Ann Allergy Asthma Immunol xxx (2014) 1e6
Contents lists available at ScienceDirect
Upper airway edema in 43 patients with hereditary angioedema Ying-Yang Xu, MS *; Yu-Xiang Zhi, MD *; Rui-Ling Liu, MS y; Timothy Craig, DO z; and Hong-Yu Zhang, MD * * Department y z
of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Department of Allergy, Tianjin Medical University General Hospital, Tianjin, China Department of Medicine and Pediatrics, Penn State University, Hershey, Pennsylvania
A R T I C L E
I N F O
Article history: Received for publication October 25, 2013. Received in revised form February 22, 2014. Accepted for publication March 2, 2014.
A B S T R A C T
Background: Upper airway edema (UAE) occurs infrequently in hereditary angioedema (HAE), but still results in significant morbidity and mortality. Objective: To assess patients with HAE and UAE to determine whether unique features exist that can predict the risk of UAE. Methods: Clinical, laboratory, and genetic data were compared between 43 patients with HAE and 743 UAE attacks and those without UAE and normal controls after ethics committee approval. Results: Most patients had their first episode of UAE in the second (25.6%), third (27.9%), and fourth (23.3%) decades of life, and the mean age at onset was 27.3 years. Evolution of UAE from initial to maximum symptoms was 4.6 hours on average, and most cases (69.8%) progressed within 4 hours. Dyspnea was the most frequent manifestation in per-episode (92.2%) and per-patient (97.7%) analyses. Men developed more asphyxiation attacks (19 vs 2) and underwent more tracheotomies (12 vs 2) than did women. UAE was associated with facial edema in half the studied patients. Patients with a positive family history of UAE had a high risk of UAE attacks. Conclusion: Symptoms limited to the upper airway should be taken seriously. Dyspnea may be the only manifestation of UAE. UAE attacks most commonly start spontaneously and usually progress rapidly, as quickly as 30 minutes, from awareness of symptoms to maximum airway involvement. Patients with a positive UAE family history are predisposed to UAE attacks, and men appear to be more apt to develop asphyxiation than women. Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Hereditary angioedema (HAE), which is caused by a deficiency of the C1 inhibitor (C1-INH), is an autosomal dominant disease.1 According to C1-INH level and its function, HAE is divided into 3 types.2e4 HAE type 1 has decreased antigenic and functional levels of C1-INH and is referred to as HAE with low C1-INH. Type 2 has decreased functional levels but normal or high antigenic levels of C1-INH and is referred to as HAE with dysfunctional C1-INH. The last type, type 3, is a new form and is called HAE with normal C1-INH. The pathogenic gene of HAE types 1 and 2 (C1-INH coding gene) is located on chromosome 11, and the specific location is q11eq13.1. Many types of mutation of the C1-INH gene, including deletion, insertion, and missense mutations, can lead to the abnormal synthesis of C1-INH and result in a low functional level of this protein.5 In type 2 HAE, mutations are typically located in the Reprints: Yu-Xiang Zhi, MD, Department of Allergy, Peking Union Medical College Hospital, #1 Shuaifuyuan, Wangfujing, Beijing 100730, China; E-mail: yuxiang_ [email protected]. Disclosures: Authors have nothing to disclose. Funding: This work was supported by the Beijing Nature Science Foundation (grant 7132200).
