Most Common Allergic Diseases: Historical Reflections in Understanding Bergmann K-C, Ring J (eds): History of Allergy. Chem Immunol Allergy. Basel, Karger, 2014, vol 100, pp 101–104 DOI: 10.1159/000358614
Urticaria and Angioedema
2
Marcus Maurer Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Germany
Urticaria and angioedema are ancient diseases. Many different names have been used to describe them, and many different theories have been postulated to explain their origin and pathogenesis. The current classification and nomenclature of urticaria and angioedema have evolved over several millennia, with many detours and problems, some of which still remain to be solved. This chapter describes the history of urticaria and angioedema. The evolution of selected aspects of today’s understanding of both conditions is also traced, based on the review of original sources and previously published research on this topic. © 2014 S. Karger AG, Basel
Urticaria Urticaria is a group of diseases characterized by the occurrence of itchy wheals (urticae), angioedema or both. Research on the history of this common
skin condition is complicated by several independent problems. Firstly, wheals and/or angioedema occur in diseases other than urticaria, many of which have only been recognized as separate entities within the last centuries (e.g. hereditary angioedema; HAE) or even decades (e.g. Schnitzler syndrome, urticarial vasculitis). Secondly, the name ‘urticaria’ is fairly new, being less than 250 years old [1]. Many different names had been used before then, including knidosis, uredo, Nesselsucht and Nesselfieber, urticatio and randados, among others (see below). This happened, in part, because of changes in the understanding of the pathogenesis and the underlying causes of this condition. Thirdly, urticaria is a heterogeneous group of conditions, and subgroups differ substantially in their clinical course and features, their underlying causes and the relevance and nature of eliciting triggers. Nevertheless, the history of urticaria and angioedema is well researched and understood, which is mainly due to the work of Schadewaldt [1], who published detailed descriptions of the history of both conditions. Downloaded by: University of Hong Kong 147.8.31.43 - 9/6/2016 6:18:23 AM
Abstract
102
More (1478–1535) tells the following story: King Richard, who apparently knew that strawberries would make him break out in hives, convened the lords of the privy council and demanded to be served strawberries, which he ate in their presence. He then left and returned after several hours to show them the urticarial rash that had developed on his arm in the meantime. King Richard blamed this on one of the lords, who he disliked. He accused the lord of witchcraft and had him killed, claiming that the lord had poisoned him [1]. Over the years, many other conditions and factors have been claimed to be responsible for the onset of urticaria. The wide array of theories on the etiology of urticaria, which includes but is not limited to the idiosyncratic theory, the humoral theory, the toxin theory, the nervous theory, the microthrombosis theory, the menstrual theory, the angioneurotic theory, the theory of inflammation, and even the meteorological theory, have previously been reviewed in detail by Czarnetzki [5]. The group of induced (or inducible) urticarias includes contact urticaria (first described by Hippocrates, see above), which occurs at skin sites exposed to contact with urticariogenic substances, as well as cholinergic urticaria and the physical urticarias. The latter are characterized by wheals and/or angioedema that occur in response to skin exposure to a physical trigger, e.g. cold (cold urticaria), pressure (delayed pressure urticaria) or friction (symptomatic dermographism). Symptomatic dermographism is believed to be the first physical urticaria to be described in the literature, in 1767 by Heberden [6]. Today, symptomatic dermographism is used synonymously with urticaria factitia, derived from the term ‘factitious urticaria’ coined by Gull in 1859 [7]. In the Middle Ages, patients with urticaria factitia/ symptomatic dermographism were beheaded or burnt alive because they were assumed to be related to the devil [8]. Solar urticaria was also first described in the 18th century and later, in 1887, identified as being sunlight dependent [9, 10]. Cold urticaria is held to have been first described in 1792 by Frank [11], cholinergic urticaria in 1924 by Duke [12], pressure urticaria in 1929 by Urbach and Fasal [13], and aquagenic urticaria in 1964 by Shelley and Rawnsley [14].
