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The allergy archives

2003; Elsevier BV; Volume: 111; Issue: 5 Linguagem: Inglês

10.1016/s0091-6749(03)80153-7

1097-6825

Murray Dworetzky, Sheldon G. Cohen, A. W. Frankland,

Historical Medical Research and Treatments

The physician of tomorrow may yet become an immunisator.1Colebrook L Almroth Wright: provocative doctor and thinker.in: Heinemann, London1854: 61Google Scholar —Sir Almroth Wright (1861-1947) Demonstration of diphtheria toxin and its pathogenicity by Pierre Roux and Alexandre Yersin at the Institut Pasteur in 18882Roux PPE Yersin AEJ Contribution à l’étude de la diphtérie.Ann Inst Pasteur. 1888; 2: 629-661Google Scholar provided a starting point for the development of serum therapy. Two years later at Koch's Institute in Berlin, Emil von Behring and Shibasburo Kitasato produced specific immunizing antitoxin.3Behring EA Kitasato S Uber das Zustandekommen der Diphtherie-Immunität und der Tetanus Immunität bei Thieren.Dtsch Med Wochenschr. 1890; 16: 1113-1114Crossref Scopus (461) Google Scholar Although an immediately apparent major contribution to the rapidly developing discipline of bacteriology and infectious diseases, this new knowledge would also prove to be a milestone in the emergence of the field of hypersensitivity. Meanwhile, revelations of toxin-antitoxin phenomena reactivated scientific interest in the long-held, ill-defined concept of poisons as causes of disease. Paul Ehrlich's 1891 report of raising antisera to the toxalbumins ricin and abrin4Ehrlich P VI. Experimentelle Untersuchungen über Immunität.Dtsch Med Wochenschr. 1891; 32: 976-977Crossref Scopus (96) Google Scholar isolated from castor bean and jequirity bean, respectively, added reason to speculate that plant-produced endotoxins and exotoxins in addition to those of bacterial sources might play possible roles in the cause of human disorders. One specific instance was that of Blackley's 1873 demonstration of the association of grass pollens with symptoms of seasonal hay fever,5Blackley CH Experimental researches on the causes and nature of catarrhus aestivas (hay fever or hay-asthma). Balliere, Tindall and Cox, London1873Google Scholar but whatever the pathogenetic relationship, it remained unexplored for the next 30 years. In the first approach to the evaluation of that aspect of grass pollen, William Dunbar in 1903 in Hamburg6William Dunbar, a native American, born in St Paul, Minnesota, remained in Germany after studying medicine at Giessen (MD 1892). In 1893, he became Director of the State Hygienic Institute at Hamburg.Google Scholar (1) identified the albumin fraction of the isolated proteid component as the active principle, (2) implicated the immunologic factor of complement deviation in the sera of subjects with hay fever, and (3) determined individual susceptibility to pollen by grading conjunctival reactions to dose-related ocular challenges. Interpreting that hay fever and hay asthma were caused by pollen toxin in susceptible individuals, Dunbar sought to duplicate the therapeutic success of passive immunization in diphtheria, applying its principle to the treatment of hay fever. Putative antiserum pharmaceutically marketed as “Pollantin” was administered by means of nasal and ocular instillation, bronchial inhalation, and subcutaneous injection.7J Hygiene. 1913; 13 (A series of reports in 1903 issues of German journals summarized): 145-148Google Scholar The latter given in combination with pollen proteid, a method designed to immunize with mixtures of antitoxin and toxin, preceded by 12 years Behring's introduction of the same principle with diphtheria toxin-antitoxin.8A method that followed Theobold Smith's technique for immunization of horses with injected mixtures of diphtheria toxin and antitoxin (T-AT). Its design allowed for gradual in vivo dissociation of antigenic toxin from the administered neutral mixtures. Apart from Dunbar's modification—substituting a putative pollen toxin preparation—Smith's suggestion in 1909 for utilization of T-AT for human use (Kolmer JA, Tuft L. Clinical immunology, biotherapy and chemotherapy. Philadelphia: Saunders, 1943; p. 491) was first used with true bacterial exotoxin (diphtheria) by Behring in 1913. (Behring EA. Ueber ein neues Diphtherieschutzmittel. Dtsch med Wochenschr 1913;39:875-6.)Google Scholar Other than objections to occasionally experienced reactions to the foreign species sera, both “Pollantin” and a competing preparation, “Graminol,”9Weichardt-Erlangen W Zur Serumbehandlung des Heufiebers.Berl Klin Wochenschr. 