reactive site or proximal hinge region; in particular, the CpG dinucleotide within the code of Arg444 results in loss of function of the protein.5,6 The mechanism of HAE with normal C1-INH is not well known, but previous studies have suggested that some cases might be associated with mutations of factor XII.7,8 HAE presents as subcutaneous or submucosal edema. The extremities, face, trunk, gastrointestinal tract, and upper airway are commonly involved.9,10 Upper airway edema (UAE), especially laryngeal swelling, can develop to obstruction of the airway, which can lead to asphyxiation.11 The manifestation of UAE is variable and includes tightness of the throat, hoarseness, enunciation difficulties, dysphagia, dyspnea, and stridor.12 UAE is unpredictable and can occur spontaneously or follow a trigger, such as trauma, medical procedure of the head and neck, or emotional stress.12,13 Although UAE is much less common than skin swelling, approaching 1 in 125 attacks,13 it is the most common cause of death in patients with HAE. The published mortality associated with UAE is 30% to 50%.14,15 For this reason, early and aggressive management of UAE is essential. In China, 58.9% of cases of UAE have been reported in registered patients with HAE. Of those who reported UAE in the past, 11.4% died of asphyxiation.16 However, the typical course and characteristics of
1081-1206/14/$36.00 - see front matter Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.anai.2014.03.003
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Y.-Y. Xu et al. / Ann Allergy Asthma Immunol xxx (2014) 1e6
UAE in Chinese patients with HAE and the relation between UAE and C1-INH level have not been examined. Therefore, the authors retrospectively analyzed the clinical characteristics of 43 patients with HAE who had swelling of the airway. The objective was to better define a cohort of patients who develop UAE to decrease the associated morbidity and mortality of HAE. Methods Patients Forty-three patients with HAE from 35 families (21 female and 22 male patients; 42 with type 1 HAE and 1 with type 2 HAE) had 743 self-reported UAE attacks. This cohort was compared with 29 patients with HAE who never had UAE as controls (non-UAE) and 50 healthy adults without HAE. All subjects were reviewed by the Department of Allergy of Peking Union Medical College Hospital from 1987 to 2013. The diagnosis of HAE was based on medical history, family history, laboratory test results, and genetic analysis results. All 43 patients had at least 1 UAE attack, and 34 had more than 1 episode of UAE. Five patients died of asphyxiation secondary to laryngeal edema. Clinical data were retrieved from medical
records and patients’ questionnaire answers (Table 1). The study was approved by the ethics committee of Peking Union Medical College Hospital. Measurement of Complement Levels The antigenic C1-INH (C1-INHa) level was quantified by the BN II System (CSL Behring, Marburg, Germany). The functional C1-INH (C1-INHf) level was measured by a chromogenic assay kit (Immunochrom, Vienna, Austria). The authors’ assay method for C1-INHa has changed over the years from a single immunodiffusion assay to immunonephelometry; however, the degree of correlation between these 2 methods is high.17 Therefore, the percentage of the normal mean was used when performing the statistical analysis. Data are present in eTable 1. Mutational Analysis To confirm the diagnosis of HAE, mutations of the C1-INH gene were analyzed in 23 patients with UAE and 50 healthy controls. Two milliliters of venous blood coagulated with ethylenediaminetetraacetic acid was obtained, and genomic DNA was extracted by
Table 1 Patients’ data Patient number
Sex
Age of UAE onset (y)
Episodes, n
FH of HAE
FH of UAE
Interval (h)a
Asphyxiationb
Tracheotomyb
Deathb
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Total
M M M M M M M M M M M M M M M M M M M M M M F F F F F F F F F F F F F F F F F F F F F
28 31 39 31 21 UNK 29 25 22 23 19 50 15 32 25 19 41 15 18 30 17 35 24 35 8 36 18 20 54 35 22 21 40 44 18 16 UNK 17 UNK UNK UNK 24 40
4 1 2 1 20c 2 4 18 5 1 2 22 3 4 4 32 1 5 1 13 20c 30c 5 1 80c 1 3 1 5 14 1 34 2 4 96 1 30c 20c 5 2 7 4 232 743
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ 35
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ 19
4.5 0.5 4 4 1.2 0.5 3 8 1.5 3 1.5 1.5 1 24 1.5 4.5 3.5 1.5 1 1 4.5 3.5 3.5 1 3.5 3.5 3.5 1.5 3 2.5 1.5 12 6 3 24 1 24 4.5 3.5 1 1 4.5 4.5
0 1 0 0 3 1 2 1 3 1 0 0 1 0 0 0 1 2 0 3 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 21
0 1 0 0 0 1 2 1 3 1 0 0 0 0 0 0 0 1 0 2 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 14
0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 1 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5
Abbreviations: , absent; þ, present; F, female; FH, family history; HAE, hereditary angioedema; M, male; UAE, upper airway edema; UNK, unknown. a Time from first awareness of symptoms to maximum symptoms. b Number of attacks related to asphyxiation, tracheotomy, or death. c The number of episodes is approximate, rather than precise.
