Extremely Delayed Diagnosis of Type II Hereditary Angioedema: Case Report and Review of the Literature

Extremely Delayed Diagnosis of Type II Hereditary Angioedema: Case Report and Review of the... Abstract We present a case with extremely late diagnosis of type II hereditary angioedema (HAE). Given recent advances in HAE treatment, we want to bring physician awareness to this condition and aid in earlier detection. HAE is a disorder associated with episodes of angioedema of the face, larynx, lips, abdomen, or extremities. Late diagnosis of HAE can lead to significant morbidity and is severely impairing due to recurring attacks. The diagnosis of HAE is ordinarily made during childhood and adolescence. Delayed diagnoses in early and middle adulthood have been documented in the literature. Gastrointestinal symptoms are common features of HAE and can be misdiagnosed as disease of primary gastrointestinal pathology, such as irritable bowel syndrome, recurrent pancreatitis, or appendicitis. These attacks are characterized by recurrent attacks of subcutaneous and submucosal edema without the presence of urticaria. We present a case of an elderly veteran whose diagnoses was extremely delayed into the eighth decade of life subsequent to unexplained abdominal symptoms. After diagnosis, the patient’s symptoms were well controlled with medication due to advances in HAE treatment. To prevent further atypically delayed diagnoses, physicians should consider HAE in patients with recurrent attacks of unexplained abdominal pain. Introduction Hereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous and/or submucosal edema without the presence of urticaria.1,2 The angioedema commonly involves the extremities, abdomen, and genitourinary tract. It also involves the face, oropharynx, and larynx, risking potential airway obstruction. Depending on the location and degree of edema, the severity may range from a mild episode to a life-threatening emergency. The diagnosis of HAE is ordinarily made during childhood and adolescence. Later diagnoses, however, can also be made in adulthood,3 with atypical delayed diagnoses being made in the elderly. We present a case of an extremely delayed diagnosis of type II HAE. Case Presentation A 78-yr-old military veteran presented with a long history of intermittent abdominal pain and swelling of the hands, feet, and scrotum since adolescence. The patient endorsed mid-epigastric abdominal pain without radiation, occurring on a weekly basis and lasting for several days. He described an extensive history of constipation and occasional diarrhea, including a significant, month-long episode in the spring of 2014 associated with abdominal pain, anorexia, and weight loss. He has since regained his weight and has not had further weight loss since. The patient’s review of systems was negative or noncontributory. The patient indicated that his maternal grandfather, mother, daughters, and two nieces have a history of episodic limb swelling. His brother has experienced similarly described recurrent abdominal pain. There is no family history of airway involvement. One niece has been diagnosed with a type of hereditary angioedema and is being treated. The patient has undergone multiple evaluations for his abdominal pain, which revealed several polyps and minor diverticulosis. The patient has been on several medications for gastroesophageal reflux disease and constipation, including lubiprostone, polyethylene glycol 3,350, and ranitidine, all without symptom improvement. Given his symptoms, family history, and unsuccessful treatments, his primary physician subsequently referred him to an allergist. Physical exam findings were unremarkable. Laboratory findings are listed in Table I. Additional workup included several C4 levels documented as low–normal or low, a normal quantitative complement C1q level, and a normal C1 esterase inhibitor level. The C1 esterase inhibitor function, however, was found to be low. His liver function tests were normal. Table I. Relevant Patient Laboratory Findings Test  Findings  Reference Range  Complement C1Q level, serum  18.0 mg/dL  11.8–23.8 mg/dL  Complement C1-INH functional level, serum  28%, 31%  Normal > 67%  Complement C1-INH level, serum  24 mg/dL  21–39 mg/dL  Test  Findings  Reference Range  Complement C1Q level, serum  18.0 mg/dL  11.8–23.8 mg/dL  Complement C1-INH functional level, serum  28%, 31%  Normal > 67%  Complement C1-INH level, serum  24 mg/dL  21–39 mg/dL  Table I. Relevant Patient Laboratory Findings Test  Findings  Reference Range  Complement C1Q level, serum  18.0 