1906; 43: 1184-1186Google Scholar introduced by Wolfgang Weichardt of Erlangen,10Weichardt, after receiving his MD (1900 Breslau), trained as an assistant to Dunbar at the Hamburg Institute of Hygiene before becoming first assistant at the Erlangen University Institute of Hygiene and Bacteriology (1905-1909) and ultimately director of its Bavarian Bacteriological Research Institute.Google Scholar found popular acceptance. Until ultimately apparent that neither “Pollantin” nor “Graminol” had any real value, claims and evaluations were based on advantages in serum sources: “Pollantin” was derived from specifically immunized horses and rabbits, and “Graminol” was derived from nontreated herbivorous animals presumed to be naturally immunized by feeding on pollinating grasses. The possibility that a true pollen toxin might not be the primary causative factor or pathopharmacologic mediator was never questioned. Nevertheless, despite its nonrewarding outcome, the experience had an unforeseen useful consequence. The introduction and widening use of “Pollantin” in clinical medicine in England brought Dunbar and his junior associate, Carl Prausnitz, into contact and appreciation of shared interests with Britain's foremost vaccinologist, Sir Almroth Wright, Director of the Inoculation Department at London's St Mary's Hospital. Among areas that Dunbar's work had opened up for further exploration was active immunization by means of subcutaneous injection of pollen proteid (“toxin”) alone for patients with hay fever sensitive to the added foreign species animal sera. That project was put aside when Dunbar, himself a patient with hay fever, manifested a violent systemic reaction on receiving from Prausnitz the first trial dose of injected grass pollen extract. In the ascendancy of his medical career, Wright had served as professor of pathology at the Army medical school in the Royal Victoria Hospital at Netley, where he conducted original bacteriologic studies on Malta Fever (brucellosis) and developed a vaccine against typhoid fever. His antityphoid immunizing agent proved to be a seminal contribution when found to be efficacious in trials of mass inoculation in British soldiers in India and in South Africa during the Boer War. After leaving his association with military medicine and being appointed professor of pathology at St Mary's in 1892, he developed a self-sustaining (enclave-like) department independent of hospital functions. His pioneering work in immunization was furthered by recruitment of a motivated staff whose participation in bench research was enabled by their generating self-support through private medical practices. With expansion of the scope of Wright's initiatives, the St Mary's-based laboratory evolved into a recognized research institute. It provided the setting for interactions of staff and trainees with visitors of international distinction and expertise in bacteriology and immunology, such as Robert Koch, Emil von Behring, Paul Ehrlich, and Elie Metchnikoff. It offered opportunities to English-speaking physicians for postgraduate study comparable with that available at European centers in Austria, Germany, and France. A group who, after returning from Wright's mentorship in London to the United States and Canada, kept in contact with the thought of forming a “society of vaccine therapists” and in 1913 founded the American Association of Immunologists.11Saunders JF Cruse JM Cohen SG Lewis Jr, RE The AAI, 1913 to 1998, in the first century of immunology.J Immunol. 1988; 141: S37-S54PubMed Google Scholar Within the inoculation department were the appropriate scientific ambiance and physical and intellectual resources for Leonard Noon (Fig 1) and John Freeman (Fig 2) to follow up Dunbar's abandoned initiative to carry out prophylactic treatment of hay fever by means of immunization against putative grass pollen toxins. Fig. 2John Freeman. (Courtesy of St Mary's Hospital)View Large Image Figure ViewerDownload Hi-res image Download (PPT)After identification of the allergenic properties of pollen and its role in hypersensitivity mechanisms, Noon and Freeman's initial reports of therapeutic benefit12Noon L Prophylactic inoculation against hay fever.Lancet. 1911; 1: 1572-1573Abstract Google Scholar, 13Freeman J Further observations on the treatment of hay fever by hypodermic injections of pollen vaccine.Lancet. 1911; 2: 814-817Abstract Google Scholar would be regarded as the seminal contribution to what would be known under the varied and changing terms of desensitization, hyposensitization, injection treatment, and immunotherapy. Out of their initiatives for clinical care and investigation evolved another first—allergy's first clinic. The institutional endeavor was operational at St Mary's approximately 4 years before Joseph Goodale undertook systematized studies of patients with hay fever and hypersensitivity within the Throat Clinic at Massa-chusetts General Hospital (1915),14Cohen SG Firsts in allergy, Boston remembered.N Engl Reg Allergy Proc. 1983; 4: 316-318Crossref Google Scholar 6 years before I. Chandler Walker's solo clinic venture for asthma and hay fever at the Peter Bent Brigham Hospital in Boston (1917),15N Engl Reg Allergy Proc. 1983; 4: 329-331Google Scholar and 9 years before Robert Cooke's multistaff clinic that opened at New York Hospital in 1920. From longstanding association with our London