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A Century of Asthma

Division of Pulmonary, Critical Care, and Sleep Medicine, MetroHealth Medical Center; and Center for Academic Clinical Research, Case Western Reserve University School of Medicine, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to E. R. McFadden, Jr., M.D., Division of Pulmonary, Critical Care, and Sleep Medicine, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. E-mail: erm2{at}cwru.edu

Summarizing the history of asthma over the life of the American Thoracic Society (ATS) is a challenging task. In 1904, when the Society began, the Index-Catalogue of the Surgeon General's Office of the U.S. Army (the Index Medicus of its time) listed 33 citations and 3 books on the subject. In contrast, 3,090 articles on asthma were published in 2000, and 191 new books were added to the Library of Congress. The story of such growth is worth the telling, for it represents clinical acumen at its best, blended with the avid use of emerging technologies, and therapeutic trial and error. Because the investigators were physicians, alleviating patient discomfort tended to take precedence over the need to understand causality and, as a result, some truly remarkable remedies were tried. It was not until the latter part of the twentieth century that advances in pathophysiology, immunobiology, and pharmacology began to be made in parallel and that solid understandings were achieved. This brief review attempts to present what was known when ATS started and how we arrived at where we are today. It deals primarily with events up through the last 15–20 years because such information is mature enough to have withstood the test of time. The most recent thoughts about asthma will be cataloged where appropriate, but their historical importance will be left to others to decide.

UNDERSTANDING THE NATURE OF ASTHMA

"Asthma" is derived from the Greek root µ, meaning "to pant heavily" or "gasp for breath" (1). The term originally did not define a disease as we understand it today, but was employed to connote respiratory symptoms of a host of pulmonary and cardiac conditions. Over time, the meaning contracted and by the beginning of the last century, most authorities thought asthma to be a unique illness characterized by "spasmodic afflictions of the bronchial tubes" (2, 3). By the time ATS began, a fair amount had been learned about the illness. The familial clustering of the disease was recognized; the signs, symptoms, and natural history of acute decompensations were detailed; the associations with nasal polyps and hay fever were solidified; and sputum and blood eosinophilia had been reported and confirmed (1, 2, 4–6). The muscle fibers encircling the bronchi had been described, the parasympathetic and sympathetic nervous systems had been discovered, and electrical excitation of the cut ends of the vagus nerve was known to reduce the bronchial lumen of animals (see citations in Reference 1).

The major contribution to understanding asthma in the nineteenth century was made by Henry Hyde Salter (1823–1871) (7) (Figure 1) . Salter was a lecturer in physiology and medicine at Charing Cross Hospital in London and was himself an asthmatic. He took a rather iconoclastic view of the thoughts of his predecessors and contemporaries and demanded that conjecture must give way to observation for progress to be made: "Respect for authority, however high, should never be pushed to the concession of anything positively observed." Salter provided a comprehensive classification of the stimuli associated with acute episodes and their proposed mechanisms. Provocations that operated directly on the air passages were called "extrinsic" and examples included exercise, cold air, laughing, coughing, sneezing, chemical and mechanical irritants, and animal and vegetable emanations. Salter also realized that external stimuli were not the cause of the condition and that something else must be operating. "There is no peculiarity in the stimulus, the air breathed is the same in the asthmatic and the nonasthmatic, the ipecacuan powder; the hay effluvium is the same in both....it is clear that the vice in asthma consists, not in the production of any special irritant, but in the irritability of the part being irritated." Salter believed asthma to involve both neural and vascular mechanisms: "The inflammation or congestion of the mucous surface appears to be the stimulus that, through the nerves of the air tubes, excites the muscular wall to contract" (7).

View larger version (134K): [in this window] [in a new window]   Figure 1. Henry Hyde Salter (1823–1871), English physician who performed extensive studies of asthma in himself and his patients. His book, On Asthma: Its Pathology and Treatment, originally published in 1860, went through a number of editions in both England and America and is generally recognized as the preeminent work on asthma in the twentieth century.

View larger version (133K): [in this window] [in a new window]   Figure 2. Sir William Osler (1849–1919), Regius Professor of Medicine at Oxford University and physician to the Radcliffe Infirmary. Author of the textbook The Principles and Practice of Medicine in 1892 and considered by many to be the most influential physician in history. Osler considered asthma to be a psychoneurosis: "All authors agree that there is, in a majority of cases of bronchial asthma, a strong neurotic element."