mg/dL  11.8–23.8 mg/dL  Complement C1-INH functional level, serum  28%, 31%  Normal > 67%  Complement C1-INH level, serum  24 mg/dL  21–39 mg/dL  Test  Findings  Reference Range  Complement C1Q level, serum  18.0 mg/dL  11.8–23.8 mg/dL  Complement C1-INH functional level, serum  28%, 31%  Normal > 67%  Complement C1-INH level, serum  24 mg/dL  21–39 mg/dL  The patient was diagnosed with type II HAE based on his symptom history, family history of angioedema, and low levels of C4 and functional C1 esterase inhibitor. In 2016, he was prescribed Icatibant, a bradykinin receptor blocker, which helped resolve six episodes of abdominal angioedema and pain in 2016 and five episodes in 2017. In each case of its use, his pain resolved over several hours, rather than over days or weeks in which he would experience pain without treatment. The patient desires to continue using on-demand Icatibant as needed for future episodes of HAE. With the low frequency of symptoms at this time in his management, prophylactic medications are not being used. Regular monitoring of transaminases is performed, as elevations are less common side effects of Icatibant. The patient was educated on the risk of using ACE inhibitors with a diagnosis of HAE and to avoid this class of medication. Discussion The mechanism by which HAE occurs is through a hereditary deficiency in functional levels of C1 esterase inhibitor (C1-INH) activity. C1-INH is a serine protease inhibitor, normally functioning as a suicide inhibitor by forming complexes with its target proteases: kallikrein, factor XIa, factor XIIa, C1s, and C1r.4 Pathogenesis of HAE involves the kallikrein–kinin and complement pathways, with activated factor XII initiating a cascade that produces bradykinin, the primary mediator of swelling via the enhancement of vascular permeability.2,3 HAE is an autosomal dominant disease, and roughly 75% of patients with HAE have a positive family history of angioedema.5 Three important subtypes of HAE have been recognized: type I, type II, and HAE with normal C1-INH (HAE-nC1 INH). More than 275 different mutations have been identified and are responsible for these diseases.2 Type I HAE involves a mutation in the C1-INH gene, SERPING1, resulting in a truncated or misfolded protein that is not secreted, accounting for about 85% of patients with HAE.2,3 Type II HAE is caused by a missense mutation, resulting in a normal C1-INH level but defective function. Finally, HAE-nC1 INH is due to either an increased activity of factor XII or is through an unidentified cause. In addition to the symptoms and signs previously described, HAE-nC1 INH may also include hemorrhage at the site of edema.4 In 20% of HAE-nC1 INH patients, the diagnosis can be made through identification of two known mutations in the factor XII gene; otherwise, it is a diagnosis of exclusion.6 We chose Icatibant for this patient for two reasons. First, it has been proven effective in acute attacks for HAE type II, due to its antagonistic effect on bradykinin receptors. Second, it is readily available in 3-mL prefilled syringes that can be administered subcutaneously at home without risk of anaphylaxis. Patients can give themselves up to three doses in a 24-h period if needed to reduce edema. Conclusion This case presentation is unique because of the extremely late diagnosis of type II HAE. There are other reports present in the literature of patients with recurrent abdominal pain resulting from HAE but having a delay in their diagnosis. Patients with recurrent abdominal pain may be misdiagnosed with a disease of primary gastrointestinal pathology, such as irritable bowel syndrome, recurrent pancreatitis, appendicitis, or colon intussusception, with an eventual diagnosis of HAE.7 Individualized treatment plans for patients of all ages should address preventive, home, and emergency measures for disease management, including long-term prophylaxis and on-demand medication with HAE identification and instructions.6 To best accomplish this, several general HAE guidelines have been published and are available; examples include the World Allergy Organization Guideline for the Management of Hereditary Angioedema3,8 and the US Hereditary Angioedema Association Medical Advisory Board 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 Inhibitor Deficiency.9 The World Allergy Organization (WAO) in collaboration with the European Academy of Allergy and Clinical Immunology (EAACI) recently proposed new guidelines in 2017 for the management of hereditary angioedema. Specifically, they recommend that attacks are treated