Y.-Y. Xu et al. / Ann Allergy Asthma Immunol xxx (2014) 1e6
3
Results Mean Age at Onset of UAE Attacks Thirty-eight of the 43 patients who had UAE were able to recall the precise date of their first UAE attack. The mean age at onset of UAE was 27.3 years (standard deviation 8.7 years, range 8.0e54.0 years). The difference in the age at onset between male and female patients was not significant, and its distribution is shown in Figure 1. Most patients had their first UAE attack in the second (25.6%), third (27.9%), or fourth (23.3%) decade of life. Interval from Onset to Maximum Development of UAE
Figure 1. Distribution of age at onset of upper airway edema (UAE). UAE episodes usually occurred in the second, third, and fourth decades of life.
For all attacks studied, the mean time from the beginning of upper airway discomfort to maximum development was 4.6 hours (standard deviation 3.3 hours, range 0.5e24.0 hours); 37.2% of patients developed maximum symptoms within 2 hours, and 32.6% developed symptoms within 2 to 4 hours (Fig 2). Manifestations of UAE
the QIAamp DNA Blood Mini Kit (Qiagen GmbH, Hilden, Germany). All 8 exons and introneexon boundaries were amplified by polymerase chain reaction on a T-Professional Standard 96 Thermocycler (Biometra GmbH, Goettingen, Germany). Polymerase chain reaction products were purified from 1.5% agarose gel by a QIAquick Gel Extraction Kit (Qiagen, Valencia, California) and then sequenced by a BigDye Terminator DNA Sequencing Kit (Applied Biosystems, Foster City, California) on an ABI PRISM 377-96 Sequencer (Applied Biosystems). Mutations were identified by BLAST (National Center for Biotechnology Information, Bethesda, Maryland; http://blast. ncbi.nlm.nih.gov/Blast.cgi) by comparison with the reference nucleotide and amino acid sequences (X54486 and P05155).
Among all 743 UAE episodes, dyspnea was observed in 685 episodes (92.2%), a sensation of tightness in the throat in 353 episodes (47.5%), difficulty with enunciation in 93 episodes (12.5%), hoarseness in 66 episodes (8.9%), dysphagia in 44 episodes (5.9%), asphyxiation in 21 episodes (2.8%), and performance of tracheotomy in 14 episodes (1.9%). On a per-patient basis, dyspnea was present in varying degrees in 42 of 43 patients with UAE (97.7%), enunciation difficulties occurred in 25 patients (58.1%), a sensation of tightness in the throat in 23 patients (53.5%), hoarseness in 17 patients (39.5%), dysphagia in 15 patients (34.9%), and asphyxiation in 14 patients (32.6%). Of the 43 patients, 9 required tracheotomy and survived; however, 5 died of asphyxiation. The frequencies of these different manifestations are illustrated in Figure 3.
Statistical Analysis
Other Preceding or Accompanying Sites of Swelling
Statistical analyses were performed using R 2.14.0 (http://www. cran-project.org/). A 2-sample t test was used to evaluate differences between patients with HAE and UAE and those without UAE, patients with UAE and asphyxiation and those without asphyxiation, and frequent and less frequent episodes by sex, age at onset, and complement levels. A P level 2 to 4 hours; 4e6, >4 to 6 hours; 6e12, >6 to 12 hours; 12e24, >12 to 24 hours.
4
Y.-Y. Xu et al. / Ann Allergy Asthma Immunol xxx (2014) 1e6
Figure 3. Various manifestations of upper airway swelling. (A) Per-episode analysis. (B) Per-patient analysis.
