The allergist in the new millennium

New millennium: The conquest of allergy (Supported by a grant from Novartis Pharmaceutical Corp., Eas t Hanover , NJ) Series editors: Donald Y. M. Leung, MD, PhD, Stanley J. Szefler, MD, and Harold S. Nelson, MD

The allergist in the new millennium Stephen I. Wasserman, MD San Diego, Calif

Allergy and immunology emerged as a distinct research area and clinical specialty in the early 20th century. As the 21st century approaches, the evolution of clinical and academic life in American medicine produces unique challenges for this field and its practitioners, educators, and investigators. How we reached our current state and a personal view of the future for the clinician and the academician in this field are discussed. (J Allergy Clin Immunol 2000;105:3-8.) Key words: Aller gy and immunolo gy, clinical pr actice and research challeng es, training in aller gy

Few events engage editors’ interest more than major closures and new beginnings. The series on The New Millennium: The Conquest of Allergy, which will appear in this Journal over the upcoming months, is one such opportunity. I have been asked by the editors to provide an introduction to this exciting series, which will address our evolving understanding of the cells, mediators, mechanisms, pathogenesis, and therapy of allergic disease. I have also been asked to place in perspective the role of the allergist in discovery: how we have achieved our current level of understanding and what the academic and clinical allergy community can still contribute to meet the challenge of eliminating allergic disorders in the upcoming century. Such a perspective must also include a discussion of current challenges facing the allergy community and, hopefully, directions for overcoming obstacles. This perspective and speculations regarding the future are highly personal and far from guaranteed.

HISTORICAL MILESTONES The earliest description of allergic disease has been attributed to the ancient Egyptians, who reported death from a wasp sting. Recognition of asthma is also ancient in both Eastern and Western traditions. Although mentioned by Maimonides, the descriptions of asthma, rhinitis, and their allergic etiology began in the early Renaissance with

From the Department of Medicine, University of California, San Diego, San Diego, Calif. Received for publication Sept 29, 1999; revised Oct 13, 1999; accepted for publication Oct 13, 1999. Reprint requests: Stephen I. Wasserman, MD, University of California, San Diego, Medical Center, 402 Dickinson St, San Diego, CA 92103. Copyright © 2000 by Mosby, Inc. 0091-6749/2000 $12.00 + 0 1/1/103610

Willis and Floyer in the 17th century and Bostock, Salter, and Wyman in the 19th century. Later in the 19th century, Quinke made his classical observations regarding angioedema; Charcot and von Leyden described the association of asthma and eosinophils and their products in the sputum of asthmatic subjects.1 These defining clinical descriptions were the essential first step because allergic diseases had to be individually recognized before they could be studied in detail and their pathogenesis and therapy investigated. Fortuitously, the full clinical descriptions of allergic diseases at the turn of the 20th century coincided with the emergence of immunology and the pioneering work of von Behring, Koch, and Bordet.1 Portier and Richet2 truly began the laboratory study of allergy in their classical experiments with immunization, sensitization, and anaphylaxis (Fig 1). Their observations that animals could become hypersensitive, rather than be protected by immunization, was the true beginning of allergy research. On the basis of their work and that of others, von Pirquet3 then defined allergy as an altered state of immune responsiveness, and it was around these concepts that a new clinical discipline was born. Cooke and Rachemann were among the earliest practitioners of this new discipline, with Cooke establishing the first American clinic of allergy in New York by the 1920s. He and his colleagues used techniques developed by Noon and Freeman1 for the extraction of pollen allergens and ushered in the era of the use of allergen extracts in skin testing and treatment of patients with allergic diseases. During the years allergy was being solidified as a clinical discipline, Schultz4 and Dale5 were independently developing in vitro techniques to characterize allergic reactions and to permit isolation of some of the key mediators of allergic reactions. Dale was the first to identify a mediator of allergic reactivity: histamine. With use of these classical in vitro techniques, Kellaway and Trethewie6 were the first to identify a material they termed slow-reacting substance of anaphylaxis. Over the next 40 years, this principle was isolated and chemically identified, its physiologic role established, and a family of therapeutic compounds to block its effect in allergic diseases developed.7 The immune reactant carrying allergic sensitivity was first recognized as an antibody in the early part of the 20th century, but not until the late 1960s was it proved by Ishizaka and Ishizaka8 and Johanssen and Bennich to be a unique immunoglobulin, termed IgE.9 Coincidentally, the histo3

