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The time has come* Richard
M. Krause, M.D. Bethesda, Md.
Dr. Patterson, Members of the Robert A. Cooke Alumni Association, Members of the Academy, participants of this Congress, and guests: It is a special honor for me to give the Robert A. Cooke Lecture for 1977 and to receive this medallion. I hope you will sense the excitement with which 1 put before you this morning a very special proposal. Just before Victor Hugo died on May 22, 1885, he wrote in his diary, “There is one thing stronger than all the armies in the world; and that is an idea whose time has come.” That is what I want to talk about-an idea whose time has co:me. And that idea is a National Program for Asthma and Other Allergic Diseases. During this hour I can provide no more than a rough sketch of such a program. Indeed, what I say will be of little consequence compared to the contributions all of you can make to this effort. If you at this Congress of Allergy and Immunology decide that a National Program for Asthma and Other Allergies is an idea whose time has come, then it will be left to all of us to work matters out--what to do and how to do it. As a possible backdrop for this proposed program, let me first s,aya few words about the life and times of Robert A. Cooke. He must have been a man of boundless energy and vitality, vigorous, inquisitive, From the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Presented at the American Congress of Allergy and Immunology, March 28, 1977, Americana Hotel, New York, N. Y. Reprint requests to: Dr. Richard M. Krause, Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rldg. 31, 7Al l-C, Bethesda, Md. 20014. *The Robert A. Cooke Memorial Lecture sponsored by The Robert A. Cooke Alumni Association in cooperation with the American Academy of Allergy.
alert, methodical, compassionate; in sum, a true physician. Of his many discoveries, two stand out; first, his demonstration of blocking antibody after desensitization, and, second, his findings on the inheritance of atopy. How did Dr. Cooke’s interest in allergy start? I found the answer to this question in an address which he gave at a banquet held in his honor at the Hotel Pierre, February 27, 1958, two years before his death. I abstract briefly from that address. i Dr. Cooke noted three factors which started him in a field which was not even called allergy in those days. First, there was his inheritance, for which he claimed no responsibility. He was a direct descendant of three generations of physicians. As he commented, “We cannot get away from those determining and determined little genes and so it is with me.” The second factor which fostered his interest in medicine and allergy was that from the age of 8 he was an asthmatic child with little in the way of relief except vomiting after syrup of ipecac and squill. Epinephrine was not yet known in 1890 and, as I shall mention shortly, ephedrine has been lost to medicine since the days of antiquity. When shipped off to boarding school, young Cooke found that his asthma disappeared after 24 hours, but his vacations were a nightmare. So he experienced firsthand, at an early age, the environmental factors of asthma. What did doctors have to say about asthma in the 1890s when Robert Cooke was battling this disease? 1 reviewed the subject in Osler’s Principles and practice of medicine, published in 1894.* Some passing mention is made of an association between hay fever and asthma, but, in the summary of the section on asthma, Osler says, “Briefly stated, bronchial asthma is a neurotic affection characterized by hyperemia and Vol. 60, No. 1, pp. l-7
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turgescence of the mucosa of the lower bronchial tubes and a peculiar exudate of mucin. The attacks may be due to direct irritation of the bronchial mucosa or may be induced reflexly, by irritation of the nasal mucosa and indirectly, too, by reflex influences, from stomach, intestines, or genital organs.” On treatment for asthma, Osler has little to contribute, although he does note that freedom from attacks can occur when a person moves from one part of the country to another. In some ways Osler’s advice to the physician and to the patient with asthma is much less helpful than the words of the twelfth century physician, Maimonides, in his Treatise on asthma.3 Maimonides was born in Cordova, Spain, in 1135 and was educated in medicine by Arabic teachers. At 28 he settled in Cairo where his fame spread as a philosopher as well as a physician. When Maimonides was appointed physician of the Court of Saladin, one of his responsibilities was to treat Saladin’s son and successor who was afflicted with asthma. Maimonides’ Treatise includes instructions to the Prince for the management of his disease. Maimonides begins his Treatise on asthma in all candor. He says, “I have no magic cure to report.” The Prince tells Maimonides that many prior physicians have prescribed remedies of all kinds-each guaranteed to cure-but not Maimonides. He gives the Prince some useful advice of a general nature for the management of asthma and then lays down dietary measures and general rules of conduct. In a time when physicians were surrounded by ignorance and relied principally on magic, Maimonides’ perceptions are refreshing. He says, “The clever skilled physician is versed in the fundamentals of medicine and thinks twice before he decides how to bring about a patient’s relief. Such a man always relies on the work of nature and keeps her from going lazy.” It is a strange accident of history that neither Maimonides, in the twelfth century, nor Osler, in the nineteenth century, employed a drug that had been used in ancient Rome for relief of asthmatic symptams. I refer here to ephedrine, a product from a plant widely distributed in the Mediterranean. We learn about ephedrine and its use in Roman times from Pliny the Elder, a compulsive man obsessed with the collection of odd bits of data, from the history of grammar to the use of the javelin4 In two years he wrote, almost without interruption, his only book, Historia Naturalis. In this he has a number of interesting things to say on the world of physics, on mankind, on food and wine, on natural history. In these matters he is often informative, frequently witty. But on medicine, Pliny is less useful. Still on occa-
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sion he strikes home. For example, he mentions a plant that some call ephedron4: “The Greeks hold various views about this plant assuring us that so wonderful is its nature, its mere touch staunches a patient’s bleedings.” Taken in sweet wine, it is used for asthma. Clearly ephedrine from the ephedra plant was widely used by Roman physicians, even though modem history holds that the drug was discovered by the Chinese. A recent textbook on pharmacology states, “Ephedrine was used in China for 5000 years before being introduced into Western medicine in 1924.“5 In 1924 it was, in fact, introduced by Dr. Carl Schmidt, an American physician who worked at the Peking Union Medical College.4 He was testing some of the traditional Chinese herbs in the hope of discovering new medications. Among these was an extract of ephedra known in China as Ma Hung. So there are treasures buried in the past, but there is an irony in this story.4 Dr. Schmidt traveled all the way to China to sift through hundreds of herbs to find possible new remedies. There he found ephedrine, but he might very well have ordered it from a chemical catalog. The drug had already been crystallized, indeed synthesized in 1887. Its chemical structure is similar to epinephrine, but until 1924 it was set aside ontheshelfasatoxicsubstancebecausehighlypotentsolutions injected into animals caused immediate death. So there was a medication on the shelf, purified and crystallized in 1887, that could have relieved young Robert Cooke’s first asthmatic attack at the age of 7. Later, of course, epinephrine was introduced, and Dr. Cooke remarked how often epinephrine injections had relieved his asthma. In fact, epinephrine played a lifesaving role in the third event which was to form Dr. Cooke’s interest in allergy. In 1908, when he was working as a young physician at Bellevue, he volunteered to do an emergency tracheotomy on a ward patient. The next day, the bacteriologic cultures revealed that the patient had diphtheria. Dr. Cooke therefore needed passive immunization with diphtheria antitoxin. Such treatment was known to have potential danger. Theobold Smith had written on the sensitivity of man and animals to this serum, and he had used Richet’s term anaphylaxis to describe adverse reactions after serum therapy. But when Dr. Cooke received the antidiphtheria horse serum there was no conception of the relationship between the shock of serum sickness on the one hand and asthma from contact with horses on the other. Before administration of the horse antitoxin was completed, Dr. Cooke was gasping for breath. Epinephrine was immediately given, and artificial respiration was applied. He regained consciousness 10 hours later.
