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The Allergy Archives: Pioneers and Milestones

2003; Elsevier BV; Volume: 111; Issue: 1 Linguagem: Inglês

10.1067/mai.2003.106

1097-6825

Sheldon Cohen, Murray Dworetzky, Oscar L. Frick,

Respiratory and Cough-Related Research

Coca and Cooke on the classification of hypersensitivenessArthur F. Coca, MD (1875-1959)The poets did well to conjoin music and medicine in Apollo, because the office of medicine is to tune the curious harp of man's body and to reduce it to harmony. —Francis Bacon, 1605Fig. 2Coca Castle, Segovia, Spain. Provided by the National Tourist Office of Spain.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Arthur's father, a composer, concert pianist, and, in the mid-1860s, a musician in the court of the Mexican emperor Maximilian, influenced and provided the training for his 2 sons to develop into accomplished pianists. After their father's death and mother's remarriage, Arthur was deprived of opportunities to both pursue his first love, music, and to follow his older brother in beginning what would eventuate in a highly successful professional performing, teaching, and conducting career. Their stepfather, in hoping to disassociate the family from relating to its past, was happy to support Arthur's educational start in any field but music.Although Arthur chose the alternative of medicine, he never left music behind. While attending Haverford College (AB 1896) and the University of Pennsylvania (MA 1899, MD 1900), he worked as an organist at Sunday church services. During a subsequent distinguished career in science and medicine, his musical talents and skills remained a conscious part of his life. He always had a piano at home and a portable dummy keyboard for disturbance-free, daily practice in his hospital work setting.After graduation from medical school, Coca was appointed to an assistantship at the University of Pennsylvania. In the research laboratory of the departmental chairman, Simon Flexner, he and fellow trainees in experimental pathology (Richard Peirce, Frederick Gay, Warfield Longcope, and Hideo Noguichi) would all go on to distinguished careers in bacteriology, infectious diseases, and/or immunology. He next spent 1907 to 1909 in Germany as a chemistry research assistant at the Heidelberg Cancer Institute with Emil Baron von Dungern of blood group fame, followed by a stay at the Philippines Bureau of Science Laboratories in Manila, where he developed a diagnostic slide test for cholera. During that 4-year period, he was credited with 16 original reports, 9 as first author, with the major number published in prestigious German scientific journals.On return to the United States in 1910, he took concurrent positions in New York as instructor in pathology and bacteriology at Cornell University Medical College and pathologist at Flushing Hospital; he held the latter position for 18 years. Cornell's teaching affiliation with New York Hospital brought Coca into contact with Robert Cooke and a research collaboration that initiated a flow of original studies on hypersensitiveness. In the subsequent establishment of a new academic-clinical division, Coca was appointed hospital chief of applied immunology and the first American medical school professor of immunology.He soon engaged in a multiplicity of research studies that included the broad spectrum of experimental sensitization, anaphylactic phenomena, identification and extraction of protein allergens, vaccination in cancer, mechanism of human sensitization, production and functions of reaginic antibodies, preparation of vaccines, pneumococcal toxins, nitrogen unit stand-ardization of fluid extracts for skin testing and injection treatments, hemolysis, and blood typing. Given Rockefeller Foundation support, he developed the first municipal-wide, cooperative blood donor program for 19 New York City hospitals, and the Blood Transfusion Betterment Association of New York, of which he served as medical director for 12 years.Coca's escalating publication experience added to his concern that German journals offered the only outlet for sophisticated reports of immunologic research. When Zeitschrift fur Immunitattsforschung suspended publication during World War I, he was instrumental in founding the Journal of Immunology in 1915 and served as first editor in chief for the next 32 years.Through research studies, collaborations, publications, and mentorships in experimental immunology and hypersensitivity, his sterling contributions were major in the development of the clinical field of allergy and asthma. In conjunction with Cooke's first allergy clinic opened in 1920, Coca's laboratory instruction was a vital component of postgraduate courses offered to physicians who then seeded establishments of new clinics both in New York and out of town. With Cooke's Cornell and Warfield Longcope's Columbia University—Presbyterian Hospital associates, he joined in organizing the 13-member