Maurer
Downloaded by: University of Hong Kong 147.8.31.43 - 9/6/2016 6:18:23 AM
Urticaria and angioedema are ancient conditions. Both are believed to have troubled even our earliest ancestors since they are also found in other animals such as horses and dogs. Also, mast cells, the key effector cells of all urticarias and most angioedemas, have been found in the skin of all mammals investigated so far. One of the earliest descriptions of urticaria comes from China, and is more than 2,000 years old. In the Huangdi Neijing [2], written before and during the early Han period around 200 BC, urticaria is referred to as Feng Yin Zheng (‘wind type concealed rash’), very similar to one of today’s traditional Chinese medicine (TCM) terms for urticaria, Feng Sao Yin Zhen (‘wind itch concealed rash’). In TCM, wind is held to be the major pathogen in urticaria, therefore other names for urticaria are wind rash (Feng Zhen) and wind rash lumps (Feng Zhen Kuai). The ‘father of Western medicine’, Hippocrates (460–377 BC), used the term ‘knidosis’ to describe elevated itching lesions caused by nettles (knido in Greek), which would appear to be the first reference to what today is called contact urticaria. Hippocrates is also believed to have first described gastrointestinal disorders as a cause of urticaria. Urticaria, in the ancient Latin medical literature, was called ‘uredo’ (urere means ‘to burn’), and ‘essera’ (meaning ‘elevation’) in the old Persian medical texts. Paracelsus (1493–1541) introduced the first German name, Leusschieppen, but this was neither useful nor used for long. The term ‘urticaria’, derived from Urtica urens (stinging nettle), was first introduced by William Cullen in the 18th century [3]. Today, urticaria is understood to be a group of diseases, most commonly classified as either acute or chronic, and spontaneous or induced by specific eliciting triggers. The underlying causes of spontaneous urticaria are still under investigation and discussion. Autoreactivity, intolerance to food components and/or bacterial infections are held to be relevant by most, but not all, contemporary authors. Even in some of the oldest reports known, urticaria is postulated to be due to food intolerance or food poisoning. Interestingly, the first case report on death from urticaria also involves hives that developed in response to food consumption [4]. In his book, The History of King Richard III, Sir Thomas
Angioedema
Urticaria and Angioedema
2
Fig. 1. Title page of Eugen Dinkelacker’s doctoral thesis on ‘acute circumscript angioedema’ in which he describes the first cases of what is today designated HAE type I/II.
Fig. 2. Title page of Quincke’s landmark paper on angioedema, which linked his name to the condition for more than 200 years.
103
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Angioedema is a common symptom in patients with wheals, either during anaphylactic reactions or in patients with chronic urticaria. The coexistence of both wheals and angioedema was recognized early on, primarily in patients with hypersensitivity reactions to food. In 1586, Marcello Donati [15] described lip swelling in a young male patient in response to the ingestion of eggs. Later reports from the mid-1600s described similar cases of angioedema in response to honey or mussels [1]. Until the late 1800s, angioedema was seen exclusively as a sign of, and linked to, urticaria, even though some cases of isolated angioedema, i.e. without wheals, were reported as early as the mid-1800s. Diez or Graves, for example, noted the danger of laryngeal edema and speculated that similar swellings may involve the mucosa of the gastrointestinal tract [1]. In 1882, it was Eugen Dinkelacker and his teacher Heinrich Irenäus Quincke [16] (1842–1922), a German internist and surgeon in Kiel, who first described HAE. Dinkelacker’s doctoral thesis (fig. 1) documented 14 cases of angioedema, some with and some without wheals. In retrospect, at least 2 of the patients described had HAE: a 22-year-old male patient with chronic recurrent facial, laryngeal and abdominal angioedema attacks of up to 3 days duration since early childhood, and his infant son. Both patients apparently used to develop prodromal symptoms, including erythema marginatum. Quincke and Dinkelacker used the term ‘acute circumscript angioedema’ for the condition they described, which soon became known as Quincke’s edema. At the time, urticaria was held to be of ‘angioneurotic’ origin, i.e. caused by an increased permeability of capillaries due to a spasm in response to neurogenic influences. It is, therefore, not surprising that Quincke and Dinkelacker both suggested that the cases of angioedema they had observed were also due to ‘angioneurosis’. In fact, the term ‘angioneurotic edema’ had been used by other authors earlier, for example by Bannister in 1880 in his description of suddenly appearing and inflammatory swellings [17]. Although Quincke, who is also known for introducing lumbar puncture as a procedure for diagnostic and therapeutic purposes, postulated that pa-