colleague, A. W. Frankland, and appreciation of his contributions to advancement in the field of allergy, we have been made aware that he entered the medical specialty in 1946 as a member of the staff of the Inoculation Department at St Mary's Hospital. Relating to the years of his service invariably recalled accounts of relevant interest, especially pertaining to personal and professional interactions and joint participation with those who pioneered the laboratory's research (ie, Sir Almroth Wright, John Freeman, and Alexander Fleming) and the history of imaginative initiatives and innovative circumstances that made for the genesis and operation of allergy's first clinic. Consequently, in the belief that Dr Frankland's remembrances and reflections held advantages for adding an extra to the tenor and content of the Noon and Freeman Allergy Archives feature, we invited his submission of materials to be integrated into our planned biographic sketches. Not only did this assumption prove to be correct, Bill Frankland's gracious and generous response provided material the intriguing tenor and content of which surpassed our expectations, so much so that to preserve the flavor of originality, authenticity, and personal touch, we favored it standing on its own. Accordingly, in lieu of our preparing profiles for Allergy Archives in the customary format, we opted to offer the reader a historically relevant retrospective. A collection of selected, verbatim, and unedited excerpts taken from Bill Frankland's memoir communications follows. —Editors My interest in allergy and aerobiology began 57 years ago, when in 1946 I began work in the Allergy Department at St Mary's Hospital, London. Freeman was my chief until I took over as Director of the Allergy Department in 1962. When I retired from St Mary's, I then worked for the next 20 years at Guy's. Medical help was required for the special extra clinics, which, in the early months of the year, only dealt with patients with seasonal symptoms due to grass pollen. If symptoms occurred at any other time of the year except summer, patients were seen in the ordinary allergy outpatient clinics. The seasonal hay fever patients were normally seen only once a year unless involved in some research project. We used to do very extensive skin prick tests on patients; we had our own laboratory to make up all our extracts and all our vaccines. People with seasonal hay fever—about 80% of them—went on a self-giving course of multiple desensitizing injections to deal with that seasonal hay fever with or without associated asthma. Between one third and one half had an associated pollen asthma. It may seem hard to believe the number of patients we could deal with in a short time, but I was criticized when the special clinic one Spring had treated over 6000 patients—I was told I had to reduce the numbers because they were overtaking the Hospital! In fact, these clinics were run in a special building at the Wright Fleming Institute. They were self-supporting, and we took no notice of the National Health when it first started, in that patients were asked to contribute if they could afford it. If they couldn’t, no matter. Leonard Noon, who died in 1913, of course I did not know, but I had a lot to do with his sister Dorothy who was in charge of the Pollen Farm (Pollinarium) when I took over running it. Freeman's main interest was in summer hay fever because he considered it his moral responsibility to continue Noon's work. I only just overlapped at the Inoculation Department with Sir Almroth Wright. The “old man” was quite a frightening personality. He sat at the end of the table in the library when we all went for tea at 4 o’clock to sit and listen to his thoughts—often anti women! On May 8, 1947, I attended his memorial service at Holy Trinity Church, Prince Consort Road, London, conducted by an old Irish friend of his, Canon J. O. Hannay, better known as the author George Birmingham. I can remember what he did not say rather than what he did say about Wright! The first day I went to work in the Allergy Department in 1946, I had to see how professional I was in making Wright's famous capillary glass tube to take blood—I never used it! Although fluent in French, German and Spanish, when he was over 75, Wright taught himself Russian so that he could be up to date with their ideas. Freeman was a great friend of Wright but not of Fleming, who followed Wright as director of the Wright-Fleming Institute. Both Wright and especially Freeman were jealous of the title of director and the Nobel Prize that Fleming achieved. Alexander Fleming was my boss for 2 years when working in the Allergy Department, and I was eventually persuaded to write a chapter on penicillin allergy in the second edition of a very popular multiauthor book on penicillin of which he was the editor. Although I was very friendly with Fleming, he would never accept that penicillin caused allergic problems because he considered that penicillin reactions