Allergy through 20 Centuries Bergmann K-C, Ring J (eds): History of Allergy. Chem Immunol Allergy. Basel, Karger, 2014, vol 100, pp 27–45 DOI: 10.1159/000358478

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Milestones in the 20th Century Karl-Christian Bergmann Allergy Centre Charité, Universitätsmedizin, Berlin, Germany

From its very beginning, the 20th century represented the period of the main breakthrough for allergology as a clinical and scientific entity. The first years of this period were extraordinarily exciting because of the discovery of the anaphylactic reaction in 1902 and its clinical diagnosis as ‘local anaphylaxis’, ‘serum sickness’ (1903) or even as ‘anaphylactic shock’ (1907). The term ‘allergy’ was coined in 1906 and led to the recognition of allergic diseases as a pathogenetic entity. The first patient organization of hay fever sufferers was founded in Germany in 1900, the same year in which the very first report on immunotherapy was published in New York. In 1911 the era of actual immunotherapy started in London, becoming scientific with the first double-blind study in 1956, and still today being regarded as the backbone of allergology. In 1919 it was shown that allergy could be transferred by blood, in 1921 by serum (Prausnitz-Küstner test) and in 1966 the mystic ‘reagins’ were recognized as immunoglobulin (Ig) E. The development of the radioallergosorbent test for quantifying specific IgE antibody was a diagnostic landmark for al-

lergists all over the world. The history of allergy diagnosis started with the introduction of a ‘functional skin test’, named the patch test in 1894. The scratch test was described in 1912 and the patch test in 1931. From 1908 the skin was tested by intracutaneous injections, and from 1930 by a ‘puncture test’ (a precursor of the prick test) which has been in worldwide use in modified variations since 1959. The rub test (‘friction test’) was added in 1961. Systematically applied provocation tests started with conjunctival provocation (1907), followed by nasal and bronchial provocation with allergens (1914 and 1925). © 2014 S. Karger AG, Basel

The 20th century is regarded as the era of modern times and was marked particularly by two world wars and the cold war arising from them. For medicine, the 20th century brought about huge progress in the diagnosis and therapy of many illnesses [1], promoted above all by the ever quicker and rapid developments in the natural sciences. This development had already started in the 19th century. Downloaded by: National Univ. of Singapore 198.143.39.65 - 8/6/2015 7:27:40 PM

Abstract

Table 1. Landmarks of medicine in the 20th century (from Halter [1])

Only in the 20th century, however, were drugs and methods developed, targeting illnesses efficiently and with lasting effect. Critics of medicine, but also some medicine historians, state that only from about 1900 did a doctor’s visit really help the patient. As a result, the population became increasingly aged in the industrialized countries of the world. In

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Fig. 1. Membership card of 1905/1906.

Germany, for example, life expectancy in this period increased by approximately 30 years. The scale of progress made in medicine during the 20th century was huge. A small selection of especially important steps is shown in table 1. Essential allergological landmarks began at the start of the 20th century, and were complemented during the following years in the area of diagnostics as well as therapy, in ever more rapid results. The author is completely aware that he cannot give an entire acknowledgment of all events and personalities involved in this progress. Besides, the article is written from a European-German view, influenced by personal allergological work since 1968. The author hereby gives his apologies should important developments not be appreciated extensively enough.

Patients First – The First Patient’s Organization for Allergy Sufferers In the first years of the 20th century, the very first patient organization (‘Heufieber-Bund’; fig. 1) was founded in Germany for patients with hay fever. An association of hay fever sufferers was noted in the association register of the royal district court of Altona (Hamburg) on September 10, 1900. The patients had been meeting since 1897 on the island of Helgoland, where their hay fever did not occur as often as on the mainland.

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1900 First ‘X-ray congress’ in Paris on the radiation discovered in 1895 1901 Karl Landsteiner describes the blood groups 1905 Fritz Schaudinn and Erich Hofmann discover the cause of syphilis, Spirochaeta pallida 1906 Alois Alzheimer describes the degeneration of the brain (‘Morbus Alzheimer’) 1910 Paul Ehrlich synthesizes the first chemotherapeutic drug against syphilis (‘Salvarsan’) 1921 Frederick Banting and Charles Best isolate insulin 1928 Alexander Fleming discovers Penicillium notatum, a mushroom which leads to the development of penicillin 1929 A 25-year-old assistant, Werner Forssmann, places the first heart catheter in a self-experiment 1948 The new antibiotic streptomycin is effective against tuberculosis and plague 1954 The first heart-lung machines are used for operations in the open heart at a standstill 1955 First polio vaccination 1958 In Sweden a heart pacemaker is implanted 1960 The anti-baby pill comes onto the market 1960 The development of the artificial kidney is finalized and the dialysis is applied clinically 1961 The first artificial heart flap is successfully implanted into a person 1964 First dilatation of narrowed heart coronary arteries 1967 Christiaan Barnard performs the world’s first successful human-to-human heart transplant; the patient survives 18 days 1968 Bone marrow transplantation is applied successfully 1982 The HIV retrovirus causing deadly immune weakness – to be called Acquired Immunodeficiency Syndrome (AIDS) – is discovered by Luc Montagnier and Robert Gallo 1990 Microsurgical procedures (‘key hole surgery’) become established in all sections of medicine 1992 The microbe Helicobacter pylori is acknowledged, nearly one hundred years after its discovery, as a main cause of gastritis and ulcera 1995 Robots conduct millimeter-exact hip joint operations in California

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Fig. 2. The Medical News dating from 1900 in New York, with one

Fig. 3. H. Holbrook Curtis.

of the first reports on immunotherapy against ragweed allergy.