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The rest is history-a long, productive life, and many discoveries, two of which I have already mentioned, the inheritance of atopy and the demonstration of blocking antibody. There is one more vignette from those early years of allergy which should be told here, for it cautions all of us who might grow too confident about our ability to prophesy the future of medicine. The story concerns Dr. Arthur F. Coca with whom Dr. Cooke worked in close association. Few here, perhaps, know that it was largely through the vigorous efforts of Dr. Coca that the American .4ssociation of Immunologists was organized in New York City in 1914. Dr. Coca then began a one-man drive to establish the Journal of Immunology, and he ultimately achieved this goal with the appearance of the first issue in February, 1916. In the establishment of the Journal, Dr. Coca met unexpected resistance from none other than Theobold Smith, who informed him that immunology was a dead science--that its day was over. I have not researched the matter, but one can imagine why Th.eobold Smith, a scholar of infection and immunity, predicted the end of the road for immunology. Infections were being cured with antiserum, and one suspects that in Dr. Smith’s mind it was only a matter of time before all infections would be controlled by immunizations. In short, he must have thought fundamental research was over and that it was time to prol:eed with application. But Dr. Coca and his colleagues, such as Dr. Cooke, had a different perception of the future. They saw immunology as a science basic to the study of allergic diseases and they struggled in those early years to relate the fundamental processes of immunology to pathogenesis. They saw too the need for some sensible classification of diseases related to immunologic phenomena. In 1923, for example, Coca and Cooke published in the Journal of Immunology, a paper on the classification of hypersensitiveness. 6 This classification is shown in Fig. 1. An early and obviously primitive effort, this classification has grown much more sophisticated over the years. But it does include a word which has remained with us. The word is atquy. This term was suggested by Professor Edward Pe:rry of Columbia University and it comes from the Greek, utopia or (yronL(y-in the sense of a strange di:sease.7 With later usage, atopy was confined to diseases in the hay fever and asthma group. On that same evening in 1958, at the Hotel Pierre when Dr. Cooke told of his early years in medicine, one of my predecessors, Dr. Justin Andrews, the Director of the National Institute of Allergy and Infectious Diseases, also spoke briefly. He noted that the
3
Hypersensitiveness I Normal 1. 2.
Dermatitis venenata Serum sickness (ordinary)
I Abnormal 1. 2. 3.
Anaphylaxis Hypersensitiveness infection Atopy (070711a)
of
FIG. 1. The classification of the phenomena of hypersensitiveness. (Adapted from Coca, A. F., and Cooke, R. A.: J. Immunol. 8:163, 1923.)
Institute had been known previously as the National Institute of Microbiology, but that just two years previously, a change had been made. “It was decided,” said Dr. Andrews, “that the time had come when allergy and immunology should be given a much more prominent place in the research stimulation which is our principal function. So the name of the Institute was changed to the National Institute of Allergy and Infectious Diseases. ” That was nearly 20 years ago. Today research of the past two decades has placed the practice of allergy on sure foundations. It is time now to build a superstructure of basic and clinical research. That is why a national program for asthma and other allergic diseases is an idea whose time has come. Let me discuss briefly with you my reasons for believing this is so. I first raised this issue last December when I met with the Directors of NIAID’s Asthma and Allergic Disease Centers and their colleagues. I said then that the time has come for two reasons. First, the science base is now ready to support a vigorous attack on asthma and other allergies. Immunology is now reinforced with pharmacology, physiology, molecular and cell biology, genetics, and biochemistry. We are learning about the amplification systems and the effector processes that are coupled to immunologic reactions. From this knowledge will flow a new immunopharmacology as well as more precise means to manipulate desensitization. Second, the time has come for a national program for asthma and other allergic diseases because these illnesses have, for too long, suffered benign neglect-not by this group of physicians, I hasten to add, but by the public and by some members of the medical community who have generally perceived allergies as little more than inconveniences. We must set to right this misapprehension. Allergies cause great suffering and hardship. Current estimates are that 35 million Americans have an allergic disease.” This is 17% of our population or about 1 in 6 persons. Asthma alone accounts for almost 9 million of these patients and causes over 2,000 deaths every year. These figures do not take into consideration other deaths that occur in which asthma is an underlying
4 Krause
cause-deaths attributed to pneumonia, bronchitis, and emphysema. And the cost-what do the allergic diseases cost every year? It is difficult to say. We have too few data. In 1975, patients with allergies made at least 43 million visits to doctors’ offices-so ambulatory care and medicine must cost over one billion dollars a year. To these costs must be added expenses for hospitalization and indirect costs due to days lost from school and from work. Asthma is one of the most common causes of school absenteeism. When it is all added up, asthma and allergic diseases cost this country billions of dollars each year, billions of dollars. And what do we spend on research? Only 10 million dollars directly on asthma and other allergic diseases. You and I and others must publicize this story and you and I and others must plan a campaign which will influence this dismal picture. Because the science is right, because the time is right, because there is a new group of young people schooled in medicine and disciplined in the biologic sciences, I say the time has come for a national program to conquer asthma and other allergic diseases. The program must be a partnership, a partnership with the medical investigator, the practitioner, the patient, the concerned citizen, a partnership between the agencies of government and the lay and professional organizations with special concern for the allergic patient. I have suggested four components for a national program for asthma and the other allergic diseases. These are as follows: (1) Basic research on the