were caused not by penicillin but by impurities in the penicillin preparations then available. When I wrote a chapter in his book, my conclusions were that “with increasing use of penicillin, allergic reactions would become more common.” Fleming made me change this to “the more recent penicillin preparations rarely cause local or general reactions.” Who was I to argue and disagree with the discoverer of penicillin? I had John Freeman as a chief, but from 1950, I hardly saw him at all, and in retrospect, it is amazing that, as a junior, by doing a double-blind control trial, I really destroyed all his work on giving asthmatics autogenous bacterial vaccines. He never discussed this trial or even the one that I did with seasonal hay fever with Rosa Augustin. I wonder whether he even read it. When everyone in the department was asked to come to a meeting so that I could discuss what I was going to carry out in these trials, he did not turn up. Nearly 2 years later, when I gave the results of the trial, again he did not come to the meeting, but he never came to any of these teatime meetings from the time that Wright died. He was a delightful man to work with in many ways, and the only time I ever heard cross words from him was when I congratulated him on reaching his 80th birthday, and he flew at me in a rage and said, “I know what you want, you want the old b— to retire, and I’m not going to.” Dr Noon and Dr Freeman were at the same school, Charterhouse, and were great friends because they were both very good at shooting. Many years later, the reason that Professor Alexander Fleming, the discoverer of penicillin, was invited to the Inoculation Department of St Mary's Hospital was not because he was a brilliant bacteriologist but because he was a good shot! St Mary's had a very good shooting team, and they wanted to increase its strength. For 34 years, Noon's father was Mathematics Master at Charterhouse School, and his mother was a sister of a famous House Master at the school, which Noon entered in 1891. Noon went to Cambridge University in 1896 as a science scholar. He obtained a Double First in his exams, so he was a brilliant undergraduate. However, it was not all work at Cambridge because he stroked his college (First Trinity) boat. Noon qualified at St Bartholomew's in London in 1903. He then obtained a research scholarship in bacteriology at the Lister Institute and also did further research at Cambridge with a John Lucas Walker scholarship. During the winter of 1905-1906, he worked in Paris at the Pasteur Institute in the laboratory of Professor Borrel. When back in London, Freeman persuaded Noon to leave St Bartholomew's and join him in Almroth Wright's laboratory in the allergy department. Wright had many different ideas in using vaccines for preventing and treating various infectious diseases. Noon thought he would try with a series of injections of solutions of Phleum pollen to see whether he could help patients with summer hay fever. In Germany, Noon and Freeman had learned that Dunbar had already tried injections for summer hay fever by injecting horse serum into patients. Dunbar theorized that horses could eat grass pollens without any symptoms: they must have formed grass pollen antibodies. These antibodies of the pollen toxin should help hay fever patients. Dunbar seems to have had some success, but also many patients developed serum sickness and, finally, tragedy occurred on injecting a horse-allergic patient. Dunbar himself had seasonal hay fever and, when given not horse serum but a grass pollen extract, had severe anaphylaxis. So Noon had been persuaded to carry out research on the treatment of seasonal hay fever by Dr Freeman when he first went to St Mary's in 1906. Both Freeman and Noon had visited Dunbar at Hamburg, who was working on seasonal hay fever and particularly how to extract what was then called “the pollen toxin.” Dunbar also had a complicated method of collecting many pure specimens of different grass pollens. Rather strangely, Dunbar had not seen Charles Blackley's paper of 1873,2Blackley CH Experimental researches on the causes and nature of catarrhus aestivus (hay fever and hay asthma). Baillière, Tindall & Cox, London1873Google Scholar which showed very definitely that grass pollen was the cause of seasonal catarrh. Noon states in his paper3Noon L Prophylactic inoculation against hay fever.Lancet. 