The onset of World War I effectively brought clinical research to a standstill in Europe. Two Americans, Isaac Chandler Walker (1883–1950) of Peter Bent Brigham Hospital and Francis Rackemann (1887–1973) (Figure 3) of Massachusetts General Hospital, experimenting with skin tests, moved the sensitization idea forward. Walker, in 1916, noted positive reactions in patients with asthma to dermal challenges with proteins derived from animals, foods, and bacteria (16–18). Not all patients responded to all agents, but there were sufficient groupings to suggest a causal classification based on "protein sensitization" (19). Almost simultaneously, Rackemann concluded that asthma could not always be proven to be of allergic origin and categorized patients as ‘intrinsic" or "extrinsic" (20). "Protein-sensitive" and "extrinsic" asthmatics were similar groups likely to be allergic to environmental antigens. They tended to have their asthma from a younger age and to be more labile. The intrinsic/protein-insensitive patients tended to be older and to have more severe disease with less clear-cut allergic elements. It was theorized that they might be sensitive to the bacteria resident in places such as the nose, sinuses, tonsils, and gums (19, 21). These groupings also had therapeutic implications. If sensitization to bacterial components was operational, it then should follow that neutralization of the organisms with specific vaccines would eliminate asthma. In the other type of patients, antigen avoidance and desensitization would at least control, if not provide a cure. Unfortunately, none of this happened with much regularity and eventually these classifications fell apart. Despite the lack of selectivity and specificity of the skin test findings, this body of work dominated the thinking about asthma for the next half-century, until the immunobiology of the disease began to be better understood. Because of Walker and Rackemann, asthma now had an operational definition. Nonetheless, it took more than 70 more years before a consensus was reached as to its important components (22).

View larger version (149K): [in this window] [in a new window]   Figure 3. Francis Rackemann (1887–1973), second president of the Society for the Study of Asthma and Allied Conditions and founder of the Allergy Clinic at Massachusetts General Hospital. Taught that asthma could be due to "extrinsic" or "intrinsic" causes and that skin tests were of great assistance in confirming the diagnosis and were often helpful in determining successful specific treatment. Reprinted by permission of the American Academy of Allergy, Asthma and Immunology.

As knowledge about asthma grew, the structural abnormalities began to be a subject of inquiry. In anticipation of modern thought, the earliest efforts at defining asthma commented on the inflammatory nature of the illness and the likely site of the disease process. Fowler and Godlee, in 1898, wrote of "inflammatory swelling or acute catarrh" of the bronchial mucous membranes (23) and Osler stated "that in many cases it [asthma] is a special form of inflammation of the smaller bronchi" (2). These descriptions were derived from microscopic examination of expectorated phlegm showing desquamated epithelium, bronchial casts, eosinophils, and "asthma crystals." Historically, much has been written about sputum, but then, as now, the ability to relate the microscopic features of mucus to the severity, natural history, and intensity of acute and chronic illness has not been as fully rewarding as hoped.

It was noted that, despite a high morbidity, relatively few people died from asthma. Ellis performed the first systematic examination of morbid anatomy in 1908 (24). He reviewed the seven cases that were then present in the literature and concluded that there was no single pathognomonic finding. In 1922, Huber and Koessler (25) examined the microscopic features of 15 reported deaths and added 6 cases of their own. Their work described the classic features of patients dying from asthma, including mucous impaction in the bronchi; thickening of the airway walls; hypertrophy of the smooth muscle; edema of the submucosa; and eosinophilic, lymphoid, and neutrophilic infiltration. They also undertook the first attempt at quantifying the extent of abnormalities present and correlating them with the type and severity of the patient's asthma. Dunnill in 1960 (26) added mucosal denudation and thickening of the basement membranes of the airways to the list.