Milestones in the 20th Century

value of patient organizations has been recognized where they contribute substantially to the understanding of the needs of allergy sufferers and cooperate with members to help themselves. Today (summer 2013), the European Federation of Asthma and Allergy Associations (EFA; www. efanet.org) is an alliance of 41 organizations in 23 different countries across Europe. EFA’s mission is to draw together a European community of patient organizations which share responsibility for substantially reducing the frequency and severity of allergies, asthma and COPD, minimizing their societal implications, improving health-related quality of life and ensuring full citizenship of people with these conditions, as well as pursuing equal health opportunities in the allergy and airways field in Europe.

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The number of members in the hay fever alliance rose rapidly from 157 in 1902 to 1,387 members only 6 years later. Among the members who joined during the first years were scientists, artists and members of the high-ranking nobility like ‘Her Majesty Victoria Eugenia, Queen of Spain’ (grandmother of the acting King of Spain, Juan Carlos). The association had three aims: ( 1) to give advice and information to patients with hay fever and their families; ( 2) to collect money to allow the stay on the island of Helgoland to patients with less money during the pollen season; ( 3) to provide sociable connections. In 1929, the first ‘advice center for allergic illnesses’ was opened by the association, and after more than 100 years the association is still active today and is highly successful regarding the achievement of these aims. In many countries around the world, the

Fig. 4. Leonard Noon.

Fig. 5. Results of conjunctival tests done by Noon following subcutaneous injections of grass pollens given in threshold values of the extract to induce a conjunctival reaction.

In 1900, in The Medical News (fig. 2) from New York, one could read about one of the first reports on the use of watery pollen extracts with ‘some eight or ten’ patients with ‘coryza’ [2]. Henry Holbrook Curtis (1856–1920; fig. 3), the ENT physician, vocal therapist in the Metropolitan Opera and inventor of the tonograph, reported ‘remarkable results’ in these patients following the subcutaneous injection and oral application of pollen extracts from the ‘old enemy rag-weed … the recognized king of pollens’. It seems that there were no other trials by him – but the idea was taken up successfully by Leonard Noon (1878–1913; fig. 4) in London. Leonard Noon published in The Lancet in 1911 the first documentation of the effectiveness of subcutaneous immunotherapy (SCIT) in grass-allergic subjects with hay fever using conjunctival provocation testing [3]. Noon was working at St. Mary’s Hospital in London when he began tests with injections of pollen extracts (fig. 5).

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After Noon’s early death, his friend John Freeman (1877–1962; fig.  6) continued this work and, only 3 months later, published a more detailed paper on the ‘hypodermic inoculations of pollen toxin’ in 20 patients [4]. In Freeman’s opinion the results were ‘disappointing’, ‘inconclusive’ or a ‘failure’ in 3 cases, and ‘moderately, fairly or eminently satisfactory’ in 16 cases. He concluded: It is claimed that this increase in immunity produced by pollen vaccine is in itself the best proof of the soundness of this line of treatment, whether prophylactic or phylactic. It is true that one does not know if this increase is sufficient for all purposes, but the change is certainly in the right direction, and must be doing good.

Freeman and Noon administered increasing doses of crudely prepared whole allergen extracts to allergy patients until their symptoms were successfully lessened. These experiments represented the beginnings of the development of ‘desensitizing immunotherapy’. Noon also made the first attempt at standardizing allergen doses and established the ‘Noon unit’ based on weight.

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Immunotherapy against Pollen and Other Allergens – The ‘Backbone of Allergology’

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For nearly 50 years following Noon’s paper there have been only anecdotic reports on the efficacy of SCIT. The first study of SCIT purporting to be a controlled trial did not appear until 1950 [5], but the study did not seem to satisfy the criteria for experimental control. In 1954, Frankland and Augustin [6] published the first double-blind placebo-controlled study of SCIT, followed by a DBPC study in the USA at the Harvard Medical School in 1965. In this study, 12 patients who were each suffering from allergic rhinitis due to ragweed pollen received verum or placebo injections. Medication and symptom score were significantly different in favor of the verum. Since then, many controlled clinical trials have confirmed the efficacy of SCIT and, although some concerns have arisen around safety, SCIT remains a valid option for treating allergic disease. In the centenary year of 2011, data were presented by use of conjunctival provocation test and allergen-specific immunoglobulin (Ig) G that replicated this observation and additionally confirmed the allergen specificity of SCIT using a double-blind design employing either grass or mite SCIT in dual grass- and mite-allergic individuals [7]. A series of publications were issued in 2011 which summarized the development and success of immunotherapy [8]. The use of skin prick tests and new allergen extraction techniques accelerated the development of

Milestones in the 20th Century

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SCIT, which became a widespread practice. Recent developments include the introduction of sublingual immunotherapy, and clinical trials of recombinant and peptide vaccines.