biology and biochemistry of the immune system. (2) Research on the pathophysiology, diagnosis, treatment, and prevention of allergic processes. (3) Training programs to increase the number of physicians and researchers who specialize in allergy, and to expand opportunities for continuing medical education in asthma and allergy. (4) A program to hasten the transfer of existing and new knowledge to the care of the patient. It is my intention to dwell briefly on each of these four issues. The$rst, basic research on the biology of the immune system, is a matter that was thoroughly reviewed by our Institute’s Task Force on Immunology and Diseases. The Task Force, under the leadership of Dr. Bernard Amos, and our staff have prepared a report and a series of important recommendations on the research opportunities in immunology. These recommendations will be published in the near future. I believe they can serve as the basis for a discussion on the needs of basic immunologic research, the research which is the foundation for future advances in allergy. Let me say only this about basic research. Evidence is emerging that the eosinophil and IgE are intimately
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involved both in allergic phenomena and in immunity to parasitic infections. Do IgE and eosinophils share a common destiny in the immune processes of allergy and parasitic diseases? To put it another way, will research on parasitic immunity shed light on the unknown pathways of allergic processes, and contrariwise will allergy research reveal the basis for parasitic immunity? The second component of a national program must focus on the need for specific research on the pathogenesis, diagnosis, treatment, and prevention of asthma and other allergic diseases. In this endeavor, we should, of course, build upon recent research achievements. There has been substantial progress in our understanding of each of four different types of allergic diseases: 1. In the case of atopic allergy, it is now recognized that the cause of tissue injury is the release of histamine and other components from mast cells, with the interaction of antigen and the IgE class of antibody. 2. In contact hypersensitivity, inflammation depends upon the interaction of the chemical agent and a self component leading to sensitization of lymphocytes and release of inflammatory lymphokines. 3. For the serum sickness prototype, it has been shown that the deposition of antigen-antibody complexes, followed by activation of the complement cascade, leads to inflammatory processes. 4. Disorders of the regulatory system can also mediate inflammation. An important example is hereditary angioedema in which either absence of Cl esterase or presence of an abnormal enzyme leads to inappropriate formation of inflammatory materials. These advances open up clinical research opportunities. I have in mind, particularly, the improvement of techniques employed for accurate diagnosis and subsequent immunotherapy of allergies due to the common allergens. Purified antigenic fractions of these allergens are needed as reagents: (1) to improve the specificity of skin tests; (2) to improve diagnosis by sensitive reliable quantitative in vitro assays of specific IgE class antibodies; and (3) to develop new in vivo respiratory tract inhalation tests to pinpoint etiologic factors in asthma and the allergic diseases. With such new diagnostic methods and reagents in hand, a much more rational approach can be taken for specific immunotherapy. We are all aware of the current inadequacies of desensitization methodology. To catalyze this basic and clinical research effort, and as part of the National Program, the NIAID will organize a Task Force on Asthma and Other Allergic Diseases, similar to our former Task Force on Immunology and Diseases. This Task Force on Asthma and Other Allergic Diseases will address a broad
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series of issues with panels working on various topics including (I) socioeconomic factors, (2) basic immunologic mechanisms in health and disease, (3) allergic diseases, the state of the art, and (4) immunologic and allergic aspects of other diseases. We are moving rapidly to get this Task Force underway, and we seek the broadest possible participation. Third, we must assessand meet the need for physicians and other medical personnel who specialize in research and practice pertaining to allergic diseases. If more physicians skilled in allergy are needed, we must develop a rational plan for increasing the number. Instruction in the principles of allergy must be strengthened in our medical curricula, and our house staffs must be more throughly trained. And let us remember, .also, the need for continuing medical education of practicing physicians-the specialist as well as the gene:ralist. In September, 1976, Dr. Philip Norman, as head of a group of :mdividual scientists, submitted a committee report on physician manpower in allergy and immunology to the General Accounting Office. It is a fine report and I hope it receives thorough study. The report note:; that there are 2,677 practitioners of allergy. This turns out to be only one specialist for 12,000 patients with allergic diseases. It is estimated that we have less than one-half the number of allergists, specialized internists, pediatricians, and dermatologists required to provide adequate medical care for asthma and other allergic diseases. The report is gloomy on the prospects of achieving the optimum number of specialized physicians in view of present, inadequate training programs. But should we be gloomy? Instead, should we not act to rectify these deficiencies? We should and we can. One aipproach which could be employed to increase the number of physicians with special training in allergy would be to strengthen the NIAID program for Asthma and Allergic Disease Centers. The Centers could place emphasis on a variety of allergic diseases, both for training purposes and for the development of new knowledge. At this Congress Dr. Kurk Bloch discussed the future practice of allergy. He sees practice diversified among the other specialties. On this there will be debate. But all of us can agree that all physicians, whatever their background, with responsibility for asthma and other allergies must have thorough training. The fourth element of a national program pertains to the process of translation from research to practice. A difficult matter this-translating new basic research knowledge into practical application and then disseminating new methods of diagnosis and treatment
5
I
I MEDICAL NEED
~i--~l FIG. 2. A systems analysis portraying the process leading from medical need to basic research to application research and develooment.