Although bronchoscopy had been performed in asthmatics since at least 1914 (27), the histologic features of biopsies were not reported until 1985 by Laitinen and associates (28). Subsequent to these seminal observations, it was quickly established that chronic inflammation was a feature of asthma in all of its stages (29). This, in turn, spurred interest in the basic biology of airway injury and repair and gave impetus to the development of therapies to limit inflammatory cascades. They also raised fears that failure to interrupt ongoing inflammation would lead to airway remodeling with permanent physiologic impairments (30). It remains to be determined whether and when this phenomenon occurs. It is also not yet clear how we can use the information about inflammation to understand the development of acute episodes or the responses to acute and chronic therapy.

As the means of measuring lung function were developed after World War II, the physiologic features of asthma were steadily unraveled and its physiology clarified. Within a period of two decades, asthma was shown to be associated with transient increases in airway resistance, reductions in forced expiratory volumes and flows, hyperinflation of the lungs and thorax, increased work of breathing, as well as abnormalities in the distribution of ventilation and perfusion and arterial blood gases. Cardiac performance was also studied and the right ventricular strain and pulmonary hypertension from compression of alveolar vessels were described, as were the factors leading to pulsus paradoxus. Many investigators made major contributions to this phase of understanding. All would agree, however, that the pioneering work of M. Henry Williams of New York and Solbert Permutt of Baltimore on cardiopulmonary physiology, Jay Nadel of San Francisco on airway function and its regulation, and Ann Woolcock (1937–2001) of Sydney, Australia (Figure 4) on the mechanical behavior of the lung in asthma were particularly helpful. The salient features of asthma could now be differentiated from other forms of airway disease and pulmonary venous hypertension. Both the acute and chronic phases of the illness were dissected and from this came understanding of the reversible nature of the physiologic abnormalities and an appreciation of their interrelationships, their role in the production of signs and symptoms, and their dynamic behavior during the onset and resolution of acute attacks (the citations for the material in this paragraph are detailed in the section on pathophysiologic manifestations in Reference 31).

View larger version (152K): [in this window] [in a new window]   Figure 4. Ann Woolcock (1937–2001), Professor of Respiratory Medicine, Founder of the Institute of Respiratory Medicine at the Royal Prince Alfred Hospital in Sydney, Australia, and an Officer of the Order of Australia. Made many contributions to the understanding of the pathophysiology, pathogenesis, and epidemiology of asthma. Figure reprinted by permission of the Australian Academy of Science.

Despite all that had been learned, our perceptions of pathophysiology even now are still far from complete (31). We have yet to obtain a firm grasp of the basic events that initiate and sustain many of the impairments seen. From a practical standpoint, however, the manner and extent to which asthma altered lung function were now established, the benefits and limitations of the available tests were delineated, and the influence of one dysfunctional element on another was recognized. As a result it became possible to assess the severity of acute episodes objectively and to determine which patients were in peril. Further, both short- and long-term fluctuations in disease activity and lung function could now be followed with precision, using simple tests.

As the awareness of pathophysiology increased, pathogenesis was explored more intensively. The bronchial hyperresponsiveness characteristic of asthma was first described in 1946 by Curry, who examined the effects of graded doses of histamine in individuals with and without asthma (32). With it came a reasonably selective laboratory test to diagnosis the disease as well as the need to understand the factors controlling airway tone (33). The seemingly capricious periodicity of asthma symptoms and therapeutic responses could now be explained in the context of fluctuations in the basic sensitivity of the tracheobronchial tree to inflammatory stimuli. As the mechanisms of airway reactivity came under investigation, techniques were developed to examine bronchoconstriction in general as well as the operational features of specific provocations. From the 1970s onward, many of the pathognomonic elements of stimuli such as antigen, exercise, viral infections, and air pollutants were uncovered (33–37). After some initial uncertainties, it became apparent that there were common elements to obstruction such as smooth muscle contraction and capillary leakage with airway wall edema, but they could be brought about through different pathways. Further, it was established that stimulus–response relationships existed to common precipitants; the intensity of which could wax and wane as bronchial reactivity changed. Thus, attacks of differing severity could result from seemingly similar exposures to diverse stimuli without there being a change in the fundamental pathogenic features of the disease. We also learned that only such provocations as antigen, some respiratory viruses, and oxidative air pollutants worsened the asthmatic condition. Because of this, treatment could be focused on preventing specific events.

