T h e new england journal o f

anniversary article

A Patient with Asthma Seeks Medical Advice in 1828, 1928, and 2012

Erika von Mutius, M.D., and Jeffrey M. Drazen, M.D.

eople have suffered from asthma for millennia.1 Although the From the Division of Pneumology–Aller- clinical presentation of asthma has probably changed little, there are many gology, University Children’s Hospital, , (E.M.); and the Pulmo- more people who now bear its consequences than there were 200 years ago. nary Division, Department of Medicine, P Brigham and Women’s Hospital and As a result of an intense interest in the condition, our understanding of its patho- biology, how to diagnose it, and — most important — how to treat it has evolved Harvard Medical School, Boston (J.M.D.). Address reprint requests to Dr. von Mutius dramatically over the past two centuries. To illustrate this change, we provide three at Pneumologie and Allergologie, Dr. von fictional reports of consultations performed for essentially the same patient, who Haunersches Kinderspital, Lindwurmstr. 4, has what we in 2012 would refer to as asthma. (A timeline of the major advances in D-80337 Munich, Germany. the treatment of asthma from 1812 through 2012 is available with the full text of N Engl J Med 2012;366:827-34. this article at NEJM.org.) Copyright © 2012 Massachusetts Medical Society. The first report is from 1828, the year that the New England Journal of Medicine and Surgery and Collateral Branches of Science joined with the Medical Intelligencer to form the Boston Medical and Surgical Journal. The second is from 1928 when the title of the publication was changed to the New England Journal of Medicine, and the third report An interactive is from the present. timeline is The three accounts reflect the way in which care was delivered at the time. The first available at account is in the voice of a general practitioner who was contacted for consultation NEJM.org about a woman with intermittent episodes of dyspnea. The second is in the voice of a generalist who works in a private practice and has an interest in asthma; the patient has been referred to this physician by her own general physician. The third account is in the voice of a sub-subspecialty physician whose practice is limited to the care of patients with asthma. The contemporary patient identified this physician as a specialist in asthma through an Internet search and is consulting him for a second opinion about the appropriateness of her asthma care. She brings to the consultation a detailed history that she wrote, as well as notes from her primary care physician and an allergist. Our three views of this medical consultation for a patient with asthma are not meant to provide a history of asthma but rather to offer a set of snapshots of the care that the same patient might have received had she sought medical advice in these distinct epochs. There are many diagnostic and therapeutic techniques that we do not mention; this does not mean that they are not important; it simply means that their use does not fit the time frame of our fictitious consultations. Finally, since this article is meant to contribute to the celebration of the Journal’s 200th anniversary, we have largely, but not exclusively, used literature from the Journal; our apologies to others who claim primacy.

1828

Office Note on Mrs. A. Smith I attended at the home of a woman aged 35 years who had just moved with her fam- ily to Boston. Her household includes herself and her husband of 17 years, four chil-