tients with ‘acute circumscript angioedema’ exhibit a disposition to develop ‘angioneurotic’ edema, he did not hold this condition to be hereditary, and the term ‘Quincke’s edema’, which is no longer used in modern classifications of angioedema, is not synonymous with HAE. In fact, it took until 1917 before Crowder and Crowder [18] discovered the autosomal dominant pattern of inheritance of HAE. In the years after Quincke’s 1882 landmark publication (fig. 2), several other authors reported similar cases of angioedema. Many of these reports describe the danger and mortality associated with laryngeal swellings, which had already been mentioned earlier. In 1888, Osler [19], who – like Dinkelacker and Quincke – described several members of one family to be affected, and who is believed to have coined the term ‘hereditary angioneurotic angioedema’, documented cases of suffocation due to laryngeal edema. Four years later, Griffiths reported the death of a patient and his daughter, both died of la-
ryngeal edema [1]. Within the following 5 years, two large families, with 33 and 110 affected members and 12 and 30 fatalities from laryngeal edema, respectively, were published [1]. Today, we know that recurrent angioedema is either inherited or acquired, and that HAE is bradykinin-mediated and different from histamine-mediated angioedema. A century ago, angioedema was often seen in response to the then popular ‘serum therapy’ and allergic mechanisms were newly discovered. As a consequence, angioedema became widely held to be an allergy, induced by anaphylactic mechanisms, rather than ‘angioneurotic’ responses. This may explain why it took 50 years after the Crowders’ description of the autosomal-dominant pattern of inheritance in HAE before Donaldson and Evans [20] discovered, in 1963, that HAE, which, as we know today, is bradykinin-mediated, to be caused by a deficiency or defect of C1INH, the inhibitor of the complement component C1.
References 1 Schadewaldt H: Geschichte der Allergie. Munich, Dustri, 1983, vol 3, chapt 2, 3. 2 Neijing H: The Su Wen of the Huangdi Neijing (Inner Classic of the Yellow Emperor). Jin dynasty, 1115–1234. 3 Cullen W: Synopsia Nosologiae Methodicae. Edinburgh, Kincaid & Creech, 1769. 4 More T: The history of King Richard III; in Campbell WE (ed): The English Works of Sir Thomas More. London, Eyre and Spottiswoode, 1931, p 426. 5 Czarnetzki BM: Urticaria. Berlin, Springer, 1986, chapt 1. 6 Heberden W: On the nettle-rash. Med Trans Coll Phys (London) 1767, p 185. 7 Gull W: On factitious urticaria. Guys Hospital Reports 1859;5:316. 8 Falk H: Beitrag zum Studium des Dermographismus. Med Diss München, 1901.
9 Borsch JF: De purpura urticata, quam vocant ‘die Nesselsucht’; med diss, Halle, 1719. 10 Veiel T: Über einen Fall von Eczema solare. Arch Derm Syph (Berlin) 1887;19:1113. 11 Frank JP: De curandis hominum morbis epitome. Mannheim, Schwan & Goetz, 1792, vol 3, p 104. 12 Duke WW: Urticaria caused specifically by the action of physical agents. J Am Med Assoc 1924;83:3. 13 Urbach E, Fasal P: Mechanische Urtikaria. Ein weiterer Beitrag zur physikalischen Allergie der Haut. Klin Wochenschr 1929; 8: 2368. 14 Shelley WB, Rawnsley HM: Aquagenic urticaria: contact sensitivity to water. JAMA 1964;189:895.
15 Donati M: De medica historia mirabile. Mantua, Osana, 1586, vol 7, chapt 3, p 304. 16 Quincke HI: Über akutes umschriebenes Hautödem. Hamburg, Monatshefte für Praktische Dermatologie, 1882, vol 1, pp 129–131. 17 Török L: Urticaria; in Jadassohn J, Marchionini A (eds): Handbuch der Haut- und Geschlechtskrankheiten. Berlin, Springer, 1928, vol 6, part 2, pp 145–215. 18 Crowder JR, Crowder TR: Five generations of angioneurotic edema. Arch Intern Med 1917;20:840–852. 19 Osler W: Hereditary angio-neurotic oedema. Am J Med Sci 1888;95:362–367. 20 Donaldson VH, Evans RR: A biochemical abnormality in heredity angioneurotic edema: absence of serum inhibition of C1-esterase. Am J Med 1963;35:37–44.