through the practicing community. This chain of events, from laboratory bench to bedside and doctor’s office, has been referred to as the transfer of knowledge and there has been much talk on how to facilitate this process. There has been much talk, also, on a translation gap between basic research and the use of medical discoveries by the health care delivery system. Let me say as an aside that viscosity in the translation system is healthy. It provides a pause in the process. There is no greater protector of the patient than the physician with a healthy skepticism about the possible benefits of new-fangled ideas. Remember Maimonides admonition-the clever physician relies on the work of nature and keeps her from getting lazy. I have no words of wisdom on this complex tangle of issues pertaining to translation, but we must address them, and we must sort them out. There is a common feeling among members of the public and among those in the political arena that a lag exists between discovery and application. We at the NIH, and those investigators supported by the NIH throughout this country, must be sure that we maintain open lines of communication to the practicing physician. And we must attend to this translation business by all manner of communication. Such matters cannot be explored fully here. But for a start, I believe we should examine carefully the processes of discovery and the means by which discovery is translated into practice. Here I would make three points. First, translation from theory to practice is a two-way process, similar to a chemical equation which is portrayed as an equilibrium with arrows pointing in both directions. Research yields new opportunities for patient care, but in the reverse direction, the needs of clinical medicine modulate the dimensions of research. Second, we can arrive at a defensible position on the complex issues concerning the transfer of knowl-
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edge only through achievement of a consensus among laboratory scientists, the practicing physician, and the general public. There must be a broad dialogue and thorough public debate. Third, translation of theory into practice requires an active process to disseminate new information. In a systems analysis, as shown in Fig. 2, the processes of translation can be depicted as a triangulation among medical need, basic research, and the development of new medical interventions. But the dynamics of the process, the information flow, must be represented by arrows pointing in both directions as shown in the figure. Research does not progress by itself, where thought and logic proceed in a vacuum. When cut off from reality, research can spiral into a sterile atmosphere circumscribed by its own dimension, as, for example, the preoccupation with syllogistic logic in the Middle Ages. There is a resonance between medical need and basic research. Basic research leads to application but application feeds back into research, a modulating force. In turn, application leads to a new intervention which is offered to the medical community to satisfy a need for diagnosis, treatment, or prevention. But before final acceptance, the new intervention is improved and modified so that finally it most nearly fits the need as perceived by medical practice. How often in medical discovery do we see this interplay between need on the one hand and research and application on the other. Dubos gives a graphic illustration of this in The Professor, the Institute and DNA, a recent book on the life of Oswald Avery.s Of special interest to us in clinical medicine are the sections of the book dealing with pneumococcal pneumonia. In 19 16, Dochez and Avery discovered specific soluble substance, the capsular material of the pneumococcus. Soon thereafter they detected specific soluble substance in the blood and urine of patients during the acute phase of pneumococcal pneumonia. Later Avery developed a clinical test on the urine which permitted the rapid identification of the pneumococcal type even before the culture was recovered from the patient. This test made use of the fact that the urine contains the specific soluble substance during the acute phase of pneumococcal pneumonia. An important advance, this test, in the days of antiserum therapy. Early diagnosis meant early treatment with antiserum and greater likelihood of success. Avery recognized that, in some way, there was tremendous importance in specific soluble substance. Every time he had a chance, he would agitate a tube of it in front of Michael Heidelberger and say, “Michael, the whole secret of bacterial specificity is
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in this little tube. When will you work on it?” Finally out of interest and friendliness, Heidelberger joined Avery and began the long, hard job of working out the chemistry of the pneumococcal polysaccharides and of developing and perfecting the type specific antisera used to treat patients with pneumococcal pneumonia. There was much trial and error as specific antisera were passed on for use in clinical practice. Those in clinical practice saw the imperfections in antiserum therapy, and they said to researchers, “Your treatment is good gentlemen, but not good enough.” Finally there came vaccines made from highly purified polysaccharides to prevent pneumococcal pneumonia by active immunization. But by that time, penicillin had overtaken the immunization approach. Now the matter did not end there. Dr. Robert Austrian and others are still probing the usefulness of pneumococcal vaccines in those who are most susceptible to pneumococcal infections, patients with sickle cell anemia, or who have had a splenectomy. Clinical trials are now under way to prove the efficacy of the pneumococcal vaccine in these individuals. So the triangulation of the pneumococcal saga is complete. The medical need was perceived in pneumococcal pneumonia. The basic research was done which laid the foundation of immunochemistry on the one hand and the development of pneumococcal antiserum and pneumococcal vaccines on the other. Finally, even in this day of antibiotics, for a large group of patients there is still a place for the prevention of pneumococcal infections through active immunization with purified polysaccharides. Now, second, on this business of translating discovery into practice, we must raise the issue of consensus. Agreement-consensus, if you will, must be reached on any new medical procedure for the management, diagnosis, and treatment of asthma and allergic diseases. Agreement requires consensus by all appropriate interested parties-the government agencies, the profession, the allergy specialists, the professional societies, and finally the patient. I do not want to speak only in generalities. In our field, on what questions do we need agreement or consensus? Though the hour is late, I should like to suggest two examples: 1. There is a need for general criteria for the diagnosis of asthma. Clinical asthma is due to several etiologic factors and effective management, and, indeed, specific treatment depends upon an etiologic classification. 2. It is necessary to establish adequate diagnostic criteria for penicillin allergy based on objective testing with new methods. Currently treatment is withheld from many patients with infections for whom
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penicillin is the drug of choice, because of a mistaken impression that a prior drug reaction is representative of true allergy. These matters require broad discussion to arrive at a consensus. Now, at last, on this whole matter of translation there comes the process of dissemination-the dissemination of new information to the physician, and the dissemination of general knowledge and advice to the patient. This Congress is a fine example of how information can be disseminated to the physicians. Other physician-oriented programs are locally organized, tailored to suit the special needs of an area. But we must also have dissemination programs for the public and for patients with asthma and other allergic diseases. In this effort we must mobilize our resources and our people-lay leaders as well as physicians. There are already several vigorous groups and societies dedicated to assistance for patients with asthma and allergies, to research, and to professional education. But we must recruit others and encourage more local participation. Beyond this, we must enlist the help and participation of other agencies-the PTA, the Associations of Christian and Hebrew Young Men and Women, for examples. While the responsibility of NIAID is basic and clinical research, as physicians we are prepared to work with you in these community efforts to assist patients with asthma and allergic diseases. And we at the NIH need the help of the community in identifying issues which require the attention of the research enterprise. Before I close let me say that you have a home in Bethesda at the NIH. NIAID is your Institute. Get to know us, and let us get to know you. Stop by and visit. Tell us your views. We have a fine clinical research program in allergy headed by Dr. Allen Kaplan and Dr. Michael Kaliner. A National Program for Asthma and the Other Al-
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7
lergic Diseases is an idea whose time has come. And we will succeed in the work ahead. I have faith in that. I know the dimensions of your commitment and at this Congress I have perceived another reservoir of power. During the social hours I have talked with your wives-with Mrs. Leonard Bernstein, of Cincinnati, for example, and Mrs. Raymond Slavin, of St. Louis. They represent that reservoir of power. Their enthusiasm for what can and must be done is contagious. They speak for the families, for the people of this country. In this National Program we need basic research on the immune system, we need clinical research on the special problems of asthma and other allergic diseases, we need diverse training opportunities for research and practice. And, finally, all of us need to address ourselves to the translation of existing and new knowledge into new ways to care for the patient.
REFERENCES 1. Siegal, S., editor: Proceedings, New York Allergy Society, February 27, 1958, N. Y. State J. Med. 59:289, 1959. 2. Osler, W.: The principles and practices of medicine, New York, 1894, D. Appleton and Company. 3. Muntner, S., editor: Treatise on asthma-The medical writings of Moses Maimonides, Philadelphia, 1963, J. B. Lippincott Co. 4. Majno, G.: The healing hand-man and wound in the ancient world, Cambridge, 1975, Harvard University Press. 5. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, ed. 4, London and Toronto, 1970, Macmillan Publishing Co., Inc. 6. Coca, A. F., and Cooke, R. A.: On the classification of the phenomena of hypersensitiveness, J. Immunol. 8:163, 1923. 7. Samter, M., editor: Excerpts from classics in allergy, Columbus, 1969, Ross Laboratories. 8. Schachter, J.: Measurement of the prevalence of respiratory allergies by interview questionnaire, J. ALLERGY CLIN. IMMUNOL. 55:249, 1975. 9. DuBos, R. J.: The professor, the institute and DNA, New York, 1976, The Rockefeller University Press.