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dren, a cook, two maids, a stable boy, and a foot- My Examination man. She sent for me with a complaint of repeated Observation of her breathing on the occasion of my shortness of breath. consultation revealed nothing far out of the ordi- nary. Her speech was full and normal. The move- The History of Her Illness ments of her chest were full. I could palpate noth- When a fit of dyspnea occurs, the patient hears a ing abnormal in her heart motion. There was no musical noise in her chest, and she must labor to swelling of her liver or her legs. I used a newly draw and expel a full breath. When she is stricken, acquired stethoscope to examine her chest. Al- it is her custom to stop all her activities and to in- though the patient could not hear the musical hale the steam coming from the spout of a kettle sounds that have been termed “wheezes,” I was that her cook keeps always at the ready. With such able to hear them. treatment, she usually recovers within one or two days. Once or twice a year she has a severe fit, My Opinion which may last for a week, and she is confined to The patient clearly suffers from an asthma; she may her sick bed. also have what has been described as “hay fever” She has suffered such fits of laborious breath- in the spring and fall.2 I believe her fits of laborious ing since her childhood. They occur at any time of breathing are similar to the asthmatic fits that Sir the year but are more common in the spring, when John Floyer suffered from and described in his the trees bloom, and in the late summer than at “Treatise of the Asthma.”3 He describes this type other times. In the winter she reports that it is of asthma as follows: “[T]he expiration is very slow common for her to be so stricken when she walks and leisurely and wheezing, and the asthmatic can from the harbor to her home, a distance of nearly neither cough, sneeze, spit nor speak freely; and a mile along a path that ascends steeply. This dif- in the asthmatic fit, the muscular fibres of the ficulty of respiration has become such a frequent bronchia and vesiculae of the lungs are contracted, occurrence that she now routinely calls for her and that produces the wheezing noise which is coach even for very short journeys outside her most often observable in expiration.” I have no con- home. During each of her periods of confinement cern that she suffers from consumption or from for childbearing, the fits were far less numerous conditions of the heart that may lead to dropsy. and severe in character, but within a few months I think that she may benefit from smoking the after she had given birth, they returned. leaf of Datura stramonium, also known as the thorn- Often, even when she is not suffering from la- apple plant. Many asthma sufferers have tried this borious breathing, she will arise in the dark of remedy, and it seems to provide relief from a fit, the night and stand at the open window, gasping even though it will not prevent a recurrence. Sev- for air. By the time that dawn arrives she has usu- eral years ago, Dr. Bree reported in the New England ally regained control of her breathing and returns Journal of Medicine and Surgery that such smoking to sleep. had a deleterious effect on a number of patients Her difficulty of respiration is accompanied by suffering from difficulty of respiration.4 However, itchy eyes and a runny nose. She has a cough with in my experience, patients such as this woman will these fits, but she does not produce phlegm. She derive benefit from such treatment in that it short- does not have hemoptysis. No one among her ens the duration of their indisposition from an family or close acquaintances has died from asthmatic fit. I recommended this treatment to my consumption. Her weight has been stable, and patient, and she tells me that she has benefited when she is not suffering from laborious breath- from it. ing, her strength is good. She has not had rheu- Comment: In the early 1800s, there were many “asth- matic fever. mas,” since this was the term for any episodic shortness of Her mother, now deceased, also suffered from breath. The physician needed to be sure that the primary difficulty of respiration; her father did not. Of her cause was not tuberculosis or cardiac disease (e.g., mitral four children, ages 14, 12, 9, and 7, her two eldest, stenosis); both were very common at the time. Once a di- both boys, have suffered from the same symptoms, agnosis of asthma (as we know it now) was established, although her oldest son has not had a fit of labo- the number of effective treatments was quite limited; in- rious breathing for more than a year. halation of smoke from burning Datura stramonium