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FIG 1. First observation of anaphylaxis in 1902. Paul J. Portier (1866-1962) and Charles R. Richet (1850-1935) made a serendipitous discovery of the phenomenon of anaphylaxis. They were encouraged by Prince Alfred of Monaco to develop a protective serum against the sting of the sea anemone while on board his cruise ship in the Mediterranean Sea. In attempting to immunize dogs against the sea anemone toxin, the scientists unwittingly sensitized the animals. Thus the dogs unexpectedly died within minutes because of sensitization to a previously nonlethal dose of toxin. The phenomenon was the opposite of the condition of protection (phylaxis), Portier and Richet’s original goal; thus they referred to it as anaphylaxis, meaning “without protection.” In their original studies, they defined 2 factors that appeared to be essential for anaphylaxis: (1) increased sensitivity to a toxin after previous injection of the same toxin and (2) an incubation period of at least 2 to 3 weeks necessary for this state of increased sensitivity to develop. In 1913 Richet received the Nobel Prize in Physiology or Medicine for his role in the pioneering discovery of anaphylaxis.

ry of our understanding of the cellular effector mechanisms of allergy occurred at the same pace. As noted above, classical immunologic principles were first elucidated at the turn of the century. Riley and West10 identified the mast cell as the cellular element most altered during acute allergic reactions, adding this cell to the eosinophil as a central contributor to allergic diseases. Our current understanding of the nature of cell-mediated immunity, the concept of B cells, T cells, the role of the thymus, the reorganization of Ig genes and T-cell receptors through the action of the enzymes RAG1 and RAG2, and the demonstration that lymphocytes generate soluble factors (cytokines/ILs) effective at a distance to modify immune responses began with Medawar, Lawrence, Burnet, and Porter, continued by Paul, David, and Tanegawa,1 and continues today to be one of the most excit-

ing, fascinating and rapidly evolving areas of biomedical research. It is on this foundation of clinical care, biochemical analyses, physiologic studies, and elucidation of complex immune pathways that our understanding of allergic diseases rests. However, rather than a stable and fixed perspective, allergy continues to rapidly evolve as new insights into the cellular and soluble contributors to allergy arise. Each issue of this Journal and other immunologic journals brings further understanding of the sophistication of the regulation of the immune response and its pertinence to allergy: new cytokines, new receptors, and new understanding of their complex interrelationships and regulation by activators, inhibitors, and complex interactive signal transduction pathways. The continued explosion of information made available through advances in genetics, and in technologies allow-

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ing the identification of patterns of gene expression in various diseases, has just begun to provide insights into allergic mechanisms and offer opportunities for therapeutic intervention in allergic disease. These insights, coupled with advances in drug design using insights from structural biology and nanotechnology, promise the ability to manipulate the allergic condition to the benefit of our patients. In all these areas of basic and translational research, practitioners of allergy have played an important role. The initial descriptions of allergic disease were made by practitioners, and it was astute clinicians who developed our understanding of the clinical nuances of allergic disorders. Likewise, advances in the pharmacotherapy of allergic disease, the discovery of the cells and mediators contributing to allergy, and elucidation of many of the intricacies of the immune response have been defined by allergist clinician scientists active in both the care of patients and in the development of new research knowledge pertinent to their patients’ problems. The intellectual foundation and current practice of our discipline were developed as a result of a unique informal collaboration of physicians, physician-investigators, and nonmedical basic scientists working to elucidate basic immunologic concepts and their pertinence to defined disease states. Thereby, in parallel with research advances, the clinical discipline of allergy was established and matured.

THE DEVELOPMENT OF THE DISCIPLINE Three fundamental issues have dogged allergy and inhibited its assuming its full place in American medicine. The first issue, respect for the discipline itself, derived from issues pertinent to the early development of the specialty. Initially, the evolving technology of allergy testing and treatment made standardization impossible. This fact was exploited by some to make overly inflated claims for the efficacy of this new field, thereby tarnishing its reputation. As allergy matured throughout the 1920s and 1930s, 2 national societies were established to improve the knowledge and skill of their members and to thereby increase the respect in which the specialty was held by patients and the profession. This movement led to attempts to identify best practices and the best practitioners, a phenomenon finding resonance all across organized medicine during that period. To identify excellent practitioners, several surgical disciplines began the board certification process and in 1936-1937 the Board of Allergy was founded as a subspecialty of the American Board of Internal Medicine.11 A parallel board was also established in pediatrics in 1944.11 The development of a board certification process and an acknowledgement of clinical excellence should have provided leadership and strengthened the discipline. Unfortunately, this process drove a wedge between board-certified pediatricians or internist allergists and those who had not been certified in either of these underlying disciplines and who therefore were ineligible to certify in allergy. Allergists not