Anaphylaxis – The Discovery of a New Field in 1902 In 1902, Paul Portier (1866–1962; fig.  7) and Charles Richet (1850–1935) [see fig. 1 in the chapter by Ring et al., this vol., p. 55] published a short, comprehensive publication, only a little more than two sides in length, after a talk before the Paris ‘Société de Biologie’ in which they first coined the term ‘anaphylactic’ reaction (anaphylaxis): ‘Nous appelons anaphylactique (contraire de la phylaxie) la propriété dont est doué un venin de diminuer au lieu de renforcer l‘immunité, lorsqu‘il est injecté à doses non mortelles’ [9] (fig. 8; online suppl. movie 1, see www.karger.com/chial100_movie1). Both authors meant to stimulate only one aspect in the field of serology and immunology, but they initiated a quite new working direction; in 1913 Richet received the Nobel Prize for this. Around the turn of the 19th century, the ideas of Robert Koch dominated the scene due to his new therapy for tuberculosis by means of tuberculin (from 1897). In 1897, Paul Ehrlich also coined the term

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Fig. 6. John Freeman. Fig. 7. Paul Portier.

Fig. 8. Paul Portier enters the congres-

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that was given to the side chain theory, and in 1892 Behring published his ‘blood serum therapy’ in Leipzig. The rapid rise of bacteriology and the possibilities of immunization against infectious diseases inspired the ‘mainstream’ of medicine during these years. In 1901, using the lab on the yacht ‘Princesse Alice II’ [see fig. 3 and 5 in the chapter by Ring et al., this vol., p. 56 and p. 57] belonging to Albert I, Prince of Monaco, Charles Richet and Paul Portier studied the toxic qualities of certain kinds of jellyfish, with which contact led to urticarial reactions. Was it possible, by the repeated injection of toxins, to make animals insensitive, tolerant or even immune? The answer was no; the opposite in fact occurred: with repeated injections after an incubation time, the slightest, subtle amount led to typical clinical reactions with tachycardia, blood pressure decrease, diarrhea, respiratory insufficiency and even death in the case of anaphylactic shock. These phenomena deviated considerably from the picture of a primary poisoning, and therein quite a new form of hypersensitivity had been discovered. The term anaphylaxis should express a defenseless state with regard to the toxin; although philologically the word was criticized, it immediately found its entrance into medical language and substituted the oldest allergological name of ‘idiosyncrasy’.

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The phenomenon of anaphylaxis stimulated, in a broad sense, research on allergic reactions in humans and animals, leading to different ‘forms of anaphylaxis’. The concept ‘allergy’ would follow that of ‘anaphylaxis’ 4 years later.

The Determining Word Is Born in 1906 On July 24, 1906, the word ‘allergy’ was first used in a publication by Clemens von Pirquet (fig. 9) in the Journal Münchener Medizinische Wochenschrift: We need a new … word for the altered state which the organism finds out by the acquaintance with any organic, living or lifeless poison … For this general concept of altered responsiveness, I suggest the term allergy. [10]

The meaning of the term has its origin in the Greek word ‘allos’ (other) and ‘ergos’ (activity). Within a few years the new expression had conquered the whole world and had edged out all older, varied names like idiosyncrasy, hypersensitivity, anaphylaxis and atopy, etc. The word ‘allergy’ represented a clinical concept which enabled one ‘to understand’ such clinical situations, the genesis of which were not yet understood. What was the background for the new word? Pirquet was an eager doctor and researcher whose main interest was always the illness of children and who

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sional hall in Paris on October 19, 1958, with Bernard Halpern, and reports on the experiments on anaphylaxis (see www. karger.com/chial100_movie1). Fig. 9. Clemens von Pirquet (1906).

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Fig. 10. Clemens von Pirquet in the Clinic for Pediatrics, Vienna, Austria.

Milestones in the 20th Century

through his good relations with American pediatricians, helping 400,000 malnourished children in Austria through the delivery of food.

Serum Sickness and the ‘Case Langerhans’ The development and use of vaccines for the prophylaxis and therapy of infectious diseases, such as diphtheria and tetanus, led to an absolutely new clinical picture – that of serum sickness (or ‘serum illness’). Firstly, only harmless side effects like urticaria and local exanthemas after injections were reported – then, however, a tragic event occurred. On April 4, 1896, the well-known Berlin pathologist Robert Langerhans (1859–1904) injected 1.2 ml of diphtheria antitoxin (‘Behring’s antiserum’) subcutaneously to his almost 2-year-old child for prophylactic reasons. Before his own eyes, his own child passed away 7 min later. Langerhans published a detailed report [11] and by 1910, 41 deaths had been described after injections of diphtheria vaccine [12]. The concept of ‘serum sickness’ as a result of anaphylactic reactions to foreign proteins was put forward by Clemens von Pirquet together with Béla Schick (1877–1967; fig. 11) in 1903 [13]. To avoid anaphylactic reactions Schick discovered a test for susceptibility to diphtheria (the Schick test), which

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constantly drew his conclusions from observations made at the sickbed. Around 1902, he first became aware of allergies when he observed that some children suffering from diphtheria developed non-disease-related and quite extreme side effects when treated with a horse serum antitoxin. These observations and conclusions led to a new pathology; not only had the increase of the bacteria penetrating the body determined the course of the illness, but also the interaction between the organism and the bacteria. A repeated contact with the same material, which he called ‘allergen’, led to the reaction between the allergen (antigen) with the counter material, the antibody. Pirquet was an all-round physician – he restructured the education of nurses and placed a high value on ‘teamwork’. In addition, the nursing staff could introduce innovations in a patient’s care and therapy. From 1924 onward, Pirquet also insisted that trainee doctors must finish a nursing training period to understand the problems in care better and to improve the cooperation between nurses and doctors. These were – at that time and still today – huge changes in the system of patient care (fig. 10). He also became an excellent organizer in other areas: after the First World War he was able to activate a large-scale child relief operation in America

Fig. 11. Béla Schick.

Fig. 12. Schick test, 1915.

Fig. 13. Nicolas Maurice Arthus.

