

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EVALIJA'I'ION OF RESULrrs

Despite the fact that every patient requires a careful history and physical examination, and laboratory studies, including blood and urine studies, nevertheless, the relief is so marked, and the side reactions, although many, so easily reversible, that there is no reason for vvithholding cortisone or AC'I'H from any asthmatic patient who requires them. Examination of the literature shows that 85 to 95 per cent of the patients who are selected with care for such treatment, derive immediate and striking benefit as regards their symptomatic improvement. It must be remembered, however, that, excepting in patients who have had a single massive exposure to their allergens, treatment is truly only symptomatic. The underlying disorder has not in any way been changed, and in many patients in whom exposure continues, the relief, however long-standirlg while the drugs are being taken, ceases to be effective often within twenty-four hours of the cessation of therapy. lJseful as these drugs are for symptomatic treatment, they have not in any way diminished the necessity for careful studies directed toward discoveriIlg the causative allergens. As in the pas~, these must be removed from the patient's environment, or where inescapable, the effects must be minimized by injection treatment. Patients with the infectious type of asthma must be evaluated more carefully than in the past, since the use of ACTH and cortisone may appear to help the patient, while the underlying infection actually spreads. No asthmatic patient should be given either drug unless the contraindicating disorders have been ruled out or carefully evaluated. Every asthmatic patient should, without doubt, have an x-ray of his chest and sinuses before treatment is initiated, or at the earliest opportunity thereafter. Not only must the patient be observed at frequent intervals during courses of AC'I'H and cortisone treatment, but also for five to ten days after ceasing the use of either, during which time the patients are especially susceptible to intercurrent infections and stress situations. If surgical interference is necessary for any cause, the question of additional ACTH or cortisone administration should be carefully considered. ILLUSTRATIVE CASE REPORTS

CASE I. W. P. G., a boy aged 9, had suffered asthma, allergic in type, since age 10 months to the present date. Symptoms were perennial, with seasonal exacerbations April 15 through October. Clinical sensitivity to cereals, pollens and molds was present, and the patient gave positive skin tests by pressure puncture and intradermal methods to tree, grass and ragweed pollens, Alternaria and house dust, wheat, rice, oats and rye. Sensitivity to egg was discovered by skin test, and subsequently proved clinically valid. Physical examination was essentially that of nonnal health, excepting.... for moderate emphysema. Urine, blood, differential count, blood smear, sedimenta-

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tion rate and serology were all within norrnallirnits. The vital capacity was 1000 cc. (nofInal, 2700 cc.). Injection treatment was advised for the pollens, and initiated January 27, 1952. Mild syrnptorns were relieved by ephedrine-iodide mixture. The clinical course was excellent until late May, 1953. On June 10, 1953, physical examination dernonstrated a lnild degree of bronchospasm. Sedimentation rate, telnperature, blood and urine were within normal limits. Symptoms were considered due to massive exposure to tree pollen during dry weather following 3 weeks of rain. A low salt diet and cortisone were prescribed, with 50 mg. of cortisone by mouth every 4 hours for 6 doses, every 6 hours for 4 doses, every 8 hours for 3 doses, and then din1inished to 25 mg. at 8 A.M. and 8 P.M. daily. Synlptoms ceased cornpletely by the second day of treatment. The patient increased in \veight from 51 to 56 pounds over a period of 21 days. The dose was reduced for 1 week to 12.5 rng. on waking and 25 mg. at bedtime, and then to 12.5 mg. at the same hours. As of August 10, 1953, the chest was clear, and no symptoms were present. The patient will resume cortisone therapy, if necessary, during the ragweed pollen season. CASE ~JII. N. 1\i., a boy aged 8, had bronchial asthma, allergic in type, since age 5, perennial, with exacerbations July through September. Sensitivities to grass, ragweed and house dust had been proved. Physical exarnination was negative, excepting for mild emphysema. Vital capacity was 900 cc. (normal, 2700 cc.). Laboratory studies for urine, blood, differential count, sedimentation rate and serology were all within norrnallirnits. Injection treatrnent was initiated M.arch 31, 1952, for pollens, rnolds and house dust. Clinical sensitivities were discovered to pea, bean and tomato, which were all eliminated from the diet, with improvement. The patient reported 2 attacks during July 1952, controlled by oral ephedrineiodide mixture, and 1 attack in August, requiring no medication. . During June 1953, with the onset of the grass pollen season, mild symptoms occurred, gradually progressing to moderate and then, by July 15, to severe difficulty. The patient was given a low salt diet and cortisone 300 mg. the first day, diminishing by 50 rng. daily to 50 mg. for the sixth day. On August 4, 1953, the chest was completely clear, the vital capacity had increased to 1700 ce., the blood and urine were within normallimits~ The patient continued with 12.5 rng. of cortisone on arising and at bedtime. CASE III. L. M., a girl aged 9, suffered bronchial asthma, allergic in type, since age 4. Wheezing occurred with upper respiratory infections. Her lungs were always clear during June and July, but she was always severely affected during August and September. Clinical sensitivity to animal danders, and also to hay and to house dust, had been determined. Physical examination was that of normal health. Urine, blood, blood sedi· mentation rate and serology were normal. Skin tests by pressure puncture and intradermal rnethods were positive to feathers, house dust and ragweed pollen. Injection treatment was initiated May 11, 1949. The patient reported no attacks during 1950, and 2 mild attacks during September 1951. Severe wheezing occurred with upper respiratory tract infection in December 1952, requiring 5 days of hospitalization and antibiotic therapy. The patient returned home, but continued mildly affected. In March, 1953, physical examination showed a typical asthmatic chest. The temperature was normal. The blood sedimentation rate was 4 111m. for 20

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minutes and 28 mm. for 1 hour. Blood: hemoglobin 15 grams, red cells 4.75, color index 1.01, white cells 5200, polymorphonuclears 37, lymphocytes 43, monocytes 1, eosinophils 19. A regimen of low salt diet and cortisone by mouth was initiated, with successive daily doses of 200 mg., 150 mg., 100 mg., 75 mg. and 50 mg., in divided doses. The patient reported on March 31, 1953, with freedom from symptoms, an increase in vital capacity from 1800 to 2300 cc., and no wheezing. The weight increased from 63 pounds on January 22, 1953 to 72 pounds on March 31, 1953. The urine and blood remained normal. The patient reported on April 14, May 16, July 29 and August 13 that she has had no symptoms since initiating cortisone therapy, which is being maintained on a 12.5 mg. twice daily. She will continue cortisone treatment through the peak of the ragweed season in midSeptember. SUMMARY

ACTH and cortisone are potent, effective weapons in the symptomatic treatment of a host of allergic disorders, and especially bronchial asthma. With carefully selected patients, who have had a thorough physical examination and the routine laboratory studies, the doses used cause no irreversible ill effects. The majority of patients will show good results within a few hours, and can be maintained for some months, with freedom of symptoms, following minimal doses. The administration of ACTH and cortisone, however, are in no sense substitutes for elimination of causative allergens or injection treatment, and their use as a substitute for these does the patient a major disservice. The physician who desires to use these agents must regard them, efficacious as they are, as temporary measures while studies are in progress, or during exacerbations caused by massive exposure in patients undergoing injection treatment. A knowledge of the physiological interrelationships, the endocrine effects, and the pharmacological results are essential if the physician is to use these drugs properly. 75 Bay State Road Boston 15, Massachusetts