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was probably the best. This agent had anticholinergic prop- Laboratory Studies erties and was the forerunner of the currently used anti- I examined the radiograph of the chest that she muscarinic agents, such as ipratropium and tiotropium.5 brought with her, which was taken within the last There were numerous other treatments, such as inhala- month. It showed hyperinflation of the lungs, but tion of the fumes of hydrocyanic acid6 or inflation of the there were no abnormal shadows; there were no lungs with a bellows.7 Fortunately, such treatments and findings that would suggest tuberculosis. Her car- many others that produced no benefit and probably diac silhouette did not show any abnormalities. caused harm are no longer used. A blood smear was made, showing 14 per cent eosinophils; in a normal person this is most often 1928 less than 5 per cent. A sputum sample was also examined, and all the polymorphonuclear leuko- Letter Regarding Mrs. A. Smith cytes observed were eosinophils. Specialized skin Dear Dr. Jones, testing was performed. She had positive reactions Thank you for referring your patient, Mrs. A. to extracts of ragweed and horse dander. Smith, for evaluation concerning a possible diag- nosis of asthma. I found the patient’s history, as My Opinion recounted in your office notes, to be complete and Your diagnosis of asthma is correct. The epi- accurate. sodes are characteristic, and there is no other likely cause suggested by her medical history or History the physical examination and laboratory find- The critical feature of her case is that Mrs. Smith, ings. In fact, the presence of eosinophils in the age 35, has been having “asthma attacks” since her blood and sputum makes the diagnosis virtually early childhood. Her attacks are characterized by certain. The positive skin tests make this case the relatively sudden onset of dyspnea; they are one of extrinsic asthma. Hypersensitivity to pro- more frequent in the spring and fall, when they are teins is the likely physiological basis of asthma, often preceded by symptoms of rhino-conjunctivi- although the exact mechanisms leading to sensi- tis. If untreated, an attack will last for a few days, tization are not clear. but if she is treated with a subcutaneous injection Treatment is difficult. Your use of adrenaline of adrenaline, as you have administered at your injections for acute attacks is appropriate8; there office, she often has relief from acute symptoms, is reason to believe that treatment with oral and the attack may or may not recur. Recently, her ephedrine may also help with her asthmatic epi- attacks have been more frequent, and she does not sodes.9 The relief is of longer duration than with feel that her breathing is improved to the point injected adrenaline and the patient can adminis- where she can carry out her responsibilities as a ter it herself. Ephedrine is not a substitute for wife and mother. injections of adrenaline when the patient is in Her mother carried a diagnosis of asthma, as extremis. do two of her children. She is currently not using The critical factor in treatment is removing the any medications. patient from exposure to the proteins to which she is sensitive. Her positive skin test to ragweed pol- Physical Examination len extract is in agreement with the clinical history Her physical examination, at a time when she was of worsening disease in the autumn. However, not having acute asthmatic symptoms, showed nor- there may be proteins to which she is allergic that mal body temperature, blood pressure, and pulse. were not included in our skin test panel. In my She had no rashes. Her nasal passages were close- experience, removing a protein from a patient’s ly examined and showed inflammation and edema exposure is very hard to accomplish. One strategy, but no polyps. Her respirations were 24 and slight- which I am loath to suggest unless there is no ly labored. She had diminished tactile fremitus. other hope, is a move to a climate where there are Expiratory wheezing of modest profusion was au- fewer proteins in the air to which the patient would dible in all lung fields. Her cardiac examination be exposed.10 was normal. There was no clubbing, cyanosis, or Comment: By 1928, the differential diagnosis of asth- edema. ma was well established, and diagnostic techniques were

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Figure 1. Asthma Cigarettes. Asthma cigarettes made from the leaves of Datura stramonium (thorn apple) were widely sold in the 1800s and into the early 1900s. These cigarettes provided a means of delivering an inhaled treatment; we now know that the active component of this smoke was antimuscarinic alkaloid. Antimuscarinic treatment of asthma has recently been stud- ied with the use of chemically synthesized moieties, such as tiotropium bromide and ipratropium bromide. Images courtesy of Mark Sanders, www.inhalatorium.com.

available that made it possible to be reasonably certain 2012 that patients did not have heart disease or pneumonia when they were labeled as asthmatic.11 Physicians of the E-Mail Message to Ms. Smith time often used the term “asthma” to refer to episodic dys- Dear Ms. Smith, pnea, but qualifiers such as “cardiac” were used. By 1928, Thank you for asking me to provide you with eosinophils in the blood and sputum were known to be a direct personal consultation concerning your characteristic of asthma.12 Skin tests for had asthma and your asthma care. I will summarize been developed and were used clinically to help clinicians the salient facts from the detailed written history identify specific offending environmental proteins. The and physician’s note you kindly provided. issues that plague us today — allergies to multiple aller- As pointed out in your written history, you have gens and difficulty in interpreting skin tests — were of had asthma since childhood. Among your earliest concern to physicians in 1928. recollections is receiving injection treatments and There was not much available in the way of treatment. later inhalation treatments for asthma in an emer- Ephedrine, an orally active sympathomimetic agent, had gency room. In your early teenage years you started been discovered in China9 and used in asthma treatment, treatment with inhaled Vanceril (beclomethasone), but other than allergen removal and adrenaline injections, two puffs twice a day; 10 years ago, you switched there was little to offer patients with asthma beyond ad- to inhaled Qvar (beclomethasone driven by a vising them to smoke “asthma cigarettes” (made from the hydrofluoroalkane [an ozone-layer–friendly] pro- leaves of D. stramonium [Fig. 1]). Theophylline was pellant), and Singulair (montelukast) was added available but was used as a diuretic; its value in the treat- to your regimen. Over the past 10 years, you have ment of asthma had not yet been discovered. Aerosol inha- tried two different “combination inhalers,” con- lation therapy had not been widely adopted by 1928, but taining both inhaled glucocorticoids and long- by the 1940s an inhaled formulation of epinephrine was acting β2-agonists — namely, Advair (fluticasone marketed for asthma treatment (Fig. 2). propionate and salmeterol) and Symbicort

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Figure 2. Personal Inhaler. The first personal inhalers allowed patients to breathe aerosols generated from epinephrine. Devices such as these were in use from the 1930s until the invention of the metered-dose inhaler in the 1950s. Image courtesy of Mark Sanders, www.inhalatorium.com.