The number of patients did not sum to 43 because the patients had different concomitant sites of edema in different episodes. Triggers of UAE Of the 743 UAE episodes, 3 were secondary to dental surgery and 4 followed head trauma, toothache, sore throat, and influenza, respectively. Five patients believed that their UAE was secondary to being tired, angry, or stressed. Most UAE episodes occurred spontaneously without an apparent trigger. Family Predisposition In this study, 43 patients with UAE from 35 families were analyzed. Of these, 19 patients with comprehensive medical records from 11 families had a family history of UAE, 16 patients from 16 families had a family history of HAE without UAE, and 8 patients did not have a family history of HAE. No difference in types
of mutation between patients with and without a family history of UAE was found. In fact, of these 11 families with a family history of UAE, 49 patients were diagnosed with HAE. Nineteen of them had comprehensive medical records and were included in the present study, whereas the remaining patients had incomplete clinical data and were excluded. Of these 49 patients with HAE, 43 (43 patients in 11 families) had UAE attacks, and only 6 failed to report UAE at the time of data recruitment. Thus, patients with positive family history of HAE with UAE had more UAE attacks than those with a family history of HAE without UAE (16 patients in 16 families). Association of UAE Severity with Sex, Age at Onset, and C1-INH Levels (C1-INHa and C1-INHf) The entire patient group was divided into 2 groups according to whether they had vs had not developed asphyxiation (positive vs
Y.-Y. Xu et al. / Ann Allergy Asthma Immunol xxx (2014) 1e6
negative). Of all 21 asphyxiation episodes, 19 occurred in men and only 2 occurred in women. There was a significant sex difference between the asphyxiation-positive and asphyxiation-negative groups (P ¼ .003). A similar sex difference (P ¼ .02) was found for whether patients underwent tracheotomy. Of all 14 tracheotomies, 12 were performed in men and 2 were performed in women. All 5 patients who died of UAE were men. No differences in C1-INH levels were found between the asphyxiation-positive and asphyxiation-negative groups. The distribution of attacks for each patient is shown in Figure 4. Patients were categorized into 2 groups according to frequency of attacks (1 vs
Contents lists available at ScienceDirect
Upper airway edema in 43 patients with hereditary angioedema Ying-Yang Xu, MS *; Yu-Xiang Zhi, MD *; Rui-Ling Liu, MS y; Timothy Craig, DO z; and Hong-Yu Zhang, MD * * Department y z
of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Department of Allergy, Tianjin Medical University General Hospital, Tianjin, China Department of Medicine and Pediatrics, Penn State University, Hershey, Pennsylvania
A R T I C L E
I N F O
Article history: Received for publication October 25, 2013. Received in revised form February 22, 2014. Accepted for publication March 2, 2014.
A B S T R A C T
Background: Upper airway edema (UAE) occurs infrequently in hereditary angioedema (HAE), but still results in significant morbidity and mortality. Objective: To assess patients with HAE and UAE to determine whether unique features exist that can predict the risk of UAE. Methods: Clinical, laboratory, and genetic data were compared between 43 patients with HAE and 743 UAE attacks and those without UAE and normal controls after ethics committee approval. Results: Most patients had their first episode of UAE in the second (25.6%), third (27.9%), and fourth (23.3%) decades of life, and the mean age at onset was 27.3 years. Evolution of UAE from initial to maximum symptoms was 4.6 hours on average, and most cases (69.8%) progressed within 4 hours. Dyspnea was the most frequent manifestation in per-episode (92.2%) and per-patient (97.7%) analyses. Men developed more asphyxiation attacks (19 vs 2) and underwent more tracheotomies (12 vs 2) than did women. UAE was associated with facial edema in half the studied patients. Patients with a positive family history of UAE had a high risk of UAE attacks. Conclusion: Symptoms limited to the upper airway should be taken seriously. Dyspnea may be the only manifestation of UAE. UAE attacks most commonly start spontaneously and usually progress rapidly, as quickly as 30 minutes, from awareness of symptoms to maximum airway involvement. Patients with a positive UAE family history are predisposed to UAE attacks, and men appear to be more apt to develop asphyxiation than women. Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Hereditary angioedema (HAE), which is caused by a deficiency of the C1 inhibitor (C1-INH), is an autosomal dominant disease.1 According to C1-INH level and its function, HAE is divided into 3 types.2e4 HAE type 1 has decreased antigenic and functional levels of C1-INH and is referred to as HAE with low C1-INH. Type 2 has decreased functional levels but normal or high antigenic levels of C1-INH and is referred to as HAE with dysfunctional C1-INH. The last type, type 3, is a new form and is called HAE with normal C1-INH. The pathogenic gene of HAE types 1 and 2 (C1-INH coding gene) is located on chromosome 11, and the specific location is q11eq13.1. Many types of mutation of the C1-INH gene, including deletion, insertion, and missense mutations, can lead to the abnormal synthesis of C1-INH and result in a low functional level of this protein.5 In type 2 HAE, mutations are typically located in the Reprints: Yu-Xiang Zhi, MD, Department of Allergy, Peking Union Medical College Hospital, #1 Shuaifuyuan, Wangfujing, Beijing 100730, China; E-mail: yuxiang_ [email protected]. Disclosures: Authors have nothing to disclose. Funding: This work was supported by the Beijing Nature Science Foundation (grant 7132200).
reactive site or proximal hinge region; in particular, the CpG dinucleotide within the code of Arg444 results in loss of function of the protein.5,6 The mechanism of HAE with normal C1-INH is not well known, but previous studies have suggested that some cases might be associated with mutations of factor XII.7,8 HAE presents as subcutaneous or submucosal edema. The extremities, face, trunk, gastrointestinal tract, and upper airway are commonly involved.9,10 Upper airway edema (UAE), especially laryngeal swelling, can develop to obstruction of the airway, which can lead to asphyxiation.11 The manifestation of UAE is variable and includes tightness of the throat, hoarseness, enunciation difficulties, dysphagia, dyspnea, and stridor.12 UAE is unpredictable and can occur spontaneously or follow a trigger, such as trauma, medical procedure of the head and neck, or emotional stress.12,13 Although UAE is much less common than skin swelling, approaching 1 in 125 attacks,13 it is the most common cause of death in patients with HAE. The published mortality associated with UAE is 30% to 50%.14,15 For this reason, early and aggressive management of UAE is essential. In China, 58.9% of cases of UAE have been reported in registered patients with HAE. Of those who reported UAE in the past, 11.4% died of asphyxiation.16 However, the typical course and characteristics of
1081-1206/14/$36.00 - see front matter Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.anai.2014.03.003
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Y.-Y. Xu et al. / Ann Allergy Asthma Immunol xxx (2014) 1e6
UAE in Chinese patients with HAE and the relation between UAE and C1-INH level have not been examined. Therefore, the authors retrospectively analyzed the clinical characteristics of 43 patients with HAE who had swelling of the airway. The objective was to better define a cohort of patients who develop UAE to decrease the associated morbidity and mortality of HAE. Methods Patients Forty-three patients with HAE from 35 families (21 female and 22 male patients; 42 with type 1 HAE and 1 with type 2 HAE) had 743 self-reported UAE attacks. This cohort was compared with 29 patients with HAE who never had UAE as controls (non-UAE) and 50 healthy adults without HAE. All subjects were reviewed by the Department of Allergy of Peking Union Medical College Hospital from 1987 to 2013. The diagnosis of HAE was based on medical history, family history, laboratory test results, and genetic analysis results. All 43 patients had at least 1 UAE attack, and 34 had more than 1 episode of UAE. Five patients died of asphyxiation secondary to laryngeal edema. Clinical data were retrieved from medical