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The time has come* Richard
M. Krause, M.D. Bethesda, Md.
Dr. Patterson, Members of the Robert A. Cooke Alumni Association, Members of the Academy, participants of this Congress, and guests: It is a special honor for me to give the Robert A. Cooke Lecture for 1977 and to receive this medallion. I hope you will sense the excitement with which 1 put before you this morning a very special proposal. Just before Victor Hugo died on May 22, 1885, he wrote in his diary, “There is one thing stronger than all the armies in the world; and that is an idea whose time has come.” That is what I want to talk about-an idea whose time has co:me. And that idea is a National Program for Asthma and Other Allergic Diseases. During this hour I can provide no more than a rough sketch of such a program. Indeed, what I say will be of little consequence compared to the contributions all of you can make to this effort. If you at this Congress of Allergy and Immunology decide that a National Program for Asthma and Other Allergies is an idea whose time has come, then it will be left to all of us to work matters out--what to do and how to do it. As a possible backdrop for this proposed program, let me first s,aya few words about the life and times of Robert A. Cooke. He must have been a man of boundless energy and vitality, vigorous, inquisitive, From the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Presented at the American Congress of Allergy and Immunology, March 28, 1977, Americana Hotel, New York, N. Y. Reprint requests to: Dr. Richard M. Krause, Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rldg. 31, 7Al l-C, Bethesda, Md. 20014. *The Robert A. Cooke Memorial Lecture sponsored by The Robert A. Cooke Alumni Association in cooperation with the American Academy of Allergy.
alert, methodical, compassionate; in sum, a true physician. Of his many discoveries, two stand out; first, his demonstration of blocking antibody after desensitization, and, second, his findings on the inheritance of atopy. How did Dr. Cooke’s interest in allergy start? I found the answer to this question in an address which he gave at a banquet held in his honor at the Hotel Pierre, February 27, 1958, two years before his death. I abstract briefly from that address. i Dr. Cooke noted three factors which started him in a field which was not even called allergy in those days. First, there was his inheritance, for which he claimed no responsibility. He was a direct descendant of three generations of physicians. As he commented, “We cannot get away from those determining and determined little genes and so it is with me.” The second factor which fostered his interest in medicine and allergy was that from the age of 8 he was an asthmatic child with little in the way of relief except vomiting after syrup of ipecac and squill. Epinephrine was not yet known in 1890 and, as I shall mention shortly, ephedrine has been lost to medicine since the days of antiquity. When shipped off to boarding school, young Cooke found that his asthma disappeared after 24 hours, but his vacations were a nightmare. So he experienced firsthand, at an early age, the environmental factors of asthma. What did doctors have to say about asthma in the 1890s when Robert Cooke was battling this disease? 1 reviewed the subject in Osler’s Principles and practice of medicine, published in 1894.* Some passing mention is made of an association between hay fever and asthma, but, in the summary of the section on asthma, Osler says, “Briefly stated, bronchial asthma is a neurotic affection characterized by hyperemia and Vol. 60, No. 1, pp. l-7
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turgescence of the mucosa of the lower bronchial tubes and a peculiar exudate of mucin. The attacks may be due to direct irritation of the bronchial mucosa or may be induced reflexly, by irritation of the nasal mucosa and indirectly, too, by reflex influences, from stomach, intestines, or genital organs.” On treatment for asthma, Osler has little to contribute, although he does note that freedom from attacks can occur when a person moves from one part of the country to another. In some ways Osler’s advice to the physician and to the patient with asthma is much less helpful than the words of the twelfth century physician, Maimonides, in his Treatise on asthma.3 Maimonides was born in Cordova, Spain, in 1135 and was educated in medicine by Arabic teachers. At 28 he settled in Cairo where his fame spread as a philosopher as well as a physician. When Maimonides was appointed physician of the Court of Saladin, one of his responsibilities was to treat Saladin’s son and successor who was afflicted with asthma. Maimonides’ Treatise includes instructions to the Prince for the management of his disease. Maimonides begins his Treatise on asthma in all candor. He says, “I have no magic cure to report.” The Prince tells Maimonides that many prior physicians have prescribed remedies of all kinds-each guaranteed to cure-but not Maimonides. He gives the Prince some useful advice of a general nature for the management of asthma and then lays down dietary measures and general rules of conduct. In a time when physicians were surrounded by ignorance and relied principally on magic, Maimonides’ perceptions are refreshing. He says, “The clever skilled physician is versed in the fundamentals of medicine and thinks twice before he decides how to bring about a patient’s relief. Such a man always relies on the work of nature and keeps her from going lazy.” It is a strange accident of history that neither Maimonides, in the twelfth century, nor Osler, in the nineteenth century, employed a drug that had been used in ancient Rome for relief of asthmatic symptams. I refer here to ephedrine, a product from a plant widely distributed in the Mediterranean. We learn about ephedrine and its use in Roman times from Pliny the Elder, a compulsive man obsessed with the collection of odd bits of data, from the history of grammar to the use of the javelin4 In two years he wrote, almost without interruption, his only book, Historia Naturalis. In this he has a number of interesting things to say on the world of physics, on mankind, on food and wine, on natural history. In these matters he is often informative, frequently witty. But on medicine, Pliny is less useful. Still on occa-
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sion he strikes home. For example, he mentions a plant that some call ephedron4: “The Greeks hold various views about this plant assuring us that so wonderful is its nature, its mere touch staunches a patient’s bleedings.” Taken in sweet wine, it is used for asthma. Clearly ephedrine from the ephedra plant was widely used by Roman physicians, even though modem history holds that the drug was discovered by the Chinese. A recent textbook on pharmacology states, “Ephedrine was used in China for 5000 years before being introduced into Western medicine in 1924.“5 In 1924 it was, in fact, introduced by Dr. Carl Schmidt, an American physician who worked at the Peking Union Medical College.4 He was testing some of the traditional Chinese herbs in the hope of discovering new medications. Among these was an extract of ephedra known in China as Ma Hung. So there are treasures buried in the past, but there is an irony in this story.4 Dr. Schmidt traveled all the way to China to sift through hundreds of herbs to find possible new remedies. There he found ephedrine, but he might very well have ordered it from a chemical catalog. The drug had already been crystallized, indeed synthesized in 1887. Its chemical structure is similar to epinephrine, but until 1924 it was set aside ontheshelfasatoxicsubstancebecausehighlypotentsolutions injected into animals caused immediate death. So there was a medication on the shelf, purified and crystallized in 1887, that could have relieved young Robert Cooke’s first asthmatic attack at the age of 7. Later, of course, epinephrine was introduced, and Dr. Cooke remarked how often epinephrine injections had relieved his asthma. In fact, epinephrine played a lifesaving role in the third event which was to form Dr. Cooke’s interest in allergy. In 1908, when he was working as a young physician at Bellevue, he volunteered to do an emergency tracheotomy on a ward patient. The next day, the bacteriologic cultures revealed that the patient had diphtheria. Dr. Cooke therefore needed passive immunization with diphtheria antitoxin. Such treatment was known to have potential danger. Theobold Smith had written on the sensitivity of man and animals to this serum, and he had used Richet’s term anaphylaxis to describe adverse reactions after serum therapy. But when Dr. Cooke received the antidiphtheria horse serum there was no conception of the relationship between the shock of serum sickness on the one hand and asthma from contact with horses on the other. Before administration of the horse antitoxin was completed, Dr. Cooke was gasping for breath. Epinephrine was immediately given, and artificial respiration was applied. He regained consciousness 10 hours later.