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certified by the parent boards began a long and eventually unsuccessful campaign for a separate, and primary, Board of Allergy. This schism and its inevitable rancor persisted until the late 1960s, when the conjoint American Board of Allergy and Immunology, sponsored by the parent Boards of Internal Medicine and Pediatrics, was established.11 This solution recognized an independent and cross-generational focus of allergy that was, however, based on a solid foundation in pediatrics or internal medicine. Since that time no efforts to establish a primary Board of Allergy have been seriously considered. Ending the battle was essential to improving the quality and standing of allergy and immunology in American medicine. It has enabled the development of the Residency Review Commission for Allergy and Immunology, which accredits residency training programs and ensures that they provide an appropriate learning environment. The Conjoint Board credentials individual physicians. After the Board has been assured by training program directors that the candidate has the appropriate knowledge, skills, and professional attributes and has been successful in passing the certification examinations in either medicine or pediatrics, the candidate is permitted entry to the American Board of Allergy and Immunology certifying examination, and if successful, is certified. Recognizing that a once-in-a-lifetime event lacks credibility, late in this centure the Board instituted time-limited certification and mandatory recertification. Two other problems persist for allergy: its outpatient focus and its mechanism, not organ-based, approach. These 2 issues have served to isolate allergy from the mainstream of medicine and pediatrics. Until very recently our academic departments of medicine and pediatrics have been heavily inpatient oriented and, except for infectious diseases (which shares much of its historic tradition with allergy and immunology), were organ based. The absence of allergists from the inpatient wards diminished them in the eyes of senior academic faculty and colored the experience of students, residents, and fellows in these departments. In addition, patients experiencing the clinical manifestations of allergic diseases are often competed for by organ-based specialists, and trainee referral habits have until very recently been developed inside the hospital. Fortunately, these patterns are changing with the strong move to ambulatory care and education in American medicine. Despite these challenges within our academic medical centers, the clustering of allergy and immunology education into approved training programs at academic centers, engendered by the certification movement, has been of enormous benefit to the education of trainees, to the care of patients, and to the development of strong research programs in allergy under the direction of physician investigators. The earliest academic allergy research helped in validating empiric therapies. Rapid progress in allergy and immunology occurred after World War II as sophisticated, physician scientist–led laboratories and training programs were developed and widely recognized. At Harvard, Hopkins, Northwestern, National

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FIG 2. A smoked drum record of the long-lived contraction of guinea pig ileum in response to SRS-A compared with brisk onset and offset of histamine-induced contractions. This recording was produced in the late 1960s in the Austen laboratory. (Reproduced with permission from SRS-A to leukotrienes. Holgate S, Dahlen SE, editors. Oxford: Blackwell; 1997.)

Jewish Medical and Research Center, Buffalo, Tulane, Washington University, and many other academic centers, such programs arose and have taken their place in the academic life of their respective institutions and fostered the development of our 80 training programs in allergy in the United States. In these programs the basic science of allergy (eg, discovery of IgE, elucidation of leukotrienes [Fig 2], definition of cytokines) has been advanced, the clinical underpinning of the discipline strengthened (eg, immunology of immunotherapy, identification and characterization of allergens), and new treatment perfected (eg, venom immunotherapy, antileukotriene pharmacotherapy). It is in such centers that the new advances to be described in detail in this series (eg, DNA vaccines, anticytokine therapy, genetic manipulation) will be translated to clinical practice.

THE PRESENT AND THE FUTURE Where then are we at the end of the 20th century? Our understanding of allergic diseases, although not complete, has advanced rapidly and progressively throughout the century, particularly in the last 25 years. Mediators of immediate hypersensitivity; cytokines regulating the allergic response; the role of T cells, mast cells, and eosinophils; and the relationships among these cells have been quite thoroughly investigated. The roles of adhesion molecules, intracellular signaling, and the genetic regulation of many of the processes that underlie asthma and allergic diseases are being elucidated. Allergy and immunology is an accepted clinical discipline with more