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Maurer
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Prof. Marcus Maurer Department of Dermatology and Allergy Charité – Universitätsmedizin Berlin, Charitéplatz 1 DE–10117 Berlin (Germany) E-Mail marcus.maurer @ charite.de
Urticaria and Angioedema
2
Marcus Maurer Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Germany
Urticaria and angioedema are ancient diseases. Many different names have been used to describe them, and many different theories have been postulated to explain their origin and pathogenesis. The current classification and nomenclature of urticaria and angioedema have evolved over several millennia, with many detours and problems, some of which still remain to be solved. This chapter describes the history of urticaria and angioedema. The evolution of selected aspects of today’s understanding of both conditions is also traced, based on the review of original sources and previously published research on this topic. © 2014 S. Karger AG, Basel
Urticaria Urticaria is a group of diseases characterized by the occurrence of itchy wheals (urticae), angioedema or both. Research on the history of this common
skin condition is complicated by several independent problems. Firstly, wheals and/or angioedema occur in diseases other than urticaria, many of which have only been recognized as separate entities within the last centuries (e.g. hereditary angioedema; HAE) or even decades (e.g. Schnitzler syndrome, urticarial vasculitis). Secondly, the name ‘urticaria’ is fairly new, being less than 250 years old [1]. Many different names had been used before then, including knidosis, uredo, Nesselsucht and Nesselfieber, urticatio and randados, among others (see below). This happened, in part, because of changes in the understanding of the pathogenesis and the underlying causes of this condition. Thirdly, urticaria is a heterogeneous group of conditions, and subgroups differ substantially in their clinical course and features, their underlying causes and the relevance and nature of eliciting triggers. Nevertheless, the history of urticaria and angioedema is well researched and understood, which is mainly due to the work of Schadewaldt [1], who published detailed descriptions of the history of both conditions. Downloaded by: University of Hong Kong 147.8.31.43 - 9/6/2016 6:18:23 AM
Abstract
102
More (1478–1535) tells the following story: King Richard, who apparently knew that strawberries would make him break out in hives, convened the lords of the privy council and demanded to be served strawberries, which he ate in their presence. He then left and returned after several hours to show them the urticarial rash that had developed on his arm in the meantime. King Richard blamed this on one of the lords, who he disliked. He accused the lord of witchcraft and had him killed, claiming that the lord had poisoned him [1]. Over the years, many other conditions and factors have been claimed to be responsible for the onset of urticaria. The wide array of theories on the etiology of urticaria, which includes but is not limited to the idiosyncratic theory, the humoral theory, the toxin theory, the nervous theory, the microthrombosis theory, the menstrual theory, the angioneurotic theory, the theory of inflammation, and even the meteorological theory, have previously been reviewed in detail by Czarnetzki [5]. The group of induced (or inducible) urticarias includes contact urticaria (first described by Hippocrates, see above), which occurs at skin sites exposed to contact with urticariogenic substances, as well as cholinergic urticaria and the physical urticarias. The latter are characterized by wheals and/or angioedema that occur in response to skin exposure to a physical trigger, e.g. cold (cold urticaria), pressure (delayed pressure urticaria) or friction (symptomatic dermographism). Symptomatic dermographism is believed to be the first physical urticaria to be described in the literature, in 1767 by Heberden [6]. Today, symptomatic dermographism is used synonymously with urticaria factitia, derived from the term ‘factitious urticaria’ coined by Gull in 1859 [7]. In the Middle Ages, patients with urticaria factitia/ symptomatic dermographism were beheaded or burnt alive because they were assumed to be related to the devil [8]. Solar urticaria was also first described in the 18th century and later, in 1887, identified as being sunlight dependent [9, 10]. Cold urticaria is held to have been first described in 1792 by Frank [11], cholinergic urticaria in 1924 by Duke [12], pressure urticaria in 1929 by Urbach and Fasal [13], and aquagenic urticaria in 1964 by Shelley and Rawnsley [14].