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The rest is history-a long, productive life, and many discoveries, two of which I have already mentioned, the inheritance of atopy and the demonstration of blocking antibody. There is one more vignette from those early years of allergy which should be told here, for it cautions all of us who might grow too confident about our ability to prophesy the future of medicine. The story concerns Dr. Arthur F. Coca with whom Dr. Cooke worked in close association. Few here, perhaps, know that it was largely through the vigorous efforts of Dr. Coca that the American .4ssociation of Immunologists was organized in New York City in 1914. Dr. Coca then began a one-man drive to establish the Journal of Immunology, and he ultimately achieved this goal with the appearance of the first issue in February, 1916. In the establishment of the Journal, Dr. Coca met unexpected resistance from none other than Theobold Smith, who informed him that immunology was a dead science--that its day was over. I have not researched the matter, but one can imagine why Th.eobold Smith, a scholar of infection and immunity, predicted the end of the road for immunology. Infections were being cured with antiserum, and one suspects that in Dr. Smith’s mind it was only a matter of time before all infections would be controlled by immunizations. In short, he must have thought fundamental research was over and that it was time to prol:eed with application. But Dr. Coca and his colleagues, such as Dr. Cooke, had a different perception of the future. They saw immunology as a science basic to the study of allergic diseases and they struggled in those early years to relate the fundamental processes of immunology to pathogenesis. They saw too the need for some sensible classification of diseases related to immunologic phenomena. In 1923, for example, Coca and Cooke published in the Journal of Immunology, a paper on the classification of hypersensitiveness. 6 This classification is shown in Fig. 1. An early and obviously primitive effort, this classification has grown much more sophisticated over the years. But it does include a word which has remained with us. The word is atquy. This term was suggested by Professor Edward Pe:rry of Columbia University and it comes from the Greek, utopia or (yronL(y-in the sense of a strange di:sease.7 With later usage, atopy was confined to diseases in the hay fever and asthma group. On that same evening in 1958, at the Hotel Pierre when Dr. Cooke told of his early years in medicine, one of my predecessors, Dr. Justin Andrews, the Director of the National Institute of Allergy and Infectious Diseases, also spoke briefly. He noted that the
3
Hypersensitiveness I Normal 1. 2.
Dermatitis venenata Serum sickness (ordinary)
I Abnormal 1. 2. 3.
Anaphylaxis Hypersensitiveness infection Atopy (070711a)
of
FIG. 1. The classification of the phenomena of hypersensitiveness. (Adapted from Coca, A. F., and Cooke, R. A.: J. Immunol. 8:163, 1923.)
Institute had been known previously as the National Institute of Microbiology, but that just two years previously, a change had been made. “It was decided,” said Dr. Andrews, “that the time had come when allergy and immunology should be given a much more prominent place in the research stimulation which is our principal function. So the name of the Institute was changed to the National Institute of Allergy and Infectious Diseases. ” That was nearly 20 years ago. Today research of the past two decades has placed the practice of allergy on sure foundations. It is time now to build a superstructure of basic and clinical research. That is why a national program for asthma and other allergic diseases is an idea whose time has come. Let me discuss briefly with you my reasons for believing this is so. I first raised this issue last December when I met with the Directors of NIAID’s Asthma and Allergic Disease Centers and their colleagues. I said then that the time has come for two reasons. First, the science base is now ready to support a vigorous attack on asthma and other allergies. Immunology is now reinforced with pharmacology, physiology, molecular and cell biology, genetics, and biochemistry. We are learning about the amplification systems and the effector processes that are coupled to immunologic reactions. From this knowledge will flow a new immunopharmacology as well as more precise means to manipulate desensitization. Second, the time has come for a national program for asthma and other allergic diseases because these illnesses have, for too long, suffered benign neglect-not by this group of physicians, I hasten to add, but by the public and by some members of the medical community who have generally perceived allergies as little more than inconveniences. We must set to right this misapprehension. Allergies cause great suffering and hardship. Current estimates are that 35 million Americans have an allergic disease.” This is 17% of our population or about 1 in 6 persons. Asthma alone accounts for almost 9 million of these patients and causes over 2,000 deaths every year. These figures do not take into consideration other deaths that occur in which asthma is an underlying
4 Krause
cause-deaths attributed to pneumonia, bronchitis, and emphysema. And the cost-what do the allergic diseases cost every year? It is difficult to say. We have too few data. In 1975, patients with allergies made at least 43 million visits to doctors’ offices-so ambulatory care and medicine must cost over one billion dollars a year. To these costs must be added expenses for hospitalization and indirect costs due to days lost from school and from work. Asthma is one of the most common causes of school absenteeism. When it is all added up, asthma and allergic diseases cost this country billions of dollars each year, billions of dollars. And what do we spend on research? Only 10 million dollars directly on asthma and other allergic diseases. You and I and others must publicize this story and you and I and others must plan a campaign which will influence this dismal picture. Because the science is right, because the time is right, because there is a new group of young people schooled in medicine and disciplined in the biologic sciences, I say the time has come for a national program to conquer asthma and other allergic diseases. The program must be a partnership, a partnership with the medical investigator, the practitioner, the patient, the concerned citizen, a partnership between the agencies of government and the lay and professional organizations with special concern for the allergic patient. I have suggested four components for a national program for asthma and the other allergic diseases. These are as follows: (1) Basic research on the