(budesonide and formoterol fumarate dehydrate). loratadine, to your treatment during the times of These medications did not improve your symp- year when you are most susceptible to symptoms; toms or lung function as compared with inhaled the loratadine was of some small help in control- beclomethasone alone, and you switched backed ling your runny nose, but there was no change to Qvar. in your asthma symptoms. Your allergist also Even with this regimen, however, your asthma referred you to a gastroenterologist, who per- symptoms are still present and bothersome. For formed 24-hour esophageal pH monitoring and example, two to three times a month you are found no abnormalities. awakened from your sleep between 3 a.m. and In the past decade, you have required treat- 4 a.m. by shortness of breath and cough; you can ment with oral prednisone on three occasions; the hear yourself wheeze. If you use your rescue al- last instance was in 2009. Each of these exacer- buterol inhaler, you are usually able to get back bations occurred during your season. You to sleep by 5 a.m. have a peak-flow meter, which you use occasion- Two years ago, skin tests were performed, and ally. Your best reading is 500 liters per minute; your total IgE level was measured. Your only posi- on most days, your peak-flow values are between tive skin tests were for house-dust mites and rag- 350 and 400 liters per minute. weed. Your total IgE level was 75 IU per milliliter. You work in an office. You live with your hus- The allergist who did the testing suggested that band and two children in a single-family home you add a nonsedating antihistamine, such as heated and air-conditioned with forced air. You

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have taken extensive measures to remove allergens but it is necessary to monitor blood levels of the from your home, including having the air ducts drug to obtain an optimum response, and some cleaned and tested for allergens. You have no pets. patients find testing to be burdensome. There is a You have never smoked, and the same is true for small chance that theophylline could make your your husband and your children. Smoking has not asthma worse by relaxing the muscle that sepa- been allowed in your workplace for more than a rates your stomach from your esophagus; if this decade. Your mother had asthma. occurred, the treatment would be stopped. Your current medications are Qvar, 80 μg per Second, Singulair could be replaced with Zyflo puff, two puffs twice a day; Singulair, 10 mg per CR (zileuton, controlled release). The active ingre- day, taken at night; and one multivitamin per day. dient in Singulair is montelukast, which blocks the You would like a single consultation and con- action of the cysteinyl leukotrienes at the CysLT1 fidential second opinion as to how your asthma receptor, whereas zileuton prevents the synthesis has been managed and how to improve your of both cysteinyl leukotrienes and dihydroxy leu- asthma control. kotrienes. There are theoretical reasons to believe On physical examination today, you looked that controlled-release zileuton would yield a clini- well. Your weight was 135 lb [61.2 kg]. Your blood cal benefit, but there are no compelling data to pressure was 110/75 mm Hg, and your pulse was support this approach. Monitoring of liver func- 77 beats per minute according to the pulse ox- tion is required during initiation of treatment imeter, which also indicated that your hemoglo- with zileuton. bin saturation while you were breathing ambient Third, Xolair (omalizumab) could be added to air was 95%. Your physical examination was your regimen. This anti-IgE monoclonal antibody largely normal. No abnormalities were noted in is given once a month by injection. There is clearly your eyes, nose, or ears. Your chest examination an allergic component of your disease; your total was normal except for the presence of scattered IgE level is elevated, but it is not so high as to pre- expiratory wheezes, which were heard best dur- clude the use of omalizumab. ing rapid, shallow breathing. There were no ab- As we discussed, I think your primary care normalities in your extremities. Your neurologic physician has done an excellent job in designing examination was normal as well. Lung-function your asthma treatment. You should discuss our testing was performed in our laboratory; the re- consultation with her and decide what is in your sults are attached to this letter (Fig. 3). best interest. I think that the diagnosis of asthma is well Comment: There have been three major changes in our established. You have a long history of asthma and understanding of asthma between 1928 and 2012. First, have had salutary symptomatic responses to asth- spirometry, which had been invented in the 1840s,13 was ma treatments, your lung-function tests still show refined by adding time to volume output, and between the reversibility of airway obstruction of more than late 1940s and early 1950s, measurements made from 15% with albuterol, and no other competing di- forced exhalations were used in the diagnosis and treat- agnosis has emerged over many years. The major ment of asthma.14 Other lung-function tests were devel- issue now is to determine whether there are ad- oped and used, and the relationships between clinical ditional treatments that could help suppress your physiology and symptoms were delineated.15 Second, asthmatic symptoms without increasing the treat- glucocorticoids were identified as an effective and useful ment burden. asthma treatment. They were first used systemically in You and your physicians have done an excel- the early 1950s16 and were subsequently made available lent job of managing your asthma. The treatments in inhaled form17,18; these agents remain the standard of you are using now are well established and known care today. Third, our understanding of the immunobiol- to be effective. There are three treatments that ogy of asthma progressed beyond the view that the es- could be added to your regimen, but it is difficult sential mechanism was an immediate hypersensitivity to be certain that they would be effective. First, reaction.19,20 Unfortunately, these advances in under- oral theophylline could be added to your regimen. standing the cell biology of asthma have not yet been Although you cannot recall having received treat- translated into new therapies, although new therapies ment with theophylline, given your age and asthma have been derived from our improved understanding of history, it is likely that you were treated with this immediate hypersensitivity responses — notably, the use agent as a child. This therapy could be of value, of leukotriene modifiers21 and anti-IgE antibodies.22