discussion group that evolved into the national (Eastern) Society for the Study of Asthma and Allied Conditions.Coca played the foremost leadership role in interdisciplinary bridging of the new field of clinical allergy with biomedical immunologic science, especially through his tenures of office as seventh president of the national Society for the Study of Asthma and Allied Conditions and 31 years (1917-1948) as founding secretary-treasurer of the American Association of Immunologists and thereafter as its lifelong honorary president. Until the founding of the Journal of Allergy in 1929, he provided space in the Journal of Immunology for publication of articles on allergy and asthma. His publication of textbooks, Essentials of Immunology for Medical Students (1925) and Asthma and Hay Fever In Theory and Practice (1931; with M. Walzer and A. A. Thommen), filled educational voids at the instructional and clinical levels.Jointly with Cooke in 1923, Coca clarified and structured a classification for the different forms of hypersensitiveness that previously had been characterized by ill-defined terminology and definition. In so designating a place for the hay fever and asthma group of disorders, he introduced the concept of atopy (Greek a-without, topos-place) that provided an innovative stepping stone in advancing the understanding of allergic phenomena.Memoirs of Coca, in adding another dimension of appreciation, call attention to the image of his persona, gentle, mild mannered, humble, nondemanding, and undivertedly dedicated to research and training missions. All the more noteworthy are the productivity and multiple meritorious accomplishments he generated within the confines of his allotted space, a single, small crowded room holding laboratory benches, animal cages, library shelves, a small desk, and a cot. The limitations of financial support, resources, setting, and conditions under which he worked would likely be unimaginable to those who move in the environment of current standards.In 1932, Cornell Medical College and New York Hospital jointly opened a newly constructed medical center, but Coca did not move with Cooke. Forming new associations, he became Medical Director of Lederle Laboratories in Pearl River, New York, and joined the faculty of Columbia University Post Graduate Medical School and Hospital as clinical professor of medicine. Although exact reasons are not known, there then were signs of scientific interpretive differences and increasing personal strains in the Cooke-Coca relationship. Additionally pertinent, it is likely that his small academic salary would not support the 2 households resulting from divorce and remarriage to his research associate, Ella Grove. Extending earlier studies in allergen extraction, poison ivy oleoresin preparations, and contact dermatitis were research interests that fit well into Lederle's commercial product development. New academic associations and clinical interactions at the Hospital's Skin and Cancer Unit directed his attention to immune and hypersensitive mechanisms in skin disorders. With Marion Sulzberger, they added the clinical entity of atopic dermatitis, heretofore known as “flexural neurodermatitis,” to the hay fever and asthma cluster of reaginic antibody-mediated, hereditarily predisposed allergic conditions.Three years into his new laboratory studies and without direct relevance to his work in the pharmaceutical industry, a surprising change in Coca's scientific acumen and perceptions began to evolve. In 1941, with 85 solid scientific publications to his credit, Coca put forth a new, unproven, tenuous concept of adverse reactions to foods. Under the descriptor of “familial non-reaginic food allergy,” he described a spectrum of symptom manifestations, the cause of which he believed could be detected by recording increased pulse rates.It became evident that his self-presumed discovery of new knowledge related to his own health problems, which had an earlier beginning in complaints of vague and subjective gastrointestinal symptoms. In-depth studies by expert professional colleagues and an evaluation in an arranged incognito visit at the Mayo Clinic, all with normal findings, offered nothing more than the diagnostic impression of anxiety. In more recent years, there was the addition of migraine to his own symptoms and his second wife's constellation of migrainous headaches, dizziness, fainting, fatigability, indigestion, and angina he anecdotally related to specific foods. Unwilling to accept an explanation of anxiety and convinced that such manifestations were diagnostically reflected in detectable pulse rate changes, he conceptualized a nonantibody allergic pathogenesis, to which he gave the name “idioblaptic allergy.”With his method of identifying presumed causative agents, psychosomatic expressions, if not neurotic behavior, ensued. He would not eat foods cooked in aluminum pots or on a gas stove burner. He incriminated so many and varied “food