as early as possible and HAE attacks are treated with either C1-INH, Ecallantide, or Icatibant. If these three agents are not available, then soluble detergent plasma or fresh frozen plasma can be given. The new guidelines recommend that patients have sufficient medication for on-demand treatment of two attacks and patients should carry this medication at all times. The advantages of using an on-demand medication are shorter time to resolution of symptoms and shorter total attack duration. The following is a review of currently available options. Plasma-derived C1-INH concentrate is available in intravenous formulation (Cinryze) and subcutaneous formulation (Haegarda); however, both have been associated with anaphylactic adverse reactions. Ruconest is the only available recombinant human C1-INH (rhC1-INH) and is only available in intravenous formulation, which is not ideal for on-demand home treatment. Ecallantide (a kallikrein inhibitor) can be used on demand in the United States; however, 3–4% of patients have reported hypersensitivity reactions to include anaphylaxis. This makes Icatibant (a bradykinin receptor antagonist) a more practical option as it can be given at home subcutaneously and the main adverse reaction is local injection site irritation according to the safety data. The authors see three potential solutions to prevent future extremely delayed diagnosis. First, increasing physician awareness of the signs and symptoms of HAE may lead to a timelier diagnosis and reduce patient suffering. Two, once the diagnosis has been made, provide family screening. In this case, our patient had a niece diagnosed with HAE; however, our patient remained undiagnosed until an extended abdominal flare led to further workup and referral to an allergy specialist. As evident with the presented case, clinical suspicion for HAE in later stages of life is a paramount to prevent unnecessary patient suffering and potential serious and preventable disease manifestations. Third, consider referral to an allergist or immunologist once the diagnosis has been made for definitive treatment. References 1 Jose J, Zacharias J, Craig T: Review of select practice parameters, evidence-based treatment algorithms, and International Guidelines for Hereditary Angioedema. Clinic Rev Allerg Immunol  2016; 51: 193. doi:10.1007/s12016-016-8546-7. Google Scholar CrossRef Search ADS   2 DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995. Record No. 114672, C1 inhibitor deficiency; [updated 2017 Apr 05, cited May 9, 2017]; [about 18 screens]. Available from http://search.ebscohost.com.ezproxy.hsc.usf.edu/login.aspx?direct=true&db=dnh&AN=114672&site=dynamed-live&scope=site. 3 Craig T, Pürsün EA, Bork K, et al.  : WAO guideline for the management of hereditary angioedema. World Allergy Organ J  2012; 5( 12): 182– 99. Google Scholar CrossRef Search ADS PubMed  4 LoVerde D, Files DC, Krishnaswamy G: Angioedema. Crit Care Med  2017; 45( 4): 725– 35. doi:10.1097/CCM.0000000000002281. Google Scholar CrossRef Search ADS PubMed  5 Zuraw BL, Bernstein JA, Lang DM, et al.  : A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol  2013; 131( 6): 1491– 3. doi:10.1016/j.jaci.2013.03.034. Google Scholar CrossRef Search ADS PubMed  6 Bouillet L, Boccon‐Gibod I, Launay D, et al.  : Hereditary angioedema with normal C1 inhibitor in a French cohort: clinical characteristics and response to treatment with icatibant. Immun Inflamm Dis  2017; 5( 1): 29– 36. doi:10.1002/iid3.137. Google Scholar CrossRef Search ADS PubMed  7 Patel N, Suarez LD, Kapur S, Bielory L: Hereditary angioedema and gastrointestinal complications: an extensive review of the literature. Case Rep Immunol  2015; 2015: 925861. doi:10.1155/2015/925861. 8 Maurer M, Markus M, Ignacio A, et al.  : The international WAO/EAACI guideline for the management of hereditary angioedema – the 2017 revision and update. Allergy  2018. doi:10.1111/all.13384. 9 Zuraw BL, Banerji A, Bernstein JA, et al.  : US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol Pract  2013; 1( 5): 458– 67. doi:10.1016/j.jaip.2013.07.002. Google Scholar CrossRef Search ADS PubMed  Author notes The views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, US Navy, US Air Force, the Department of Defense, or the US Government. Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Military Medicine Oxford University Press

Extremely Delayed Diagnosis of Type II Hereditary Angioedema: Case Report and Review of the Literature

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Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2018.