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12 Before bronchodilator After bronchodilator Predicted

10 PEFR 8 6

6 4 FEF50 4 FEV1 2 2 FEF75

FVC Volume (liters) 0 0 0 1 2 3 4 5 6 7 −2 Seconds Flow (liters/sec) −4

−6 PIFR

−8

−10

−12 0 1 2 3 4 5 6 Volume (liters)

Predicted Value Spirometry Before Bronchodilator (lower limit of 95% CI) After Bronchodilator change from % of % of before actual predicted mean actual predicted treatment FVC (liters) 4.78 105 4.51 (3.46) 5.12 113 7

FEV1 (liters) 3.01 80 3.75 (2.89) 3.7 98 22 FEV1/FVC (%) 63 75 83 (75) 72 86 14 FEF25–75 (liters/sec) 1.87 46 4.03 2.64 65 41 PEFR (liters/sec) 6.64 75 8.74 10.17 116 53 FET (sec) 7.89 7.89

Figure 3. Spirometric Results for Ms. Smith.

Although the forced expiratory volume in 1 second (FEV1) is within the normal range of the predicted value, the ratio of FEV1 to forced vital capacity (FVC) is low. The patient’s FEV1 increases to almost 700 ml with inhaled albuterol, indicating that she has substantial reversible airway obstruction. The tracings and data shown are similar to the data displays provided by many spirometers that are currently available. FEF25–75 denotes forced expiratory flow between 25 and 75% of FVC, FET forced expiratory time, IFR inspiratory flow rate, PEFR peak expiratory flow rate, and PIFR peak inspiratory flow rate.

Our patient is current in her medical knowledge and is Conclusions using medical information widely available on the Inter- net to help in the management of her chronic condition. These three case histories illustrate that asthma The consultant used measures of lung function to quan- as a disease has not changed for two centuries. We tify her physiological deficit. The consultant also mea- have made real progress in identifying patients sured the patient’s IgE level, which was consistent with with asthma and in understanding its biologic allergic asthma, and provided the information needed for basis and its treatment. Progress has also been anti-IgE treatment, should the patient elect this approach. made in diagnostic testing, which has been re- The patient has used all the standard asthma therapies fined to measure lung function with great accuracy but has residual symptoms. The consultant outlines other and repeatability. In addition, we can measure the asthma treatments that the patient could try, highlight- lung’s responsiveness to triggering agents and ing the need to try different treatments to see whether one thereby obtain objective indications of disease ac- or another will work. Sadly, we still do not have a way to tivity, in addition to the patient’s history. We have predict a given patient’s response to therapy. come to realize that allergic responses often sub-