biology and biochemistry of the immune system. (2) Research on the pathophysiology, diagnosis, treatment, and prevention of allergic processes. (3) Training programs to increase the number of physicians and researchers who specialize in allergy, and to expand opportunities for continuing medical education in asthma and allergy. (4) A program to hasten the transfer of existing and new knowledge to the care of the patient. It is my intention to dwell briefly on each of these four issues. The$rst, basic research on the biology of the immune system, is a matter that was thoroughly reviewed by our Institute’s Task Force on Immunology and Diseases. The Task Force, under the leadership of Dr. Bernard Amos, and our staff have prepared a report and a series of important recommendations on the research opportunities in immunology. These recommendations will be published in the near future. I believe they can serve as the basis for a discussion on the needs of basic immunologic research, the research which is the foundation for future advances in allergy. Let me say only this about basic research. Evidence is emerging that the eosinophil and IgE are intimately
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involved both in allergic phenomena and in immunity to parasitic infections. Do IgE and eosinophils share a common destiny in the immune processes of allergy and parasitic diseases? To put it another way, will research on parasitic immunity shed light on the unknown pathways of allergic processes, and contrariwise will allergy research reveal the basis for parasitic immunity? The second component of a national program must focus on the need for specific research on the pathogenesis, diagnosis, treatment, and prevention of asthma and other allergic diseases. In this endeavor, we should, of course, build upon recent research achievements. There has been substantial progress in our understanding of each of four different types of allergic diseases: 1. In the case of atopic allergy, it is now recognized that the cause of tissue injury is the release of histamine and other components from mast cells, with the interaction of antigen and the IgE class of antibody. 2. In contact hypersensitivity, inflammation depends upon the interaction of the chemical agent and a self component leading to sensitization of lymphocytes and release of inflammatory lymphokines. 3. For the serum sickness prototype, it has been shown that the deposition of antigen-antibody complexes, followed by activation of the complement cascade, leads to inflammatory processes. 4. Disorders of the regulatory system can also mediate inflammation. An important example is hereditary angioedema in which either absence of Cl esterase or presence of an abnormal enzyme leads to inappropriate formation of inflammatory materials. These advances open up clinical research opportunities. I have in mind, particularly, the improvement of techniques employed for accurate diagnosis and subsequent immunotherapy of allergies due to the common allergens. Purified antigenic fractions of these allergens are needed as reagents: (1) to improve the specificity of skin tests; (2) to improve diagnosis by sensitive reliable quantitative in vitro assays of specific IgE class antibodies; and (3) to develop new in vivo respiratory tract inhalation tests to pinpoint etiologic factors in asthma and the allergic diseases. With such new diagnostic methods and reagents in hand, a much more rational approach can be taken for specific immunotherapy. We are all aware of the current inadequacies of desensitization methodology. To catalyze this basic and clinical research effort, and as part of the National Program, the NIAID will organize a Task Force on Asthma and Other Allergic Diseases, similar to our former Task Force on Immunology and Diseases. This Task Force on Asthma and Other Allergic Diseases will address a broad
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series of issues with panels working on various topics including (I) socioeconomic factors, (2) basic immunologic mechanisms in health and disease, (3) allergic diseases, the state of the art, and (4) immunologic and allergic aspects of other diseases. We are moving rapidly to get this Task Force underway, and we seek the broadest possible participation. Third, we must assessand meet the need for physicians and other medical personnel who specialize in research and practice pertaining to allergic diseases. If more physicians skilled in allergy are needed, we must develop a rational plan for increasing the number. Instruction in the principles of allergy must be strengthened in our medical curricula, and our house staffs must be more throughly trained. And let us remember, .also, the need for continuing medical education of practicing physicians-the specialist as well as the gene:ralist. In September, 1976, Dr. Philip Norman, as head of a group of :mdividual scientists, submitted a committee report on physician manpower in allergy and immunology to the General Accounting Office. It is a fine report and I hope it receives thorough study. The report note:; that there are 2,677 practitioners of allergy. This turns out to be only one specialist for 12,000 patients with allergic diseases. It is estimated that we have less than one-half the number of allergists, specialized internists, pediatricians, and dermatologists required to provide adequate medical care for asthma and other allergic diseases. The report is gloomy on the prospects of achieving the optimum number of specialized physicians in view of present, inadequate training programs. But should we be gloomy? Instead, should we not act to rectify these deficiencies? We should and we can. One aipproach which could be employed to increase the number of physicians with special training in allergy would be to strengthen the NIAID program for Asthma and Allergic Disease Centers. The Centers could place emphasis on a variety of allergic diseases, both for training purposes and for the development of new knowledge. At this Congress Dr. Kurk Bloch discussed the future practice of allergy. He sees practice diversified among the other specialties. On this there will be debate. But all of us can agree that all physicians, whatever their background, with responsibility for asthma and other allergies must have thorough training. The fourth element of a national program pertains to the process of translation from research to practice. A difficult matter this-translating new basic research knowledge into practical application and then disseminating new methods of diagnosis and treatment
5
I
I MEDICAL NEED
~i--~l FIG. 2. A systems analysis portraying the process leading from medical need to basic research to application research and develooment.