Fig. 14. Alexandre Besredka (right) beside Elias Metchnikoff (left) in the Institute Pasteur, Paris, France, 1914.

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The Idea of Anaphylaxis Received Growing Interest … Following the publication on anaphylaxis in 1902 [9], a number of allergologists around the world revealed more details on the phenomenon; hence, the ‘local anaphylaxis’. Local Anaphylaxis Nicolas Maurice Arthus (1862–1945; fig.  13) postulated in 1903 the term ‘local anaphylaxis’, also known as ‘Arthus reaction’ [14]. Arthus had also observed that repeated injections of non-toxic materials (e.g. milk, horse serum) in the skin of rabbits led to stronger and stronger defensive reactions at the site of the injection. Inflammation and focal necroBergmann

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made him world famous (fig. 12). The test involved a small sample of toxin injected under the skin. If the subject did not have the necessary antibodies, a rash developed around the injection site, indicating a positive result, and a vaccine then could be administered. The test and vaccine eventually led to the eradication of the childhood disease that attacked 100,000 Americans in 1927, leading to about 10,000 deaths. The observation of the ‘serum illness’ as a now and then fatal result of an injection of antiserum and its avoidance by way of the ‘Schick test’ shows the close connection of allergology and clinical immunology. This fruitful connection of both disciplines was particularly very clear at the beginning of 20th century.

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Fig. 17. Richard Otto. Fig. 18. Paul Uhlenhuth.

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sis of the skin appeared in increasing strength from injection to injection after approximately 6–8 h. Later the Arthus reaction was seen as a type of local type III hypersensitivity reaction (immune complex mediated), mainly as local vasculitis due to deposits of IgG-based immune complexes in dermal blood vessels. Anaphylactic Shock and ‘Local Immunity’ In 1907, Alexandre Besredka (1870–1940; fig. 14) published the term ‘anaphylactic shock’ [15]. At the Institute Pasteur in Paris, Besredka tried to inhibit

Milestones in the 20th Century

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the toxic (anaphylactic) effect from vaccines (foreign serums) by an ‘anti-anaphylactic vaccination’. The attempts failed and the term anaphylactic shock has remained until this day. In 1919, Besredka also published his ideas on ‘local immunity’. This exists predominantly from secretory IgA, which works independently of the serum IgA. Therefore, he was later named as the father of ‘mucosal immunity’.

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Fig. 15. Victor Henri Hutinel. Fig. 16. Karl Hansen.

Fig. 19. Arthur Fernandez Coca. Fig. 20. Robert Anderson Cooke.

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Alimentary Anaphylaxis In 1908 the French pediatrician Victor H. Hutinel (1849–1933; fig. 15) reported on cases of anaphylactic reactions induced by food – the ‘alimentary anaphylaxis’ [16].

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the differentiation of proteins was shown by Paul Uhlenhuth (1870–1957; fig. 18), a hygienist and serologist in Freiburg, Germany [19].

The Word ‘Atopy’ Has Remained to This Day

However, in clinical reality with humans an universal shock mostly does not occur, rather only one or several symptoms of a shock are clearly apparent, which we want to call ‘shock fragments’.

Richard Otto (1872–1952; fig. 17) worked at the Imperial Health Centre in Berlin and documented further important details of anaphylaxis: the incubation time is between 8–10 days, the reaction is specific and stops approximately 2–3 months later, the sensitization can be transferred passively by mothers to their newborns and a large number of antigens (animal, herbal, bacterial) are able to induce anaphylactic reactions, including non-toxic antigens [18]. That the anaphylactic reaction may also be used for

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Arthur Fernandez Coca (1875–1959; fig. 19) and Robert Anderson Cooke (1880–1960; fig.  20) first used the term ‘atopy’ at a congress in 1921 in Washington and published it in 1923 [20]. By the term ‘atopy’, Coca and Cooke understood the spontaneously (e.g. without former vaccination) appearing diseases hay fever and asthma, with a genetic disposition within families. The word ‘atopy’ was first used only in the USA, but later became global. Many physicians and scientists use the term for any IgEmediated reaction (even those that are appropriate and proportional to the antigen), but many pediatricians reserve the word ‘atopy’ for a genetically mediated predisposition to an excessive IgE reaction. An exact definition is yet to be agreed. In 1915 Coca founded the scientific journal, Journal of Immunology. As a young man, Cooke suffered from asthma which was particularly apparent when riding the horse-drawn ambulance as an intern. During his internship he was also exposed to diphtheria and suffered a nearly fatal reaction when given

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Anaphylaxis in the Clinical Routine Richet and Portiers’ founding theory of anaphylaxis was first based only on findings from animal experiments and had great influence upon clinical allergy. Karl Hansen (fig. 16) later (1941) created the concept of the ‘anaphylactic shock fragment’ with asthma [17]. He wrote:

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a prophylactic injection of diphtheria antitoxin. These experiences certainly further stimulated his interest in allergy. On February 19, 1919, at New York Hospital, he opened the first clinic devoted to allergy. This clinic served not only as an outpatient service for the treatment of allergic individuals, but also as a center for research and training in allergy. In 1932, the entire clinic was moved to Roosevelt Hospital, where Dr. Cooke was appointed Director of Allergy. Cooke also helped establish the standardization of allergens by nitrogen content, as determined by the Kjeldahl method. He described ‘blocking antibodies’ and in doing so provided one of the earliest logical concepts for the clinical improvement of allergen immunotherapy.