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stantially contribute to both chronic persistent not understand the fundamental causes of asth- asthma and acute exacerbations of asthma symp- ma. Hence, we do not have therapies that address toms, although this association may have been the underlying mechanisms; we have no cure for overemphasized. The current focus is on immune asthma. The medications at hand provide relief of responses in affected patients; we believe that air- symptoms and improve lung function and airway way inflammation plays a critical role in asthma, responsiveness, but they do not prevent exacerba- but the precise nature of that inflammation re- tions or progression of disease, and the most de- mains a mystery. The knowledge that asthma runs sirable accomplishment, the primary prevention in families has become the basis for very sophisti- of asthma, is a vision that has not yet become a cated studies of the genetics of asthma, but not reality. much of its heritability can be explained by all the Disclosure forms provided by the authors are available with genes identified to date. In spite of all the progress the full text of this article at NEJM.org. achieved over the past two centuries, we still do

References 1. Marketos SG, Ballas CN. Bronchial 8. The proper use of the hypodermic sy- clomethasone diproprionate: a new ste- asthma in the medical literature of Greek ringe. Boston Med Surg J 1922;187:590. roid aerosol for the treatment of allergic antiquity. J Asthma 1982;19:263-9. 9. Thomas WS. Ephedrin in asthma: a asthma. Br Med J 1972;1:585-90. 2. Catarrhus aestivus, or hay fever. Boston clinical report. Am J Med Sci 1926;171:719. 18. Davies G, Thomas P, Broder I, et al. Med Surg J 1833;8:341-7. 10. Bell R. Experience in search of a cure Steroid-dependent asthma treated with 3. Floyer JS. A treatise of the asthma, di- for asthma in the far Southwest; with ob- inhaled beclomethasone diproprionate: a vided into four parts. London: Printed for servations of the comparative value of dif- long-term study. Ann Intern Med 1977;86: Richard Wilkin at St. Paul’s Churchyard, ferent sections in respiratory diseases. 549-53. 1698. Boston Med Surg J 1901;144:395-7. 19. Bousquet J, Chanez P, Lacoste JY, et al. 4. Dr. Bree. Letter on stramonium. N Engl 11. Current literature. Boston Med Surg J Eosinophils and asthma. N Engl J Med J Med Surg 1812;1:411-6. 1922;186:48-52. 1991;324:1514-5. 5. Peters SP, Kunselman SJ, Icitovic N, et 12. Turnbull JA. Disturbances caused by 20. Robinson DS, Hamid Q, Ying S, et al.

al. Tiotropium bromide step-up therapy for proteins. Boston Med Surg J 1920;182:493-7. Predominant TH2-like bronchoalveolar adults with uncontrolled asthma. N Engl 13. The spirometer as a means of diagno- T‑lymphocyte population in atopic asthma. J Med 2010;363:1715-26. sis. Boston Med Surg J 1847;36:436-40. N Engl J Med 1992;326:298-304. 6. Granville AB. Further observations on 14. Goggio AF. The abnormal physiology of 21. Drazen JM, Israel E, O’Byrne PM. the internal use of the hydrocyanic (Prussic) chronic pulmonary emphysema. N Engl J Treatment of asthma with drugs modify- acid, in pulmonary complaints; chronic Med 1944;231:672-7. ing the leukotriene pathway. N Engl J Med catarrhs; spasmodic coughs; asthma; hoop- 15. McFadden ER Jr, Kiser R, DeGroot WJ. 1999;340:197-206. ing cough; and some other diseases, with Acute bronchial asthma. N Engl J Med 22. Milgrom H, Fick RB Jr, Su JQ, et al. full directions for the preparation and ad- 1973;288:221-5. Treatment of allergic asthma with mono- ministration of that medicine. N Engl J 16. Thorne GW, Forsham PH, Frawley TF, clonal anti-IgE antibody. N Engl J Med Med Surg 1820;9:193-7. et al. The clinical usefulness of ACTH and 1999;341:1966-73. 7. Chiarenti F. A cure for the asthma. cortisone. N Engl J Med 1950;242:824-34. Copyright © 2012 Massachusetts Medical Society. N Engl Med Rev J 1827;1:329-30. 17. Brown HM, Storey G, George WH. Be-

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