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than 4000 board-certified members, approximately 80 active training programs, and 200 physician trainees and a very large research portfolio. Taken together with the immense promise and progress of genetic research, the ever more thorough elucidation of cytokine networks and signal transduction pathways, and the advancing development of new drugs to manipulate these targets, we should be on the verge of a golden era of research and clinical care in the areas of allergy and immunology. Will we see this golden era? The future of research does look quite bright and we can be realistically enthusiastic about the ability of allergy and immunology researchers to continue to contribute to our understanding of human disease. The success of the human genome project and advancing technologies for assessing the activation and participation of multiple genes in human disease gives hope for the elucidation of the multiple pathways important in allergic diseases and for the development of new targets of therapy. We can realistically expect that over the next several decades progress will continue to be made in our ability to manipulate immune response and to translate these advances into the clinical care of patients. There are some clouds on this horizon, however. The rapid consolidation of the large pharmaceutical industry has made development of all but the most blockbuster of drugs tenuous. Although allergy is common, and thus provides a potentially large market, it is likely that most new therapies will be aimed at subsets of patients in whom a particular disease-engendering pathway is primary. Hence it is likely that many of the new drugs will not be blockbusters. At present our promising, but small, biotechnology industry continues to struggle. Only a few such companies have developed products and seem assured of a long-term future. Many others may serve as toolboxes for larger pharmaceutical companies, and it is possible, but by no means certain, that their developing insights will flourish. The unprecedented economic prosperity of the past decade has fueled speculative investment and provided capital for many of these ventures. The next economic downturn, however, bodes ill for companies dependent on this volatile source of support. Another major challenge to the allergist and immunologist in this otherwise rosy scenario is the rather rapid loss of the physician investigator from the American research scene. The expansion of managed care, the extensively discussed but yet to be solved problems regarding how the National Institutes of Health supports patient-centered research, and the tendency to fund the most reductionist research possible, has created disadvantages for the physician investigator studying clinically relevant issues.12 Moreover, the increasing demands for clinical productivity placed on academic faculty, coupled with decreased clinical income consequent to such activities, inhibits the traditional cross-subsidy of research and teaching in our academic medical centers. The recognition of the need to use hard money support for clinical departments as well as the preclinical ones and the successful development of strategies to do so will

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be a defining struggle for the next generation of Academic leaders in American medicine. One major positive element for research in allergy and immunology has been the internationalization of the discipline. Approximately half the articles published in this Journal and half the abstracts presented at the annual meeting of the American Academy of Asthma, Allergy, and Immunology come from outside the United States. Thus the unique health care environment and economics of the United States are not to be the only drivers of advances in allergy and immunology. Perhaps a repeat of the late 19th century, which saw American scientists spending time in European laboratories, will again occur but on a global scale. Major challenges on the clinical horizon are widely recognized. We know that, for unclear reasons, the atopic state and allergic diseases are increasing despite our growing therapeutic options. With the reluctance of Western governments to fund current levels of health care, such increases in needed and available care presage further artificial constraints. In the United States this means decreased compensation for care provided to insured individuals and in the further expansion of the medically uninsured population. However, the increasingly recognized economic benefit provided specialists caring for more severely affected patients, taken together with development of complex and challenging new therapies, bodes well for the clinical practitioner of allergy. The development of highly selective and specific therapies for allergic disorders will require the ability to make increasingly precise diagnoses in patients with allergy, to fully elucidate the specific allergens mediating their disease, and to understand, in the finest detail, the mechanisms by which their disease is engendered. This challenge can only be met by well-trained specialists in allergy because it will require real expertise to manage these new therapies and the more severely ill patients for whom they will be targeted.13 Another opportunity for allergy is presented by the challenge to improve the health of populations. This has already begun to focus attention on early diagnosis and intervention in individuals. The next challenge will be to intervene in populations to prevent allergic disorders before they start. There are some special issues pertinent to the training programs of allergy and immunology. The dual challenge of less clinical revenue and an increasingly reductionist approach required to garner research funding has conspired to squeeze the allergist-physician-investigatorteacher. These stresses are now widely recognized and are shared by all disciplines. Although solutions are not yet assured, I am optimistic that the jewel in the crown of American medicine, the rigorous and scientifically based training of future physicians, will not be abandoned. Attrition in our training programs has ceased, applicant quality is high, and jobs are plentiful. As an outpatient discipline, allergy is ideally organized to participate in the full transition to outpatient-focused clinical education and care. The intellectual, societal, and economic oppor-

tunities in allergy continue to provide for a career of immense personal satisfaction.