1911; 1: 1572-1573Abstract Google Scholar that hay fever is caused by a soluble toxin found in the pollens of the grasses. This toxin is innocuous to normal individuals. Noon wrote that the pollen extract was prepared by Dunbar's method of extraction with distilled water, aided by freezing and thawing several times. The extracts were boiled for 10 minutes after having been sealed in glass tubes. This treatment was not found to decrease the activity at all. He also states in the paper that Timothy grass (Phleum pratense) was found to yield the most active extract. It may seem strange that Noon took the Fellowship of the Royal College of Surgeons and the Cambridge Degree in Surgery at a very early age. It is for this reason that, in the paper in The Lancet, he is described as “Mr Noon” and not “Dr Noon.” Why he took these surgical degrees and not a medical degree is not known. It has been reported that it seems incredible that the extract was boiled for 10 minutes because many allergists have stated that this must have destroyed the activity of the pollen solution. Rosa Augustin, an immunologist in the Allergy Department at St Mary's Hospital, was asked by me to repeat what Noon did. Freeman said that Dunbar definitely insisted that the distilled water had to be very fresh. It was found that if the pH was 7.0, 10 minutes' boiling did not, as Dunbar stated, cause any decrease in activity. If the pH was 6.8 or 7.2, then the activity was very quickly destroyed. Boiling for 20 minutes had the same effect. Fresh distilled water has a pH of 7.0. It was my casual remark to Augustin that stressed that boiling for 10 minutes did not destroy the activity of the pollen extract so long as the water was freshly distilled. Noon realized that if a series of injections was going to be given, an increase of each dose would have to be very small, and Freeman said he was told by Noon, “We will create a new unitage. Let's multiply everything by a million, and then there will be no fractions involved. One unit is one millionth-fold dilution of the pollen in water.” Or, as Noon originally stated, “One unit of pollen toxin can be extracted from the thousandth part of a milligram of Phleum pollen.” He also found that what he called a measurement of the patient's resistance was the strength of pollen extract necessary to excite a conjunctival reaction. He stated that only 4 units would give a reaction in a very pollen-sensitive patient, but 70 units in the less sensitive, while a normal individual would not react to 20,000 units. It must be remembered that all Noon's work on the sensitivity of pollen in humans was not performed by skin tests but by conjunctival testing. Noon was so sure that his method of giving injections of the pollen extract to the pollen-sensitive patient would give good clinical results that the paper he produced in 19113Noon L Prophylactic inoculation against hay fever.Lancet. 1911; 1: 1572-1573Abstract Google Scholar only showed in early June the results of the lessening sensitivities of the conjunctival testing, and he left it to Freeman later on in the year to describe how clinically effective this treatment was.4Freeman J Further observations on the treatment of hay fever by hypodermic inoculation of pollen vaccine.Lancet. 1911; 2: 814Abstract Google Scholar Noon had tuberculosis and was feeling very ill. Almroth Wright, who could not measure Noon's opsonic index, nevertheless told him that his phagocytes needed stimulating, and he advised Noon to take continuous mild exercise. We know that, at this time, Wright was treating tuberculosis in the ward by a series of injections and also using pneumothorax and complete rest. Wright did admit that his injections required a regulation of dosage which was often a matter of great difficulty and, in some cases, impossible. There is no record that Noon had any injections from Wright, but Wright's advice of mild exercise seems to have started Noon's rock climbing with friends in the Peak District, and later he decided to go rock climbing on Mount Snowdon in Wales. There he had a very severe hemoptosis and eventually died in January 1913 aged 35. At the end of Noon's paper, he states that, “This work is now in the hands of my colleague, Dr Freeman,” so he knew he was incapable of continuing the work that he had set out to do. Indeed, when working in the laboratory, he began to lose weight and developed a cough with a night temperature so that, when his sputum became positive with tubercule bacilli, he was banished from the laboratory. When he started working with grass pollen, Leonard Noon quite naturally wanted as much grass pollen collected for carrying out his experimental work, particularly in man. To collect the pollen in the summer, he asked his sister, Dorothy, to collect as much as possible. She collected grass pollen from different grasses, but as Noon states in his paper in 1911,2Blackley CH Experimental researches on the causes and nature of catarrhus aestivus (hay fever and hay asthma). Baillière, Tindall & Cox, London1873Google Scholar he found that Timothy grass (Phleum pratense ) was the strongest pollen to use. Dorothy therefore spent most of her time collecting Timothy grass pollen, which has a relatively late and short season of pollination in the UK. Dorothy devised a method of producing grass pollen on a vast scale at the Pollen Farm, the so-called Pollinarium by Dr Freeman (Fig 3). She also instructed the local villagers to come and hand cut the individual grass stems. She told them exactly when they had to cut the grass-pollinating heads just