records and patients’ questionnaire answers (Table 1). The study was approved by the ethics committee of Peking Union Medical College Hospital. Measurement of Complement Levels The antigenic C1-INH (C1-INHa) level was quantified by the BN II System (CSL Behring, Marburg, Germany). The functional C1-INH (C1-INHf) level was measured by a chromogenic assay kit (Immunochrom, Vienna, Austria). The authors’ assay method for C1-INHa has changed over the years from a single immunodiffusion assay to immunonephelometry; however, the degree of correlation between these 2 methods is high.17 Therefore, the percentage of the normal mean was used when performing the statistical analysis. Data are present in eTable 1. Mutational Analysis To confirm the diagnosis of HAE, mutations of the C1-INH gene were analyzed in 23 patients with UAE and 50 healthy controls. Two milliliters of venous blood coagulated with ethylenediaminetetraacetic acid was obtained, and genomic DNA was extracted by
Table 1 Patients’ data Patient number
Sex
Age of UAE onset (y)
Episodes, n
FH of HAE
FH of UAE
Interval (h)a
Asphyxiationb
Tracheotomyb
Deathb
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Total
M M M M M M M M M M M M M M M M M M M M M M F F F F F F F F F F F F F F F F F F F F F
28 31 39 31 21 UNK 29 25 22 23 19 50 15 32 25 19 41 15 18 30 17 35 24 35 8 36 18 20 54 35 22 21 40 44 18 16 UNK 17 UNK UNK UNK 24 40
4 1 2 1 20c 2 4 18 5 1 2 22 3 4 4 32 1 5 1 13 20c 30c 5 1 80c 1 3 1 5 14 1 34 2 4 96 1 30c 20c 5 2 7 4 232 743
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ 35
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ 19
4.5 0.5 4 4 1.2 0.5 3 8 1.5 3 1.5 1.5 1 24 1.5 4.5 3.5 1.5 1 1 4.5 3.5 3.5 1 3.5 3.5 3.5 1.5 3 2.5 1.5 12 6 3 24 1 24 4.5 3.5 1 1 4.5 4.5
0 1 0 0 3 1 2 1 3 1 0 0 1 0 0 0 1 2 0 3 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 21
0 1 0 0 0 1 2 1 3 1 0 0 0 0 0 0 0 1 0 2 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 14
0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 1 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5
Abbreviations: , absent; þ, present; F, female; FH, family history; HAE, hereditary angioedema; M, male; UAE, upper airway edema; UNK, unknown. a Time from first awareness of symptoms to maximum symptoms. b Number of attacks related to asphyxiation, tracheotomy, or death. c The number of episodes is approximate, rather than precise.
Y.-Y. Xu et al. / Ann Allergy Asthma Immunol xxx (2014) 1e6
3
Results Mean Age at Onset of UAE Attacks Thirty-eight of the 43 patients who had UAE were able to recall the precise date of their first UAE attack. The mean age at onset of UAE was 27.3 years (standard deviation 8.7 years, range 8.0e54.0 years). The difference in the age at onset between male and female patients was not significant, and its distribution is shown in Figure 1. Most patients had their first UAE attack in the second (25.6%), third (27.9%), or fourth (23.3%) decade of life. Interval from Onset to Maximum Development of UAE
Figure 1. Distribution of age at onset of upper airway edema (UAE). UAE episodes usually occurred in the second, third, and fourth decades of life.
For all attacks studied, the mean time from the beginning of upper airway discomfort to maximum development was 4.6 hours (standard deviation 3.3 hours, range 0.5e24.0 hours); 37.2% of patients developed maximum symptoms within 2 hours, and 32.6% developed symptoms within 2 to 4 hours (Fig 2). Manifestations of UAE
the QIAamp DNA Blood Mini Kit (Qiagen GmbH, Hilden, Germany). All 8 exons and introneexon boundaries were amplified by polymerase chain reaction on a T-Professional Standard 96 Thermocycler (Biometra GmbH, Goettingen, Germany). Polymerase chain reaction products were purified from 1.5% agarose gel by a QIAquick Gel Extraction Kit (Qiagen, Valencia, California) and then sequenced by a BigDye Terminator DNA Sequencing Kit (Applied Biosystems, Foster City, California) on an ABI PRISM 377-96 Sequencer (Applied Biosystems). Mutations were identified by BLAST (National Center for Biotechnology Information, Bethesda, Maryland; http://blast. ncbi.nlm.nih.gov/Blast.cgi) by comparison with the reference nucleotide and amino acid sequences (X54486 and P05155).