allergies” that his wife had to maintain a special kitchen to take care of his theorized needs. For sweetener, he would use only either a personal supply of sugar that was refined through 9 successive dialyses or hydrolyzed lactose. He would read only newspapers and magazines that were preheated in an oven to bake the lint, ink, and print. Protection against exposure to dust and tobacco odors kept him from attending theater to see his great niece, starring actress Imogene Coca (see bibliography listing), perform on stage and to insist that visiting family members who were smokers change their clothes before entering his home.On retirement in 1948 at age 73, Coca opened an office in Oradell, New Jersey, where he resided since joining Lederle, for a private practice limited to “idioblaptis and familial non-reaginic food allergy.” After lunch, he studied pulse rate changes in schoolchildren in an Oradell classroom. From similar observations on dementia in patients in a state mental hospital, he suggested a causal relationship between food allergy and insanity. He published 13 articles and 2 books on the subject, one reached a third edition, and assumed the role of evangelist, spreading his message with frenetic effort.Coca's inexplicable, if not irrational, transition was unfathomable to those who had been familiar with his previous healthy skepticism of unproven concepts, unquestioned honesty, and insistence on pursuit of the scientific method. The ultimate outcome was even more distressing to colleagues. Resentful of critical opinions, angered by refusals to accept his dogma, and hurt by advice not to take on private practice in a controversial area, Coca broke off longstanding friendships and isolated himself from former associates and colleagues. He abandoned memberships and attendance at meetings of professional organizations, even those in which he played a founding role, the American Academy of Allergy and the Allergy Round Table.In retrospect, perhaps earlier instances of opinionation and personal bias breaking through a humble and gentle nature might have foreshadowed Coca's emerging behavioral and attitudinal changes. Chase recalled one episode when Coca, editorially disagreeing with the interpretations and conclusions of a study, refused to accept for publication a set of 5 papers on placental transmission of experimental anaphylactic sensitization. Forced to relent only after the influential William Park of the Journal of Immunology editorial board pounded on his desk and demanded publication, Coca never forgave the young author and investigator, Bret Ratner. Then there was his personal pique at Cooke's adoption of Stull's protein nitrogen unit and discontinuation of Coca total nitrogen technique for the standardization of allergen extracts, a move that progressed to open rift and separation.In 1959, at the time of his death at age 84, Coca left memories of divergent images. First, there was the legacy of imaginative scientist, accomplished editor, creative investigator, and ceaseless author who early on had been deservedly honored. Sadly, the second Arthur Coca was reduced to being critically questioned and doubted. How unfortunate, for the latter occupied the years that held the alternative of opportunity and promise of glorious return to unlimited retirement time at mastery of the piano.The indefatigable pursuit of an unattainable perfection, even though it consists in nothing more than in the pounding of an old piano, is what alone gives a meaning to our life on this unavailing star. —Logan Pearsall Smith “Afterthoughts,” 1931Allergy, atopy, and anaphylaxisIn a paper read at the annual meeting of the American Association of Immunologists in 1922 and subsequently published in a 2-section (each part individually authored) article, Arthur Coca and Robert Cooke introduced a new classification of hypersensitiveness. That it would provoke a storm of controversy was suggested by Cooke in noting in his introductory paragraph that “a classification by any branch of science usually carries with it an air of finality. The present classification is not suggested in that way for we recognize fully the many loopholes in our knowledge of the subject.” The major source of controversy about the classification was the introduction of what came to be known as the “atopic theory.” Whatever and regardless of their intent, the term atopy continues in common use almost 8 decades later, and therefore their contribution remains a rightly judged classic in the literature of the field of allergy and asthma.Long before the appearance of that journal article, there had been incidentally reported notes, without explanations or interpretations, of unusual reactions to injections of both toxic and otherwise innocuous materials. Laboratory experiments during which sudden death occurred after repeat injections of the biologic source substances included work by Magendie in 1839 and by von Behring, Flexner, and Richet and Héricort between 1893 and 1894. Richet and Portier in 1902 recognized the fatal reactions to infected jellyfish toxin to be a systemic immune phenomenon, which they termed anaphylaxis (Gr. a [na] contrary to, phylaxis protection). A follow-up study by Arthus with horse serum demonstrated that the sensitizing and eliciting steps were a function of foreign protein rather than toxin molecules per se.2Cohen SG Zelaya-Quesada M Portier, Richet, and the discovery of anaphylaxis: a centennial.J Allergy Clin Immunol. 