Some of the above-described discoveries were quite fortuitous. Our group was working on the effects of treatment on exercise-induced asthma during a particularly difficult winter in Boston. The experimental laboratory was separate from the hospital and the subjects would hurry up a hill to escape the cold. As a result, they began to wheeze as soon as they entered the building, causing the cancellation of the planned experiments. I became aware of Salter's observations on the effects of cold air in asthma at about the same time and decided to see whether we could find out what was happening. Working with the Army's Environmental Research Laboratory in Natick, Massachusetts, we were able to systematically examine the impact of thermal events on respiratory heat exchange and airway function (35). The greatest fun, however, was having the pleasure of providing an objective verification of the observations of an insightful man who lived in the previous century.

Arguably, the immunobiology of asthma had its beginnings in the discovery that the mediators of immediate hypersensitivity had profound biologic activities. Dale and Laidlaw in 1911 demonstrated the physiologic activity of histamine and its role in anaphylactic shock (38). Other milestones included the work of Prausnitz and Küstner in 1921 (39) on the identification of a passively transferable reagin, recognition of slow-reacting substance of anaphylaxis in 1940 by Kellaway and Trethewie (40), the finding of histamine in tissue mast cells in 1953 by Riley and West (41), the discovery of immunoglobulin E in 1966 by Ishizaka and associates (42), and the confirmation that the house dust mite was the source of antigenicity for house dust by Voorhorst and coworkers in 1967 (43).

The discovery of the generation of prostaglandins and leukotrienes from arachidonic acid by Bengt Samuelsson (44) (Figure 5) and their synthetic production by E. J. Corey (Figure 6) greatly expanded the field. K. Frank Austin, Jeffrey Drazen, E. J. Corey, and the group at the Peter Bent Brigham Hospital (45) were able to show that the cysteinyl leukotrienes had profound effects on lung function in patients with asthma. These, and earlier observations in animal models, stimulated the search for compounds with antileukotriene activity and helped foster the use of this class of agents clinically.

View larger version (131K): [in this window] [in a new window]   Figure 5. Bengt Samuelsson (1934–), Nobel Laureate in Physiology or Medicine in 1982, Professor of Medical and Physiological Chemistry, Chairman of the Department of Chemistry, Dean of the Medical Faculty, and Rector of the Karolinska Institute. His pioneering work on the transformation products of arachidonic acid led to the discovery of endoperoxides, thromboxanes, and leukotrienes. His research on the biochemistry and biology of these compounds led to major insights in thrombosis, inflammation, and allergy. Reprinted by permission from S. G. Cohen, M. Samter, editors. Excerpts from Classics in Allergy, 2nd ed. Carlsbad, CA: Symposia Foundation; 1992, p. 196.

View larger version (119K): [in this window] [in a new window]   Figure 6. Elias J. Corey (1928–), Sheldon Emery Professor of Chemistry at Harvard University. Nobel Laureate in Chemistry in 1990 for his development of the theory and methodology of organic synthesis that ultimately allowed chemists to create synthetic versions of organic chemicals in the laboratory. His work, in collaboration with that of his colleagues on immunology and physiology at Harvard Medical School and the School of Public Health, led to an understanding of the airway effects of the leukotrienes in asthma. Reprinted from S. Holgate, S.-E. Dahlen, editors. SRS-A to Leukotrienes: The Dawning of a New Treatment. Oxford; Blackwell Science; 1997, p. xxv.

As the importance of mast cells, basophils, and eosinophils was systematically examined, knowledge about the biology of asthma grew exponentially. Most recently, T lymphocytes have also been implicated and data are accumulating that asthma may be related to an imbalance in helper T cell Type 1 and 2 immune responses, but firm conclusions are not yet available. As the above-described information unfolded, it was theorized that the pathology of asthma could represent an interaction between resident and infiltrating inflammatory cells and the airway epithelium (46). The bevy of inflammatory mediators, cytokines, and chemokines available in such a setting could both initiate and sustain inflammation and produce the physiologic and clinical features of the disease (46, 47). This meant that once again operational concepts would have to be modified and that no one biochemical or cellular element produced the asthmatic diathesis. Rather, a network of interacting substances from multiple sources seems to be required. With this realization came a new set of opportunities. No single hypothesis presented to date could explain asthma and no one treatment was likely to eliminate it.