The Transferability of an Allergy by Blood, or the Search for the ‘Malefactor’ Following the observation and description of serum sickness as a result of treatment with foreign proteins by Pirquet [13] in 1903, the search for the trigger of these reactions in humans was intensified. The question arose as to whether these were cells, or if a protein in the serum triggered the reactions.

Milestones in the 20th Century

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Among the first steps to clarification – with the final outcome being the discovery of IgE – an event in Central Park in New York has to be mentioned. A usually healthy 35-year-old waiter with negative family history underwent a blood transfusion (600 ml) for primary anemia. Two weeks later, and without recognizable reason, he suffered from an attack of asthma 5 min after entering a horse carriage in the park. He received epinephrine and when he entered the park again the next day another asthma attack occurred. He was brought to the acute day ward by Dr. Ramirez (fig. 21), who tested the patient ‘for a large number of food and bacterial proteins, pollens etc. with negative results, finally, however, obtaining a positive reaction to horse dandruff, measuring 1.5 cm in diameter and reacting as a 1:20,000 dilution’. The blood donor was a persistent asthmatic who was also positive to horse dandruff. Dr. Ramirez rightly concluded that the allergy had been transferred along with the blood. He made the demand for future blood donors to be asked whether they were allergy sufferers, and concluded that ‘the presence of these “anaphylactic bodies” in the donor’s blood caused no untoward effects on the recipient during or immediately following the transfusion’ in the absence of an allergen.

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Fig. 21. Maximilian H. Ramirez. Fig. 22. Karl Prausnitz.

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This unusual case was published in 1919 [21]. The short case report shows exactly how history at this time was handled and from a single observation important conclusions could be gleaned. Some years later, in 1922, Frugoni reported [22] a similar but experimentally induced case in which a rabbit allergy was transferred to a healthy 12-yearold girl. After playing with a rabbit she suffered from rabbit allergic rhinoconjunctivitis, urticaria and cough, which developed after she had received a blood transfusion from a donor with rabbit allergy.

The Transferability of an Allergy through Serum Is Proved Only 3 years after Ramirez’s observation, Karl Prausnitz (1876–1963; fig.  22) and his assistant Heinz Küstner (1897–1963; fig. 23) in distant Wroclaw (today in Poland) published their discovery that allergy can be transferred with serum, with cells playing no role [23]. Heinz Küstner worked at the Hygiene Institute in Wroclaw (1897–1963) as a junior scientist in Prausnitz’s department. He was allergic to fish and provided an opportunity for Prausnitz to demonstrate the passive transfer of fish antibodies to somebody who was not allergic to fish, i.e. to himself. Prausnitz was allergic to pollen, but could

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eat fish without problems. Küstner’s serum was injected in various dilutions into Prausnitz’s skin. The next day he injected a fish extract near the injection sites of Küstner’s serum as well as other areas. Only the areas where Küstner’s serum had been injected reacted with an immediate wheal and flare. With this experiment and publication in German (in 1921) [23] and English (in 1962), the earlier ideas of toxins and anti-toxins in allergic diseases were overcome. Sheldon Cohen (2004) summarized: Thus even though the allergic antibody had not yet been characterized, a scientific immunologic basis for investigating allergic phenomena had thereby been initiated. [24]

The Prausnitz-Küstner reaction remained the classical method for demonstrating and quantifying allergen-specific antibodies for many decades. In 2005, Johansson (fig.  24) transfused defined amounts of IgE antibodies to an allergen and measured the degree and duration of IgE reactivity in the recipient by skin prick tests and basophil allergen threshold activation. It was concluded that after transfusion of plasma with >10 kU/l of IgE antibodies the recipient could have allergen-reactive basophiles for up to 7 weeks [25].

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Fig. 23. Heinz Küstner. Fig. 24. S.G.O. Johansson, June 1992.

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Fig. 25. Zoltan Ovary.

Fig. 26. Example of a passive cutaneous anaphylaxis reaction (Cox JSG, 5th March 1969).

In 1958, Zoltan Ovary (1907–2005; fig.  25) described the passive cutaneous anaphylaxis test (fig. 26). In this test an animal (usually a guinea pig) is injected intradermally with antibody (usually IgE) and subsequently challenged intravenously with a mixture of antigen and Evans blue dye 24–48 h later. A dark-blue area indicates a positive reaction due to the leakage of the dye at the site of antigen-antibody reactions. Ovary worked until his 98th year and summarized his fascinating life as an allergologist in his autobiography, entitled Souveniers [26]. The test was an advancement of the Prausnitz-Küstner tests for experimental purposes and was very important regarding the search for antibodies in small quantities.

Scientific Allergy Diagnostics After earlier, predominantly casuistic observations about nasal, conjunctival and cutaneous reactions, mostly after accidental contact with allergens, diagnostic tests were scientifically founded by Charles Harrison Blackley. Before him the induction of allergic symptoms was generally only speculated

Milestones in the 20th Century

about, and there were hardly any experiments. In 1873 he wrote: It is, however, much easier to try and theorise than to carry out experiments, and especially when these would have to be tried on the theoriser’s own person. [27]

Scratch Test The description of the scratch test on the skin by Blackley in 1873, involving pollen extracts scratched into his own skin, was a landmark in the development of allergy diagnostics. This ‘scarification test’ was described in more detail in 1912 by Oscar Menderson Schloss (1882–1952) [see fig. 2 in the chapter by Wüthrich, this vol., p. 111] as a ‘scratch test’ [28] and was made very popular by Isaac Walker as ‘an asthma test’ after 1917 [29]. According to Hans Schadewaldt this started ‘the history of modern allergological skin tests … after the introduction of the ‘Läppchenprobe’ (patch test), by the German dermatologist Josef Jadassohn (1863– 1936; fig. 27) in the year 1894. In 1896 he named the simple application of test substances without injury a ‘functional skin test’ [30].