2002; 110: 331-336PubMed Google ScholarIn 1906, von Pirquet first introduced the term allergie to mean altered reactivity. With its description as a pathophysiologic state established, Doerr, in 1914, attempted a classification of hypersensitiveness on the basis of a division of allergic reactions into those occurring from antigenic substances and those from nonantigenic substances. Coca and Cooke, in objecting to that sole immunologic criterion, offered a new classification under the broad heading of hypersensitiveness with subdivisions of normal (dermatitis venanata and serum disease) and abnormal (anaphylaxis, hypersensitiveness of infection, and atopy).Hypersensitiveness was defined as “a susceptibility in man and animal” that is mediated by a special mechanism and that might be specifically influenced (toward increased or diminished sensitiveness) by the suitable administration of the exciting agent; included were those states or conditions in which sensitiveness can be diminished by administration of the exciting agent, such as in hay fever, asthma, dermatitis venenata, and anaphylactic sensitiveness. The term atopy (Gr. a without, topy place) was coined in consultation with Edward D. Perry, Professor of Greek and Sanskrit at Columbia University, to denote the sense of a strange disease.Cooke detailed distinguishing features of each of the abnormal forms of hypersensitiveness. Anaphylaxis was (1) manifested only against proteins capable of inducing the production of demonstrable in vitro precipitating antibodies, (2) passively transferable to normal animals in the sera of sensitized animals, (3) completely removable by the procedure of desensitization, (4) not inherited, and (5) most importantly, in the acute reaction, in symptoms and pathologic changes, different characteristically in the guinea pig, the rabbit, and the dog. In contrast, atopy (1) was exhibited against both nonprecipitinogenic and precipitinogenic substances; (2) had not been shown to be passively transferrable to healthy individuals with blood serum from sensitive individuals; (3) could be greatly lessened, although not completely removed, by injection of the active substance; (4) was inherited subject to a “dominant gen” (sic); and (5) was expressed in pathologic changes, of which the more important were different from those of anaphylactic reactions in the guinea pig, rabbit, or dog. The hypersensitiveness of infection and the so-called normal reactions of dermatitis venenata and serum disease were referred to, but Cooke did not dwell on those phenomena.The controversy that followed the introduction of the classification concerned itself mainly with the distinction between anaphylaxis and atopy. Earlier, in 1916, Cooke and Vander Veer3Cooke RA Vander Veer A Human sensitization.J Immunol. 1916; 1 (This article and hereditary factors were discussed in J Allergy Clin Immunol 2002;110:677-80): 201-305Google Scholar presented data for a hereditary component in allergic diseases and concluded that the tendency to become allergic was hereditary. They suggested that the factor of inheritance was a dominant characteristic. Initially, Cooke believed that the clinical manifestations of allergy were anaphylactic in nature, but in the present article he separated hay fever, asthma, urticaria, and eczema from anaphylaxis, designating atopy as peculiar to humans and anaphylaxis characteristic of lower animals.The differences of opinion about the theory were reflected in texts published between 1928 and 1945. Accepting the atopic theory were prominent contemporary clinical allergists, including Tuft, Criep, Sultzberger,4Louis Tuft and Leo Criep were internists who had their indoctrination to allergy as attendees at a Cooke-Coca New York Hospital postgraduate course. Marion Sulzberger, a dermatologist, collaborated with Coca at the Skin and Cancer Unit of the Columbia University Postgraduate School and Hospital; they were jointly responsible for defining atopic dermatitis.Google Scholar and Feinberg.A longer list of clinicians and medical scientists, referred to as the unitarian school, objected to the distinction between either atopy and anaphylaxis or between atopy and allergy. Duke preferred the term allergy to either anaphylaxis or atopy, reasoning that “each seems to commit one to a theory.” Thomas and Rowe used the terms atopy and allergy interchangeably. Vaughan stated “we shall continue here with the more generally accepted (term) allergy.” A