EVOLUTION OF THERAPY

Historically, the therapy of asthma has been driven by trial and error. When ATS was initiated only a few specific medications were known, but practitioners understood the importance of separating palliation from prophylaxis. A detailed summary of the treatment of asthma in the early twentieth century was written by Orville Brown of St. Louis University in 1917 (48). Efforts at "control" consisted of diet, rest, breathing exercises, facilitation of inspiration and expiration by the application of external pressures, vibratory massage of the chest, living at high altitude, residing in the desert, moving to the country, moving to the city, sleeping out of doors, avoidance of known triggers, immunizations or desensitization, and hypnosis. Nothing tried worked very well. In fact, some remedies were downright dangerous. Immunization consisted of "autogenous vaccines made from bacteria," diphtheria antitoxin, or proteins from pollens. At that time such material was prepared in horses and deaths occurred when it was then given to patients with allergies to these animals (11).

The regular use of inhalants for acute symptoms and chronic control was also suggested, but until the first medical atomizer was introduced in 1938 (49) the only way to generate an aerosol was to burn medicinal powders or impregnated papers or inhale smoke from "asthma cigarettes" (48). The most common ingredients prescribed were iodides, organic nitrites, stramonium, belladonna, atropine, hyoscyamus, tobacco smoke, and menthol. Morphine, cocaine, and chloroform were also inhaled or injected directly into the trachea with a needle or through a bronchoscope (48). As with prophylaxis, there were no outstanding advances. Addiction to cocaine soon became a recognized hazard of asthma care and so it was recommended that the drug be used as little as possible.

Viewed from today, one tends to look askance at the material in the preceding list, but it consists of mucolytics, smooth muscle relaxants, bronchodilators, cough suppressants, vasoconstrictors, mild counterirritants, and neurally active ingredients that reduced tachypnea, dyspnea, and anxiety. One can also express unease about the boldness of instrumenting the tracheobronchial tree of patients with asthma in 1914. In reality, however, the performance of endoscopy in this period needs to be balanced against the forward-thinking decision in 1985 to perform airway biopsies (28) and the questionable wisdom of undertaking pulmonary denervation to cure asthma in 1959 (50). In any event, because nothing available could be relied on, nontraditional treatments of asthma abounded. Some of the more esoteric ones included "electric light baths"; application of the Roentgen ray; direct instillation of tincture of iodine, silver nitrate, adrenaline, and atropine into the tracheobronchial tree via endoscopy; and "neural adjustments" (48). Two of the more remarkable "adjustments" included "pouring a gallon or more of cold water on the back of the neck of the asthmatic two to three times a day from a height of two feet" or "applying high frequency current—to such nerves as the vagus, spinal accessory, phrenic and sympathetic ... by placing the positive electrode on the neck or introducing it into the nose."

In a sense, the modern pharmacologic era for asthma began in the 1920s. By then dissatisfaction with the slow onset of action and unpleasant side effects of the anticholinergic alkaloids in plant leaves initiated a search for better drugs. Strong coffee and tea were suggested as remedies by Salter (7), but the xanthines did not draw much therapeutic attention until 1921, when Macht and Ting determined that they relaxed smooth muscle (51). Hirsch then used theophylline suppositories to treat asthma in 1922 (52) and aminophylline made its appearance in 1937 (53). We now know that the methylxanthines are not more potent than the congeners of atropine, but they are orally active, and considerably easier for the patient to use. As a result, they became the treatment of choice and remained so for about four decades. The decline in use began in the early 1980s, when they were shown to be less efficacious than the sympathomimetics. Other contributing factors included a narrow therapeutic window, variable pharmacokinetics, and a toxic potential that increased with blood levels. Even with this information, the methylxanthines did not quietly fade away. They were old friends with stanch defenders. Pro and con debates took place in the literature and at national meetings for years, but eventually other agents that were safer and required less monitoring supplanted them.