CONCLUSION Allergy clearly shares, with our medicine and pediatric colleagues, in the medical issues of the turn of the century: funding constraints, the problems wrought by for-profit health care, and the all-too-prevalent bottom-line approach taking over academic institutions. We can take solace from the knowledge that the public consistently indicates its support for more biomedical research and for advances in health care. Our programs in training, research, and clinical care remain high priorities for the American public. Moreover, allergy and immunology has other unique and positive features, which bode well for its success in the future. It is an outpatient discipline, poised to participate in the continuing transition from inpatient to outpatient care. As a mechanistic-based specialty, the discipline is not subject to the potential development of a single organ-based therapy, which might eliminate its patient base (ie, isoniazid for tuberculosis, vaccine for polio). Allergy and immunology continues to be an intellectually challenging discipline that crosses into all realms of medicine, thereby maintaining its intellectual vigor and academic viability. At the clinical level, the promise of new drugs and therapies for diseases heretofore untreatable will continue to provide the allergist and immunologist with ample challenge. Allergists are indeed fortunate that they have not been seduced into a constraining, highly technical procedure: a procedure that can be superseded by advances in technology thereby causing tremendous dislocation to the practitioners of that discipline or one that is inordinately sensitive to the whims of health care bureaucrats. Even the reliance on allergy skin testing and injections has been diminished in recent years and will continue to decrease as new therapies emerge. This change in emphasis liberates the allergist-immunologist from a potential economic squeeze. Talented clinicians in allergy have long engaged in clinical research complementing the bench science of their academic colleagues, and this tradition will continue and expand to ensure the most positive future for allergy and its patients. To truly optimize the future of allergy, its training programs, professional societies, practitioners, and certifying boards must continue to work together in a strong coalition. This coalition has focused not on individual special interests but on what is best for patients and populations with, or at risk of, allergic disease. Such a focus has provided the credibility to efforts to improve our teaching, research, and practice environments and is after all the reason for our specialty in the first place. I am confident that these organizations will continue in this cooperative mode. Therefore I believe that the allergist-immunologist in the new millennium will continue to contribute to the understanding of the mechanisms underlying allergic diseases; continue to improve the health of our patients, their families, and the population at large; and continue to educate the next generation of clinicians and physician investiga-

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tors-educators. As readers of this series will note, the excitement of the field is immense and the promise even greater, and the future is indeed bright for investigators, teachers, practitioners in allergy, and, most important, for their patients. The challenge is clear and the goal attainable if the allergy community continues to keep “its eyes on the prize”: the eradication of allergic diseases by the end of the next century. REFERENCES 1. Cohen SG, Samter M. Excerpts from classics in allergy. Carlsbad (CA): Symposia Foundation; 1992. 2. Portier P, Richet C. De l’action anaphylactique de quelques venins. C R Soc Biol (Paris) 1902;54:170-2. 3. von Pirquet C. Allergie. Munch Med Wochenschr 1906;53:1457-61. 4. Schultz WH. Physiologic studies in anaphylaxis, I: the reaction of smooth muscle of the guinea-pig sensitized with horse serum. J Pharmacol Exp Ther 1909;1:566-7.

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5. Dale HH, Laidlaw PP. The physiological action of β-iminazolylethylamine. J Physiol 1910;41:318-44. 6. Kellaway C, Trethewie E. The liberation of a slow reacting smooth muscle stimulating substance in anaphylaxis. Q J Exp Physiol 1940;30:121-45. 7. SRS-A to leukotrienes: the dawning of a new treatment. In: Holgate S, Dahlen SE, editors. Oxford: Blackwell Science; 1997. 8. Ishizaka K, Ishizaka T: Human reaginic antibodies and immunoglobulin E. J Allergy 1968;42:330-63. 9. Johansson SGO, Bennich H. Immulogical studies of an atypical (myeloma) immunoglobulin. J Immunol 1967;98:381-94. 10. Riley J, West GB. Histamine and tissue mast cells. J Physiol 1953;120:528-37. 11. American Board of Medical Specialties. Annual report and reference handbook. Evanston (IL): Research and Education Foundation; 1999. 12. Moy E, Mazzaschi AJ, Levin RJ, Blake DA, Griner PF. Relationship between National Institutes of Health research awards to US medical schools and managed care market penetration. JAMA 1997;278:217-21. 13. Metcalfe DD. The future role of the allergist-immunologist. Prim Care 1995;25:885-90.