modification in his second edition (1939) noted that “atopy will be used in this book to indicate that a group of allergic phenomena can be demonstrated by passive transfer, but not in the same sense that it indicates the fundamental difference from other branches of allergy, such as serum disease.” Seegal and Seegal, after reviewing the work on atopy and anaphylaxis, concluded that they were “inclined to believe that the mechanism of the two reactions is essentially the same” but granted that there is an hereditary predisposition to become sensitive. Ratner noted that Coca and Grove's belief in the distinctiveness of atopic re-agin, which they had so named,5Cited by Ratner, Becker, and Coca in Coca, Walzer, and Thommen.Google Scholar and its difference from antibodies in serum disease was not consistent with other findings. In particular, there was a prior study by Cooke and Spain5Cited by Ratner, Becker, and Coca in Coca, Walzer, and Thommen.Google Scholar on the biologic reactions of natural and artificial sensitization in human subjects, which did not demonstrate any fundamental serologic differences. Urbach and Gottlieb, after a detailed review and point-by-point refutation, concluded by agreeing with Zinsser that “anaphylaxis to proteins in animals and all forms are basically related (and due to) a cellular reaction between antigen and antibody based on prior contact.”Several distinguished immunologists, including Zinsser, Doerr, Weil, Wells, Landsteiner, and Longcope,5Cited by Ratner, Becker, and Coca in Coca, Walzer, and Thommen.Google Scholar lined up on the side of the unitarian school in believing that precipitating and anaphylactic sensitizing antibodies were the same but conceded that the concept of atopy was not yet completely disproved. At the same time, the definition of hypersensitivity and of allergy gradually changed to become more limited to manifestation of an immunologic mechanism. However, considerable confusion about the definition of allergy has continued to persist through the years. Becker cites an example that related to his membership on an International Union of Immunologic Societies committee to establish nomenclature for hypersensitivity. After a period of greater than 9 years, the committee was not able to agree on the meaning of the term allergy . Nevertheless, the term continues in common use despite lack of an established scientific definition.As Cooke had predicted, there would be many loopholes in their classification, and indeed, they sharply modified their views over the years. Cooke, even more so than many of his early supporters, went so far in 1947 as to suggest that the term be dropped.6Cooke RA in Cooke RA, editor, op cit, p. 102.Google Scholar The inconsistent association between demonstrable immediate hypersentivity and clinical manifestations of asthma, rhinitis, or both gave reason for an intermediate view. As expressed by Pepys: “The essential feature of atopy . . . [is] that form of immunologic reactivity now identified as IgE antibody that is readily produced in response to common allergens of the patient's environment.”7Pepys in Gell and Coombs, op cit.Google Scholar In Pepy's opinion, joined by other clinical investigators, atopy would be demonstrated by eliciting one or more positive wheal-and-flare reactions to a few (4-6) skin test allergens without consideration of or regard to causative relevance.8Davies in Lessoff, op cit.Google Scholar In practice, application of that principle offered a criterion for diagnosis of a constitutionally predisposed allergic state referred to as the “allergic diathesis.”The notion that atopy was limited to human subjects, a major source of disagreement, must have puzzled veterinarians, who for years had taken care of allergy in their patients.10Mueller GH Kirk RW Scott DW Small animal dermatology.in: 4th ed. Saunders, Philadelphia1989: 450Google Scholar, 11Radostits OM Gay GC Blood DC et al.Veterinary medicine.in: 9th ed. Saunders, Philadelphia2000: 1710-1711Google Scholar, 12Wittich FW Spontaneous allergy (atopy) in the lower animal.J Allergy. 1941; 12: 247-251Abstract Full Text PDF Scopus (37) Google Scholar In a seminal report Wittich12Wittich FW Spontaneous allergy (atopy) in the lower animal.J Allergy. 