through the practicing community. This chain of events, from laboratory bench to bedside and doctor’s office, has been referred to as the transfer of knowledge and there has been much talk on how to facilitate this process. There has been much talk, also, on a translation gap between basic research and the use of medical discoveries by the health care delivery system. Let me say as an aside that viscosity in the translation system is healthy. It provides a pause in the process. There is no greater protector of the patient than the physician with a healthy skepticism about the possible benefits of new-fangled ideas. Remember Maimonides admonition-the clever physician relies on the work of nature and keeps her from getting lazy. I have no words of wisdom on this complex tangle of issues pertaining to translation, but we must address them, and we must sort them out. There is a common feeling among members of the public and among those in the political arena that a lag exists between discovery and application. We at the NIH, and those investigators supported by the NIH throughout this country, must be sure that we maintain open lines of communication to the practicing physician. And we must attend to this translation business by all manner of communication. Such matters cannot be explored fully here. But for a start, I believe we should examine carefully the processes of discovery and the means by which discovery is translated into practice. Here I would make three points. First, translation from theory to practice is a two-way process, similar to a chemical equation which is portrayed as an equilibrium with arrows pointing in both directions. Research yields new opportunities for patient care, but in the reverse direction, the needs of clinical medicine modulate the dimensions of research. Second, we can arrive at a defensible position on the complex issues concerning the transfer of knowl-
6
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edge only through achievement of a consensus among laboratory scientists, the practicing physician, and the general public. There must be a broad dialogue and thorough public debate. Third, translation of theory into practice requires an active process to disseminate new information. In a systems analysis, as shown in Fig. 2, the processes of translation can be depicted as a triangulation among medical need, basic research, and the development of new medical interventions. But the dynamics of the process, the information flow, must be represented by arrows pointing in both directions as shown in the figure. Research does not progress by itself, where thought and logic proceed in a vacuum. When cut off from reality, research can spiral into a sterile atmosphere circumscribed by its own dimension, as, for example, the preoccupation with syllogistic logic in the Middle Ages. There is a resonance between medical need and basic research. Basic research leads to application but application feeds back into research, a modulating force. In turn, application leads to a new intervention which is offered to the medical community to satisfy a need for diagnosis, treatment, or prevention. But before final acceptance, the new intervention is improved and modified so that finally it most nearly fits the need as perceived by medical practice. How often in medical discovery do we see this interplay between need on the one hand and research and application on the other. Dubos gives a graphic illustration of this in The Professor, the Institute and DNA, a recent book on the life of Oswald Avery.s Of special interest to us in clinical medicine are the sections of the book dealing with pneumococcal pneumonia. In 19 16, Dochez and Avery discovered specific soluble substance, the capsular material of the pneumococcus. Soon thereafter they detected specific soluble substance in the blood and urine of patients during the acute phase of pneumococcal pneumonia. Later Avery developed a clinical test on the urine which permitted the rapid identification of the pneumococcal type even before the culture was recovered from the patient. This test made use of the fact that the urine contains the specific soluble substance during the acute phase of pneumococcal pneumonia. An important advance, this test, in the days of antiserum therapy. Early diagnosis meant early treatment with antiserum and greater likelihood of success. Avery recognized that, in some way, there was tremendous importance in specific soluble substance. Every time he had a chance, he would agitate a tube of it in front of Michael Heidelberger and say, “Michael, the whole secret of bacterial specificity is
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in this little tube. When will you work on it?” Finally out of interest and friendliness, Heidelberger joined Avery and began the long, hard job of working out the chemistry of the pneumococcal polysaccharides and of developing and perfecting the type specific antisera used to treat patients with pneumococcal pneumonia. There was much trial and error as specific antisera were passed on for use in clinical practice. Those in clinical practice saw the imperfections in antiserum therapy, and they said to researchers, “Your treatment is good gentlemen, but not good enough.” Finally there came vaccines made from highly purified polysaccharides to prevent pneumococcal pneumonia by active immunization. But by that time, penicillin had overtaken the immunization approach. Now the matter did not end there. Dr. Robert Austrian and others are still probing the usefulness of pneumococcal vaccines in those who are most susceptible to pneumococcal infections, patients with sickle cell anemia, or who have had a splenectomy. Clinical trials are now under way to prove the efficacy of the pneumococcal vaccine in these individuals. So the triangulation of the pneumococcal saga is complete. The medical need was perceived in pneumococcal pneumonia. The basic research was done which laid the foundation of immunochemistry on the one hand and the development of pneumococcal antiserum and pneumococcal vaccines on the other. Finally, even in this day of antibiotics, for a large group of patients there is still a place for the prevention of pneumococcal infections through active immunization with purified polysaccharides. Now, second, on this business of translating discovery into practice, we must raise the issue of consensus. Agreement-consensus, if you will, must be reached on any new medical procedure for the management, diagnosis, and treatment of asthma and allergic diseases. Agreement requires consensus by all appropriate interested parties-the government agencies, the profession, the allergy specialists, the professional societies, and finally the patient. I do not want to speak only in generalities. In our field, on what questions do we need agreement or consensus? Though the hour is late, I should like to suggest two examples: 1. There is a need for general criteria for the diagnosis of asthma. Clinical asthma is due to several etiologic factors and effective management, and, indeed, specific treatment depends upon an etiologic classification. 2. It is necessary to establish adequate diagnostic criteria for penicillin allergy based on objective testing with new methods. Currently treatment is withheld from many patients with infections for whom
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penicillin is the drug of choice, because of a mistaken impression that a prior drug reaction is representative of true allergy. These matters require broad discussion to arrive at a consensus. Now, at last, on this whole matter of translation there comes the process of dissemination-the dissemination of new information to the physician, and the dissemination of general knowledge and advice to the patient. This Congress is a fine example of how information can be disseminated to the physicians. Other physician-oriented programs are locally organized, tailored to suit the special needs of an area. But we must also have dissemination programs for the public and for patients with asthma and other allergic diseases. In this effort we must mobilize our resources and our people-lay leaders as well as physicians. There are already several vigorous groups and societies dedicated to assistance for patients with asthma and allergies, to research, and to professional education. But we must recruit others and encourage more local participation. Beyond this, we must enlist the help and participation of other agencies-the PTA, the Associations of Christian and Hebrew Young Men and Women, for examples. While the responsibility of NIAID is basic and clinical research, as physicians we are prepared to work with you in these community efforts to assist patients with asthma and allergic diseases. And we at the NIH need the help of the community in identifying issues which require the attention of the research enterprise. Before I close let me say that you have a home in Bethesda at the NIH. NIAID is your Institute. Get to know us, and let us get to know you. Stop by and visit. Tell us your views. We have a fine clinical research program in allergy headed by Dr. Allen Kaplan and Dr. Michael Kaliner. A National Program for Asthma and the Other Al-
The time has come
7
lergic Diseases is an idea whose time has come. And we will succeed in the work ahead. I have faith in that. I know the dimensions of your commitment and at this Congress I have perceived another reservoir of power. During the social hours I have talked with your wives-with Mrs. Leonard Bernstein, of Cincinnati, for example, and Mrs. Raymond Slavin, of St. Louis. They represent that reservoir of power. Their enthusiasm for what can and must be done is contagious. They speak for the families, for the people of this country. In this National Program we need basic research on the immune system, we need clinical research on the special problems of asthma and other allergic diseases, we need diverse training opportunities for research and practice. And, finally, all of us need to address ourselves to the translation of existing and new knowledge into new ways to care for the patient.
REFERENCES 1. Siegal, S., editor: Proceedings, New York Allergy Society, February 27, 1958, N. Y. State J. Med. 59:289, 1959. 2. Osler, W.: The principles and practices of medicine, New York, 1894, D. Appleton and Company. 3. Muntner, S., editor: Treatise on asthma-The medical writings of Moses Maimonides, Philadelphia, 1963, J. B. Lippincott Co. 4. Majno, G.: The healing hand-man and wound in the ancient world, Cambridge, 1975, Harvard University Press. 5. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, ed. 4, London and Toronto, 1970, Macmillan Publishing Co., Inc. 6. Coca, A. F., and Cooke, R. A.: On the classification of the phenomena of hypersensitiveness, J. Immunol. 8:163, 1923. 7. Samter, M., editor: Excerpts from classics in allergy, Columbus, 1969, Ross Laboratories. 8. Schachter, J.: Measurement of the prevalence of respiratory allergies by interview questionnaire, J. ALLERGY CLIN. IMMUNOL. 55:249, 1975. 9. DuBos, R. J.: The professor, the institute and DNA, New York, 1976, The Rockefeller University Press.