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Passive Cutaneous Anaphylaxis Test

Fig. 27. Josef Jadassohn. Fig. 28. Bruno Bloch.

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Fig. 29. Patch test with pieces of textiles.

Fig. 30. Skin drill for prick test from Pirquet.

Precursor of the Prick Test In 1890, Robert Koch presented his tuberculin at the 10th International Medical Congress in Berlin, and demonstrated a subcutaneous tuberculin test.

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Pirquet modified the tuberculin test by giving a drop of tuberculin on the skin of the forearm and then using a ‘Pirquet-drill’ (fig. 30) to scarify the skin under the tuberculin drop. This was the precursor of the skin prick test. Pirquet demonstrated his test for the first time in Vienna on June 6, 1907 [33]. The ‘puncture method’ was then further recommended by Freeman in 1930 for dermal testing and inoculation for vaccines [34]. This ‘modified prick test’, as it is used today, was developed by Mrs. Helmtraut Ebruster and was published in 1959 [35]. She worked for a short time at the University Clinic for Dermatology in Vienna. The test became the most commonly used allergy test worldwide; however, of H. Ebruster there are no known pictures and we know very little about her life.

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Around 1928, the patch test was popularized and developed further by Bruno Bloch (1878–1933; fig. 28), leading the test to general recognition as the ‘Jadassohn-Bloch patch test’ (fig. 29, from Berger and Hansen [31]). The generally accepted term ‘patch test’ was coined by Marion Baldur Sulzberger (1895– 1983) [see fig. 6 in the chapter by Wallach and Taïeb, this vol., p. 88] in 1931, who, together with Fred Wise, popularized the test in the USA [32].

Intracutaneous Test On March 22, 1908, Felix Mendel (1862–1925), working in Essen, Germany, recommended the intracutaneous application of tuberculin, not as a diagnostic tool but as a way of vaccination [36]. His name is almost forgotten. Some months later, on August 10, 1908, Charles Mantoux (1877–1947) published the tuberculin test in the same way, known today as the Mendel-Mantoux test [37]. Béla Schick used the intracutaneous test (fig. 31) for the detection of immunity to diphtheria and Robert A. Cooke published the method in New York in 1915 [37]. In the early years there was considerable disagreement as to the relative advantages of the intracutaneous (or ‘endermal’) test in comparison to the scratch test, which was simpler and safer. The endermal test was more sensitive, but more dangerous when not properly used, and fatalities had been reported as a consequence [38]. So it was proposed by Vaughan [39]:

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Fig. 31. Positive intracutaneous tests; from + to +++.

The safe procedure is invariably to apply scratch tests before testing endermally with the same allergens.

Rub Test The technically easiest skin test for proving a sensitization was first described in 1961 as a ‘rub test’ by Albert Oehling [40]. He demonstrated the test in a carpenter with an allergy to obeche wood using the native wood. The ‘rub test’ has proven to be a very reliable, easily demonstrable and extremely simple method for detection of IgE-mediated allergy, inducing an immediate reaction with various inhalative and ingestive allergens. Fig. 32. Albert Calmette.

Conjunctival Provocation

Milestones in the 20th Century

[41, 42]. Therefore, for some years the test was named the Calmette and Wolff-Eisner ophthalmo reaction. Noon and Freeman used the test successfully in 1911 for measuring the effectiveness of immunotherapy (fig. 33, from Urbach [43]).

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The ‘ophthalmo reaction’ was used by Blackley in 1873 for the diagnosis of hay fever, but the method fell into oblivion. In 1907, Léon Charles Albert Calmette (1863–1933; fig. 32) and Alfred Wolff-Eisner (1877–1948) published the usefulness of the conjunctival test for the diagnosis of tuberculosis

Nasal Provocation Test The development of the nasal provocation test started with the publication of a case report by the British physician William P. Kirkman (1827–1852), who reported in a local medical journal in 1852 [44]. In 1851 at around Christmas time, Kirkman, who suffered from hay fever, had a flowering grass in his greenhouse ‘loaded well with pollen’. He took some pollen in his hand and inhaled them through his nose. He sneezed immediately and developed all the symptoms of hay fever over the next hour. In this way, the deliberate nasal application of pollen had led to hay fever symptoms outside of the pollen season in an experiment. The Boston laryngologist Joseph Lincoln Goodale (1868–1957) systematically studied the nasal allergen provocation in the diagnosis of allergic rhinitis and, in 1914, published the test in detail for the diagnosis of horse asthma [45]. Between 1914 and 1916 he tested more than 400 patients suffering from rhinitis due to animal dander, food and pollen on the nasal mucosa. In 1925, William W. Duke (1883–1946; fig. 34) suggested the test as a routine procedure [46]. He made modifications in an effort to avoid overly intense reactions by spraying dilutions of 1:1,000 pollen extract into the nose. In 1930, outside of the pollen season, Efron and Penfound blew a small amount of dried pollen into

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one side of the nose [47]. When the patient was allergic to pollen hay fever, symptoms of varying severity ensued; it was reported that some patients had severe nasal and conjunctival symptoms. In 1933, Erich Urbach (1893–1946) developed and proposed the ‘cotton applicator method’ (Stieltupfermethode; fig. 35) to allow provocation with allergen extracts [48]. From 1935 the allergens were given as powder into the nose, termed the powder puff test [49].