1941; 12: 247-251Abstract Full Text PDF Scopus (37) Google Scholar documented the occurrence of hay fever in dogs with positive intracutaneous, ophthalimic, and passive transfer (P-K) test reactions to ragweed pollen. A standard veterinary textbook defines atopy as “a common, genetically programmed, pruritic dermatitis of dogs and cats in which the patient becomes sensitized to predominantly inhaled environmental allergens.”10Mueller GH Kirk RW Scott DW Small animal dermatology.in: 4th ed. Saunders, Philadelphia1989: 450Google ScholarThrough the years, the sharp distinction between atopy and anaphylaxis became less and less acceptable. Four decades after proposal of the Coca-Cooke view of the categories of hypersensitiveness and its engendered differences, near consensus was reached in the favorably received presentation of a revised and restructured classification. In a move to bring order to the system of pathoimmunologic processes, Coombs and Gell,9Coombs RRA Gell PGH Classification of allergic reactions responsible for allergic reactions underlying disease.in: Clinical aspects of immunology. Blackwell, London1943: 217-237Google Scholar in 1963, grouped anaphylaxis and atopic allergies in one class (type 1, immediate hypersensitivity) of 4 proposed categories.Current state-of-the-art textbooks reflect today's consensus that atopy and allergy or anaphylaxis are basically the same. Blumenthal defined atopy as an adverse immune reaction involving IgE antibodies. A geneticist clearly aware of hereditary influences, he used allergy and atopy interchangeably in his review. Kjellman and Bjorkstein (1997) did not directly define atopy but noted that “food hypersensitivity, especially of the immediate type, is linked to the atopic state.” In their discussion of natural history and prevention of food hypersensitivity, the terms allergy , atopy , and sensitization were used interchangeably, with atopy referring mainly to the clinical diseases and allergy and sensitization to the process. In a second text (1998) the authors followed the same line in referring to atopic family history in allergic rhinitis and allergic asthma.Currently, the proposed hygiene theory has upset preconceived beliefs of present-day allergists and might well require rethinking. Recent studies have suggested that exposure to a variety of antigens might reduce the onset of allergic disease in subsequent years. For example, in one report findings suggested that exposure to 2 or more dogs or cats in the first year of life might reduce the subsequent risk of allergic sensitization to multiple allergens in childhood.13Owenby D Cole Johnson C Peterson EL Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age.JAMA. 2002; 288: 963-972Crossref PubMed Scopus (579) Google Scholar A second report stated that endotoxin levels in dust from children's mattresses were inversely related to the childhood occurrence of hay fever, atopic asthma, and atopic sensitization.14Braun-Fahrländer C Riedler J Herz U et al.Environmental exposure to endotoxin and its relation to asthma in school children.N Engl J Med. 2002; 347: 869-877Crossref PubMed Scopus (1514) Google Scholar Findings like these would likely have horrified Coca and Cooke and equally must come as a shock to present-day clinical allergists. Is it any wonder that the Coca and Cooke classification was full of “loopholes.”In the final analysis the concept of atopy remains a seminal contribution. It has been said that one of the problems in defining the specialty of allergy and clinical immunology is that it has no organ of its own. Only a few years after the founding of the first allergy clinic in the United States by Cooke in 1920, the introduction of the concept of atopy stimulated discussion, inspired research, and recognized a constellation of diseases providing the equivalent of an “organ,” through which it has had a major effect in establishing the specialty of allergy and clinical immunology.“When I use a word,” Humpty Dumpty said, “… it means just what I chose it to mean—neither more nor less.” “The question is,” said Alice, “whether you can make words mean so many different things.” —Lewis Carroll15Carroll L Through the looking glass.1872Google Scholar Coca and Cooke on the classification of hypersensitivenessArthur F. Coca, MD (1875-1959)The poets did well to conjoin music and medicine in Apollo, because the office of medicine is to tune the curious harp of man's body and to reduce it to harmony. —Francis Bacon, 1605Arthur's father, a composer, concert pianist, and, in the mid-1860s, a musician in the court of the Mexican emperor Maximilian, influenced and provided the training for his 2 sons to develop into accomplished pianists. After their father's death and mother's remarriage, Arthur was deprived of opportunities to both pursue his first love, music, and to follow his older brother in beginning what would eventuate in a highly successful professional performing, teaching, and conducting career. Their stepfather, in hoping to disassociate the family from relating to its past, was happy to support Arthur's educational start in any field but music.Although Arthur chose the alternative of medicine, he never left music behind. While attending Haverford College (AB 1896) and the University of Pennsylvania (MA 1899, MD 1900), he worked as an organist at Sunday church services. During a subsequent distinguished career in science and medicine, his musical talents and skills remained a conscious part of his life. He always had a piano at home and a portable dummy keyboard for disturbance-free, daily practice in his hospital work setting.After graduation from medical school, Coca was appointed to an assistantship at th