Maurer
Downloaded by: University of Hong Kong 147.8.31.43 - 9/6/2016 6:18:23 AM
Urticaria and angioedema are ancient conditions. Both are believed to have troubled even our earliest ancestors since they are also found in other animals such as horses and dogs. Also, mast cells, the key effector cells of all urticarias and most angioedemas, have been found in the skin of all mammals investigated so far. One of the earliest descriptions of urticaria comes from China, and is more than 2,000 years old. In the Huangdi Neijing [2], written before and during the early Han period around 200 BC, urticaria is referred to as Feng Yin Zheng (‘wind type concealed rash’), very similar to one of today’s traditional Chinese medicine (TCM) terms for urticaria, Feng Sao Yin Zhen (‘wind itch concealed rash’). In TCM, wind is held to be the major pathogen in urticaria, therefore other names for urticaria are wind rash (Feng Zhen) and wind rash lumps (Feng Zhen Kuai). The ‘father of Western medicine’, Hippocrates (460–377 BC), used the term ‘knidosis’ to describe elevated itching lesions caused by nettles (knido in Greek), which would appear to be the first reference to what today is called contact urticaria. Hippocrates is also believed to have first described gastrointestinal disorders as a cause of urticaria. Urticaria, in the ancient Latin medical literature, was called ‘uredo’ (urere means ‘to burn’), and ‘essera’ (meaning ‘elevation’) in the old Persian medical texts. Paracelsus (1493–1541) introduced the first German name, Leusschieppen, but this was neither useful nor used for long. The term ‘urticaria’, derived from Urtica urens (stinging nettle), was first introduced by William Cullen in the 18th century [3]. Today, urticaria is understood to be a group of diseases, most commonly classified as either acute or chronic, and spontaneous or induced by specific eliciting triggers. The underlying causes of spontaneous urticaria are still under investigation and discussion. Autoreactivity, intolerance to food components and/or bacterial infections are held to be relevant by most, but not all, contemporary authors. Even in some of the oldest reports known, urticaria is postulated to be due to food intolerance or food poisoning. Interestingly, the first case report on death from urticaria also involves hives that developed in response to food consumption [4]. In his book, The History of King Richard III, Sir Thomas
Angioedema
Urticaria and Angioedema
2
Fig. 1. Title page of Eugen Dinkelacker’s doctoral thesis on ‘acute circumscript angioedema’ in which he describes the first cases of what is today designated HAE type I/II.
Fig. 2. Title page of Quincke’s landmark paper on angioedema, which linked his name to the condition for more than 200 years.
103
Downloaded by: University of Hong Kong 147.8.31.43 - 9/6/2016 6:18:23 AM
Angioedema is a common symptom in patients with wheals, either during anaphylactic reactions or in patients with chronic urticaria. The coexistence of both wheals and angioedema was recognized early on, primarily in patients with hypersensitivity reactions to food. In 1586, Marcello Donati [15] described lip swelling in a young male patient in response to the ingestion of eggs. Later reports from the mid-1600s described similar cases of angioedema in response to honey or mussels [1]. Until the late 1800s, angioedema was seen exclusively as a sign of, and linked to, urticaria, even though some cases of isolated angioedema, i.e. without wheals, were reported as early as the mid-1800s. Diez or Graves, for example, noted the danger of laryngeal edema and speculated that similar swellings may involve the mucosa of the gastrointestinal tract [1]. In 1882, it was Eugen Dinkelacker and his teacher Heinrich Irenäus Quincke [16] (1842–1922), a German internist and surgeon in Kiel, who first described HAE. Dinkelacker’s doctoral thesis (fig. 1) documented 14 cases of angioedema, some with and some without wheals. In retrospect, at least 2 of the patients described had HAE: a 22-year-old male patient with chronic recurrent facial, laryngeal and abdominal angioedema attacks of up to 3 days duration since early childhood, and his infant son. Both patients apparently used to develop prodromal symptoms, including erythema marginatum. Quincke and Dinkelacker used the term ‘acute circumscript angioedema’ for the condition they described, which soon became known as Quincke’s edema. At the time, urticaria was held to be of ‘angioneurotic’ origin, i.e. caused by an increased permeability of capillaries due to a spasm in response to neurogenic influences. It is, therefore, not surprising that Quincke and Dinkelacker both suggested that the cases of angioedema they had observed were also due to ‘angioneurosis’. In fact, the term ‘angioneurotic edema’ had been used by other authors earlier, for example by Bannister in 1880 in his description of suddenly appearing and inflammatory swellings [17]. Although Quincke, who is also known for introducing lumbar puncture as a procedure for diagnostic and therapeutic purposes, postulated that pa-