before they began pollinating. If they were cut too soon, a lot of time was wasted waiting for the pollen to come; if too late, a lot of pollen would be lost. Dorothy was not an easy manager, and of the villagers, she said, “and some are incompetent and I cannot teach them simple things.” Dorothy Noon was in charge of pollen collecting for the next 40 years after her brother's death and only stopped doing so when a full-time botanist was employed by the Allergy Department at St Mary's Hospital. John Freeman was born in Leeds but went to school in the South of England at Charterhouse. One year later, Noon went to the same school, and because of their proficiency in shooting, they remained friends forevermore, although Noon went to Cambridge and Freeman to Oxford University. He served in the South African War before finishing his clinical studies at St Mary's Hospital, where he came under the influence of Almroth Wright with the great experiment of injection therapy prophylactically and therapeutically. It was Wright who persuaded the Army medical authorities that typhoid-paratyphoid A and B vaccine was an essential prophylactic in war. Freeman joined Wright in the Bacteriological Department and, by 1907, had done enough research work to write his MD thesis on “Studies on immunization.” Noon and Freeman spent the winter of 1905-1906 at the Pasteur Institute and later went to Germany to visit Dunbar, who was very involved in trying to treat hay fever with injections. The first successful treatment of hay fever by a series of injections was described in 1911 by Noon,3Noon L Prophylactic inoculation against hay fever.Lancet. 1911; 1: 1572-1573Abstract Google Scholar and the clinical effects were described by Freeman.4Freeman J Further observations on the treatment of hay fever by hypodermic inoculation of pollen vaccine.Lancet. 1911; 2: 814Abstract Google Scholar During the 1914-1918 War, Freeman worked with Wright as a Liaison Officer with Russian Army Medical Service: Wright had already self-taught himself Russian. Later, they both went to Boulogne to study wound sepsis. Freeman's third war came in 1939 when, in the Inoculation Department with his wife, Violet, he established the local blood bank. After the war, although on paper he was Director of Clinical Bacteriology, in practice he spent all his time building up the Allergy Department and his extensive private practice. In 1948, when the National Health Service came out, Freeman said that he would have nothing to do with it because he was not going to take instructions from politicians and the hospital. He had a department that was financially self-sufficient because it sold pollen and vaccines by arrangement with the firm Park Davis. Patients who came to the clinic were not charged in any way, and many—over 30,000—gave themselves self-administered injections according to build-up and maintenance schedules. These were usually of grass pollen, but sometimes they were injections of animal allergies. Preseasonal injections of pollens required over 50 injections given either daily or every other day. The high dose aimed at was 1 mL of 100,000 Noon units. Reactions did sometimes occur, but patients with their own adrenaline knew that they had to immediately give themselves an injection of adrenaline for any untoward reaction. He considered that anyone over the age of 15 years should be capable of self-inoculation. Symptomatic treatment of patients with severe symptoms and often an associated pollen asthma was, in Freeman's day, very ineffective, so perhaps it is not so amazing that so many subjects were willing to self-inoculate. Those who came for treatment just before the pollen season started would come into hospital for “rush desensitization.” The word he coined seems to have stuck, not so the “idiotoxin” of pollen or the many complaints that now might be considered to have an allergic and possibly genetic basis, which he described as the “toxic idiopathies.” Later, he thought that “protein idiopathies” was a better term.5Freeman J Skin reactions in asthma, etc.Practitioner. 1926; 116: 73-78Google Scholar Freeman did not know how many years “vaccination against hay fever” should be given. By 1914, there was the suggestion that perhaps 3 years would be enough.6Freeman J Vaccination against hay fever and report of results during the last three years.Lancet. 1914; 1: 1178-1180Abstract Scopus (65) Google Scholar Freeman tested patients with many different pollens but thought that weed pollen was not important in England, as was undoubtedly the case in the USA, as he had been told by “Clewes of Buffalo, USA, who first introduced the use of a pollen vaccine for hay fever in America.”7Freeman J Toxic idiopathies: the relationship between hay and other pollen fevers, animal asthma, food idiosyncrasies, bronchial and spasmodic asthma, etc.Proc R Soc Med. 1920; 13: 129-148PubMed Google Scholar He described food allergies, and as so often, the details are charmingly written: “Th