Inhalation Tests In 1925, the brothers Simon S. (1892–1957) and Charles S. Leopold (1896–1960) developed and published an inhalation technique for allergens, primarily for experimental tests and not for routine diagnostics [50]. It seems that the test was not popular. Later, in 1952, Schiller and Lowell used aerosolized allergens for inhalation with special emphasis on house dust, but also with extracts of pollen and Alternaria. Following the inhalation, vital capacity and expiratory rates were measured at intervals of 1 min. A reduction of 10% in vital capacity was considered as evidence of sensitivity. The incidence of skin reactions was much higher than of pulmonary reactions, and there were no pulmonary reactions with allergens which did not result in skin reactions [51].

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Fig. 33. Positive conjunctival test. Fig. 34. William Duke.

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Fig. 35. The cotton applicator method according to Urbach.

Fig. 36. Teruko and Kimishige Ishizaka.

In 1956, Wilhelm Gronemeyer (1912–1990) and Erich Fuchs (1921–2008) published the ‘inhalation pneumometry test’ as a routine method in Germany which was especially designed for the diagnosis of occupational asthma. A positive inhalation test was seen as the ultimate proof of a clinically relevant sensitization [52].

Discovery of IgE and Slow Reacting Substances

Milestones in the 20th Century

Fig. 37. Bengt Ingemar Samuelsson.

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Kimishige Ishizaka (born in 1925) and Teruko Ishizaka (born in 1926; fig. 36) isolated IgE from the serum of sufferers of hay fever caused by ragweed, immunized rabbits and absorbed the antiserum with IgG, IgA, IgM and IgD. Using the supernatant after the absorptions, a Prausnitz-Küstner reaction was induced, and a new Ig class, named gamma E (erythema), had been detected [53]. The time had come for the discovery of IgE. S.G.O. Johansson and H. Bennich had at the same time identified a previously unknown Ig in a patient with a myeloma, which they named after his initials, IgND [54]. It turned out that this IgND was identical to IgE, and the long search for the ‘reagins’ was over!

Allergological research was inspired by the discovery of IgE. Its quantitative determination in serum for diagnostic purposes was groundbreaking. In the blood of healthy individuals only small quantities of IgE could be found, while patients with type 1 allergies had elevated amounts – just as in an IgEinduced allergy. The quickly following development of the radioallergosorbent test and its wide use was another diagnostic landmark for the work of allergists all over the world.

Discovery of Leukotrienes In 1982, Bengt Ingemar Samuelsson (born in 1934; fig. 37) received the Nobel Prize in Medicine/ Physiology for identifying leukotrienes as the littleunderstood ‘slow reacting substance of anaphylaxis’, which had been found in allergic inflammation many years earlier. Samuelsson’s work greatly advanced the understanding of the biological role of leukotrienes as mediators in asthma, allergy and inflammation.

References

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15 Besredka A, Steinhardt E: De l’anaphylaxie et de l’antianaphylaxie vis-a-vis du serum de cheval. Ann Inst Pasteur 1907;21:117. 16 Hutinel VH: Intolérance pour le lait et anaphylaxie chez les nourrissons. Clin Paris 1908;3:227. 17 Hansen K: Asthma als Schockfragment. Wien Klin Wochenschr 1941;54:175. 18 Otto R: Zur Frage der Serumüberempfindlichkeit. Münch Med Wochenschr 1907;54: 1665. 19 Uhlenhuth P, Haendel L: Untersuchungen über die praktische Verwertbarkeit der Anaphylaxie zur Erkennung und Unterscheidung verschiedener Eiweissarten. Z Immun Forsch 1909/1910;4:761. 20 Coca AF, Cooke RA: On the classification of the phenomenon of hypersensitiveness. J Immunol 1923;8:163. 21 Ramirez MH: Horse asthma following blood transfusion: report of case. J Am Med Assoc 1919;73:984–985 22 Frugoni C: Studi sull’astma bronchiale cum particolare riguardo all’asma anafilattico. Polliclinico Med 1922;29:179. 23 Prausnitz K, Küstner H: Studien über die Überempfindlichkeit. Zbl Bakt 1921; 86: 160–169. 24 Frankland AW: Carl Prausnitz: a personal memoir. J Allergy Clin Immunol 2004;114: 700–705. 25 Johansson SG, Nopp A, van Hage M, Olofsson N, Lundahl J, Wehlin L, Söderström L, Stiller V, Oman H: Passive IgE-sensitization by blood transfusion. Allergy 2005; 60: 1192–1199. 26 Ovary Z: Souveniers: Around the World in Ninety Years. New York, India Ink Press, 1999. 27 Blackley CH: Experimental Researches on the Causes and Nature of Catarrhus Aestivus (Hay-Fever or Hay-Asthma). London, Bailliere, Tindeall & Cox, 1873, p 73.