The adrenergic agonists actually entered the pharmacopoeia earlier than the methylxanthines, but their progress was slower. Pills of "adrenal substance" were first administered in 1900 to patients with asthma (54). Because this route of administration unknowingly limited bioavailability there was only a modest effect. Epinephrine was subsequently given "hypodermatically" by Bullowa and Kaplan in 1903 (55) and as an aerosol by Barger and Dale in 1910 (56) with prompt symptomatic improvement. The next agent of this class, isoproterenol, did not appear until 1949 (57) and the self-contained metered-dose inhaler to deliver it was invented in 1956 (58). Although effective, these drugs produced annoying cardiac and systemic side effects. Further, the introduction of the metered-dose inhaler brought with it concerns about safety, overreliance on medications, and ultimately the patients' ability to use the device correctly. The first two issues remain incompletely resolved, recurring themes even to the present, while the third was at least partially addressed by the introduction of spacer devices and dry powder inhalers. Manipulation of the catecholamine side chain conferred increased selectivity for the ß₂-adrenergic receptor and with it, greater potency and longer durations of action. As development advanced, a minimum of 11 adrenergic agents made their appearance over the next 20–25 years (59). Each fell by the wayside and, ultimately, albuterol and terbutaline became the treatments of choice to relieve acute obstruction. They, in turn, gave way to the very long-acting compounds such as salmeterol and formoterol that are now available for the treatment of chronic disease. The most recent trend is to combine these drugs with inhaled steroids in a single inhaler on the assumption that they provide more benefit this way than when given individually. It has also been suggested that the long-acting sympathomimetics when administered alone may contribute to a loss of control of asthma and even death. In both of these situations, firm conclusions await further experimentation.

As the sympathomimetics were being chemically altered, the atropine molecule was modified to limit systemic and neural absorption. Ipratropium was introduced into practice in 1975 (60). Its role in chronic asthma remains limited, but ipratropium has undergone a bit of resurgence in acute situations (31).

For the most part, therapy of chronic asthma consisted of treating bronchospastic episodes as they arose by using medications intermittently. When the physiology of asthma was better understood, antispasmodics were given on a continuous basis to attempt to lower airway tone. As the formulations of drugs were changed, the interval between treatments was eventually reduced from a typical regimen of every 4 hours around the clock to twice daily and even once daily. Management was immensely simplified, but there was still no way of interrupting the underlying pathologic sequence.

Glucocorticoids offered the first hope in this area. They were tried in acute asthma in 1956 (61) and then in chronic disease. As effective as steroids were, serious side effects developed with continuous use, thereby restricting long-term oral administration. Since the original studies, literally hundreds of articles have appeared but as of 2004, basic issues such as the optimal doses to employ, the time lag to response, and the mechanism of action in acute asthma still remain elusive (31). In an effort to minimize unwanted consequences, aerosolized beclomethasone and betamethasone were introduced in the early 1970s (62, 63). After mild initial enthusiasm, their benefits began to emerge as the doses were adjusted. Modifying the steroid molecule increased potency and first-pass metabolism and showed that inhaled corticosteroids could be a major means of reducing the inflammation of asthma. Now, it became possible to treat the underlying pathology with the hope of limiting symptomatic expression.

By the 1980s, a significant part of the therapeutic evolution had ended. "Smokes and fumes" were long gone and empiricism was being eroded. More importantly, much of the modern armamentarium currently employed to reverse obstruction and control the asthmatic diathesis was in place. It now became feasible to explore the differences in efficacy between various types of pharmacologic agents as well as to examine the relative potencies of new drugs that were developed within a given class. The benefits of controlled trials were increasingly obvious, for we were now not only concerned about whether a drug was useful, but also about how well and safely it worked compared with its fellows.

Eventually, the treatment of asthma was codified in national and then international guidelines (22). Besides providing a framework for management, these efforts served to foster further investigation into patient care by highlighting the deficiencies in our knowledge. "Consensus opinion" has still not given way completely to objective documentation, but we are moving a long way in that direction.

The next phase of understanding will likely be the most exciting yet. Application of the technologies available from emerging fields like genomics, proteomics, pharmacogenetics, informatics, and molecular pharmacology and physiology will produce unparalleled advances at multiple levels. The expectation is that ATS, as it has in the past hundred years, will continue to play a lead role in facilitating the creation of this new knowledge and serve as a forum for its dissemination.

FOOTNOTES

Supported in part by grants HL3791 and HL07288 from the National Heart, Lung, and Blood Institute.

Conflict of Interest Statement: E.R.Mc.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form February 11, 2004; accepted in final form May 12, 2004

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