tients with ‘acute circumscript angioedema’ exhibit a disposition to develop ‘angioneurotic’ edema, he did not hold this condition to be hereditary, and the term ‘Quincke’s edema’, which is no longer used in modern classifications of angioedema, is not synonymous with HAE. In fact, it took until 1917 before Crowder and Crowder [18] discovered the autosomal dominant pattern of inheritance of HAE. In the years after Quincke’s 1882 landmark publication (fig. 2), several other authors reported similar cases of angioedema. Many of these reports describe the danger and mortality associated with laryngeal swellings, which had already been mentioned earlier. In 1888, Osler [19], who – like Dinkelacker and Quincke – described several members of one family to be affected, and who is believed to have coined the term ‘hereditary angioneurotic angioedema’, documented cases of suffocation due to laryngeal edema. Four years later, Griffiths reported the death of a patient and his daughter, both died of la-
ryngeal edema [1]. Within the following 5 years, two large families, with 33 and 110 affected members and 12 and 30 fatalities from laryngeal edema, respectively, were published [1]. Today, we know that recurrent angioedema is either inherited or acquired, and that HAE is bradykinin-mediated and different from histamine-mediated angioedema. A century ago, angioedema was often seen in response to the then popular ‘serum therapy’ and allergic mechanisms were newly discovered. As a consequence, angioedema became widely held to be an allergy, induced by anaphylactic mechanisms, rather than ‘angioneurotic’ responses. This may explain why it took 50 years after the Crowders’ description of the autosomal-dominant pattern of inheritance in HAE before Donaldson and Evans [20] discovered, in 1963, that HAE, which, as we know today, is bradykinin-mediated, to be caused by a deficiency or defect of C1INH, the inhibitor of the complement component C1.
References 1 Schadewaldt H: Geschichte der Allergie. Munich, Dustri, 1983, vol 3, chapt 2, 3. 2 Neijing H: The Su Wen of the Huangdi Neijing (Inner Classic of the Yellow Emperor). Jin dynasty, 1115–1234. 3 Cullen W: Synopsia Nosologiae Methodicae. Edinburgh, Kincaid & Creech, 1769. 4 More T: The history of King Richard III; in Campbell WE (ed): The English Works of Sir Thomas More. London, Eyre and Spottiswoode, 1931, p 426. 5 Czarnetzki BM: Urticaria. Berlin, Springer, 1986, chapt 1. 6 Heberden W: On the nettle-rash. Med Trans Coll Phys (London) 1767, p 185. 7 Gull W: On factitious urticaria. Guys Hospital Reports 1859;5:316. 8 Falk H: Beitrag zum Studium des Dermographismus. Med Diss München, 1901.
9 Borsch JF: De purpura urticata, quam vocant ‘die Nesselsucht’; med diss, Halle, 1719. 10 Veiel T: Über einen Fall von Eczema solare. Arch Derm Syph (Berlin) 1887;19:1113. 11 Frank JP: De curandis hominum morbis epitome. Mannheim, Schwan & Goetz, 1792, vol 3, p 104. 12 Duke WW: Urticaria caused specifically by the action of physical agents. J Am Med Assoc 1924;83:3. 13 Urbach E, Fasal P: Mechanische Urtikaria. Ein weiterer Beitrag zur physikalischen Allergie der Haut. Klin Wochenschr 1929; 8: 2368. 14 Shelley WB, Rawnsley HM: Aquagenic urticaria: contact sensitivity to water. JAMA 1964;189:895.
15 Donati M: De medica historia mirabile. Mantua, Osana, 1586, vol 7, chapt 3, p 304. 16 Quincke HI: Über akutes umschriebenes Hautödem. Hamburg, Monatshefte für Praktische Dermatologie, 1882, vol 1, pp 129–131. 17 Török L: Urticaria; in Jadassohn J, Marchionini A (eds): Handbuch der Haut- und Geschlechtskrankheiten. Berlin, Springer, 1928, vol 6, part 2, pp 145–215. 18 Crowder JR, Crowder TR: Five generations of angioneurotic edema. Arch Intern Med 1917;20:840–852. 19 Osler W: Hereditary angio-neurotic oedema. Am J Med Sci 1888;95:362–367. 20 Donaldson VH, Evans RR: A biochemical abnormality in heredity angioneurotic edema: absence of serum inhibition of C1-esterase. Am J Med 1963;35:37–44.
104
Maurer
Downloaded by: University of Hong Kong 147.8.31.43 - 9/6/2016 6:18:23 AM
Prof. Marcus Maurer Department of Dermatology and Allergy Charité – Universitätsmedizin Berlin, Charitéplatz 1 DE–10117 Berlin (Germany) E-Mail marcus.maurer @ charite.de