Among all 743 UAE episodes, dyspnea was observed in 685 episodes (92.2%), a sensation of tightness in the throat in 353 episodes (47.5%), difficulty with enunciation in 93 episodes (12.5%), hoarseness in 66 episodes (8.9%), dysphagia in 44 episodes (5.9%), asphyxiation in 21 episodes (2.8%), and performance of tracheotomy in 14 episodes (1.9%). On a per-patient basis, dyspnea was present in varying degrees in 42 of 43 patients with UAE (97.7%), enunciation difficulties occurred in 25 patients (58.1%), a sensation of tightness in the throat in 23 patients (53.5%), hoarseness in 17 patients (39.5%), dysphagia in 15 patients (34.9%), and asphyxiation in 14 patients (32.6%). Of the 43 patients, 9 required tracheotomy and survived; however, 5 died of asphyxiation. The frequencies of these different manifestations are illustrated in Figure 3.
Statistical Analysis
Other Preceding or Accompanying Sites of Swelling
Statistical analyses were performed using R 2.14.0 (http://www. cran-project.org/). A 2-sample t test was used to evaluate differences between patients with HAE and UAE and those without UAE, patients with UAE and asphyxiation and those without asphyxiation, and frequent and less frequent episodes by sex, age at onset, and complement levels. A P level 2 to 4 hours; 4e6, >4 to 6 hours; 6e12, >6 to 12 hours; 12e24, >12 to 24 hours.
4
Y.-Y. Xu et al. / Ann Allergy Asthma Immunol xxx (2014) 1e6
Figure 3. Various manifestations of upper airway swelling. (A) Per-episode analysis. (B) Per-patient analysis.
The number of patients did not sum to 43 because the patients had different concomitant sites of edema in different episodes. Triggers of UAE Of the 743 UAE episodes, 3 were secondary to dental surgery and 4 followed head trauma, toothache, sore throat, and influenza, respectively. Five patients believed that their UAE was secondary to being tired, angry, or stressed. Most UAE episodes occurred spontaneously without an apparent trigger. Family Predisposition In this study, 43 patients with UAE from 35 families were analyzed. Of these, 19 patients with comprehensive medical records from 11 families had a family history of UAE, 16 patients from 16 families had a family history of HAE without UAE, and 8 patients did not have a family history of HAE. No difference in types
of mutation between patients with and without a family history of UAE was found. In fact, of these 11 families with a family history of UAE, 49 patients were diagnosed with HAE. Nineteen of them had comprehensive medical records and were included in the present study, whereas the remaining patients had incomplete clinical data and were excluded. Of these 49 patients with HAE, 43 (43 patients in 11 families) had UAE attacks, and only 6 failed to report UAE at the time of data recruitment. Thus, patients with positive family history of HAE with UAE had more UAE attacks than those with a family history of HAE without UAE (16 patients in 16 families). Association of UAE Severity with Sex, Age at Onset, and C1-INH Levels (C1-INHa and C1-INHf) The entire patient group was divided into 2 groups according to whether they had vs had not developed asphyxiation (positive vs
Y.-Y. Xu et al. / Ann Allergy Asthma Immunol xxx (2014) 1e6
negative). Of all 21 asphyxiation episodes, 19 occurred in men and only 2 occurred in women. There was a significant sex difference between the asphyxiation-positive and asphyxiation-negative groups (P ¼ .003). A similar sex difference (P ¼ .02) was found for whether patients underwent tracheotomy. Of all 14 tracheotomies, 12 were performed in men and 2 were performed in women. All 5 patients who died of UAE were men. No differences in C1-INH levels were found between the asphyxiation-positive and asphyxiation-negative groups. The distribution of attacks for each patient is shown in Figure 4. Patients were categorized into 2 groups according to frequency of attacks (1 vs