28 Schloss OM: A case of allergy to common food. Am J Dis Child 1912;3:341. 29 Walker I: Studies in the sensitisation of patients with bronchial asthma to bacterial proteins. J Med Res 1917;37:487. 30 Jadassohn J: Zur Kenntnis der medikamentösen Dermatosen. Verh Dtsch Derm Ges 1986;5:103. 31 Berger W, Hansen K: Allergie. Leipzig, Thieme, 1940. 32 Sulzberger MB, Wise F: The contact or patch-test in dermatology. Arch Dermatol Syph 1931;23:519. 33 von Pirquet C: Tuberkulindiagnose durch cutane Impfung. Berlin Klin Wochenschr 1907;1907:644. 34 Freeman J: Rush inoculation. Lancet 1930;i: 744. 35 Ebruster H: Der Pricktest, eine neuere Cutanprobe zur Diagnose allergischer Erkrankungen. Wien Klin Wochenschr 1959; 71:551–554. 36 Mendel F: Die von Pirquetsche Hautreaktion und die intrakutane Tuberkulinbehandlung. Med Klin 1908;4:402. 37 Cooke RA: The treatment of hay fever by active immunization. Laryngoscope 1915; 25: 108. 38 Harris LH, Shure N: Sudden death due to allergy tests. J Allergy 1950;21:208. 39 Vaughan WT, Black JH: Practice of Allergy, ed 3. St Louis, Mosby, 1984, p 168. 40 Oehling A, Gronemeyer W: The use of rub test in wood allergy. Abstract 143 of the 4th International Congress. International Congress Series No 42. New York, Allergology, 1961. 41 Calmette LCA: Sur un nouveau procédé de diagnostic de la tuberculose chez l’homme par l’ophthalmo-réaction à la tuberculine. CR Acad Sci 1907;144:1324–1326.

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1 Halter H: Traum vom ewigen Leben. Spiegel 1999;14:131–138. 2 Curtis HH: The immunizing cure of hayfever. Med News 1900;77:16–18. 3 Noon L: Prophylactic inoculation against hay fever. Lancet 1911;i:1572–1573. 4 Freeman J: Further observations on the treatment of hay fever by hypodermic inoculations of pollen vaccine. Lancet 1911;ii: 814–817. 5 Bruun E: Le traitement des états allergiques par désensibilisation spécifique. Acta Allerg 1950;3(suppl 1):239. 6 Frankland AW, Augustin R: Prophylaxis of summer hay-fever and asthma: a controlled trial comparing crude grass-pollen extracts with the isolated main protein component. Lancet 1954;1055–1057. 7 Dreborg S, Lee TH, Kay AB, Durham SR: Immunotherapy is allergen-specific: a double-blind trial of mite or timothy extract in mite and grass dualallergic patients. Int Arch Allergy Immunol 2012;158:63–70. 8 Ring J, Gutermuth J: 100 years of hyposensitization: history of allergen-specific immunotherapy (ASIT). Allergy 2011;66:713– 724. 9 Portier P, Richet C: De l’action anaphylactique de certain nénins. CR Soc Biol 1902; 54:170. 10 Pirquet C: Allergie. Münch Med Wochenschr 1906;53:1457. 11 Langerhans R: Tod durch Heilserum! Berl Klin Wochenschr 1896;33:602. 12 Lamson RW: Sudden death associated with the injection of foreign substances. J Am Med Assoc 1924;82:109. 13 Pirquet C, Schick B: Zur Theorie der Inkubationszeit. Wien Klin Wochenschr 1903; 16:758. 14 Arthus M: Injections répétées de sérum de cheval chez le lapin. CR Soc Biol 1903; 55: 817–820.

42 Wolff-Eisner A: Die kutane und konjunktivale Tuberkulinreaktion, ihre Bedeutung für Diagnostik und Prognose der Tuberkulose. Z Tuberk 1907;12:21–25. 43 Urbach E: Klinik und Therapie der allergischen Krankheiten. Vienna, Maudrich, 1935. 44 Kirkman W: Case of hay fever. Prov Med Surg J 1852;12:360. 45 Goodale JL: Studies regarding anaphylactic reactions occurring in horse asthma and allied conditions. Ann Ot 1914;23:273. 46 Duke WW: Allergy, Asthma, Hay Fever, Urticaria and Other Manifestation of Reaction. St Louis, Mosby, 1925.

47 Efron BG, Penfound WT: A nasal test with dry pollens in the diagnosis of seasonal hay fever. J Allergy 1930;2:43. 48 Urbach E: Methodik des Allergennachweises. Münch Med Wochenschr 1933; 80: 134. 49 Urbach E: Fortschritte in der Testung und Behandlung allergischer Kranker. Wien Klin Wochenschr 1935;48:251. 50 Leopold SS, Leopold CS: Bronchial asthma and allied allergic disorders. J Am Med Assoc 1925;84:731. 51 Schiller IW, Lowell FC: The inhalation test as a diagnostic procedure with special emphasis on the house dust allergen. J Allergy 1952;23:234.

52 Fuchs E, Gronemeyer W, Iwanoff I: Der inhalative Antigen-Pneumometrie-Test zur Ermittlung des aktuellen Allergens bei berufsbedingtem Asthma bronchiale. Dtsch Med Wochenschr 1956;81:339. 53 Ishizaka K, Ishizaka T, Hornbrook MM: Physicochemical properties of reaginic antibody. 5. Correlation of reaginic activity with γE-globulin antibody. J Immunol 1966;97:840–853. 54 Johansson SG: Raised levels of a new immunoglobulin class (IgND) in asthma. Lancet 1967;ii:951–953.

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Milestones in the 20th Century

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Prof. Dr. med. Karl-Christian Bergmann Allergie-Centrum-Charité, Charité – Universitätsmedizin Luisenstrasse 2 DE–10117 Berlin (Germany) E-Mail karlchristianbergmann @ googlemail.com

Milestones in the 20th century.

From its very beginning, the 20th century represented the period of the main breakthrough for allergology as a clinical and scientific entity. The fir...
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