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Abstract

Abstract We present a case with extremely late diagnosis of type II hereditary angioedema (HAE). Given recent advances in HAE treatment, we want to bring physician awareness to this condition and aid in earlier detection. HAE is a disorder associated with episodes of angioedema of the face, larynx, lips, abdomen, or extremities. Late diagnosis of HAE can lead to significant morbidity and is severely impairing due to recurring attacks. The diagnosis of HAE is ordinarily made during childhood and adolescence. Delayed diagnoses in early and middle adulthood have been documented in the literature. Gastrointestinal symptoms are common features of HAE and can be misdiagnosed as disease of primary gastrointestinal pathology, such as irritable bowel syndrome, recurrent pancreatitis, or appendicitis. These attacks are characterized by recurrent attacks of subcutaneous and submucosal edema without the presence of urticaria. We present a case of an elderly veteran whose diagnoses was extremely delayed into the eighth decade of life subsequent to unexplained abdominal symptoms. After diagnosis, the patient’s symptoms were well controlled with medication due to advances in HAE treatment. To prevent further atypically delayed diagnoses, physicians should consider HAE in patients with recurrent attacks of unexplained abdominal pain. Introduction Hereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous and/or submucosal edema without the presence of urticaria.1,2 The angioedema commonly involves the extremities, abdomen, and genitourinary tract. It also involves the face, oropharynx, and larynx, risking potential airway obstruction. Depending on the location and degree of edema, the severity may range from a mild episode to a life-threatening emergency. The diagnosis of HAE is ordinarily made during childhood and adolescence. Later diagnoses, however, can also be made in adulthood,3 with atypical delayed diagnoses being made in the elderly. We present a case of an extremely delayed diagnosis of type II HAE. Case Presentation A 78-yr-old military veteran presented with a long history of intermittent abdominal pain and swelling of the hands, feet, and scrotum since adolescence. The patient endorsed mid-epigastric abdominal pain without radiation, occurring on a weekly basis and lasting for several days. He described an extensive history of constipation and occasional diarrhea, including a significant, month-long episode in the spring of 2014 associated with abdominal pain, anorexia, and weight loss. He has since regained his weight and has not had further weight loss since. The patient’s review of systems was negative or noncontributory. The patient indicated that his maternal grandfather, mother, daughters, and two nieces have a history of episodic limb swelling. His brother has experienced similarly described recurrent abdominal pain. There is no family history of airway involvement. One niece has been diagnosed with a type of hereditary angioedema and is being treated. The patient has undergone multiple evaluations for his abdominal pain, which revealed several polyps and minor diverticulosis. The patient has been on several medications for gastroesophageal reflux disease and constipation, including lubiprostone, polyethylene glycol 3,350, and ranitidine, all without symptom improvement. Given his symptoms, family history, and unsuccessful treatments, his primary physician subsequently referred him to an allergist. Physical exam findings were unremarkable. Laboratory findings are listed in Table I. Additional workup included several C4 levels documented as low–normal or low, a normal quantitative complement C1q level, and a normal C1 esterase inhibitor level. The C1 esterase inhibitor function, however, was found to be low. His liver function tests were normal. Table I. Relevant Patient Laboratory Findings Test  Findings  Reference Range  Complement C1Q level, serum  18.0 mg/dL  11.8–23.8 mg/dL  Complement C1-INH functional level, serum  28%, 31%  Normal > 67%  Complement C1-INH level, serum  24 mg/dL  21–39 mg/dL  Test  Findings  Reference Range  Complement C1Q level, serum  18.0 mg/dL  11.8–23.8 mg/dL  Complement C1-INH functional level, serum  28%, 31%  Normal > 67%  Complement C1-INH level, serum  24 mg/dL  21–39 mg/dL  Table I. Relevant Patient Laboratory Findings Test  Findings  Reference Range  Complement C1Q level, serum  18.0 mg/dL  11.8–23.8 mg/dL  Complement C1-INH functional level, serum  28%, 31%  Normal > 67%  Complement C1-INH level, serum  24 mg/dL  21–39 mg/dL  Test  Findings  Reference Range  Complement C1Q level, serum  18.0 mg/dL  11.8–23.8 mg/dL  Complement C1-INH functional level, serum  28%, 31%  Normal > 67%  Complement C1-INH level, serum  24 mg/dL  21–39 mg/dL  The patient was diagnosed with type II HAE based on his symptom history, family history of angioedema, and low levels of C4 and functional C1 esterase inhibitor. In 2016, he was prescribed Icatibant, a bradykinin receptor blocker, which helped resolve six episodes of abdominal angioedema and pain in 2016 and five episodes in 2017. In each case of its use, his pain resolved over several hours, rather than over days or weeks in which he would experience pain without treatment. The patient desires to continue using on-demand Icatibant as needed for future episodes of HAE. With the low frequency of symptoms at this time in his management, prophylactic medications are not being used. Regular monitoring of transaminases is performed, as elevations are less common side effects of Icatibant. The patient was educated on the risk of using ACE inhibitors with a diagnosis of HAE and to avoid this class of medication. Discussion The mechanism by which HAE occurs is through a hereditary deficiency in functional levels of C1 esterase inhibitor (C1-INH) activity. C1-INH is a serine protease inhibitor, normally functioning as a suicide inhibitor by forming complexes with its target proteases: kallikrein, factor XIa, factor XIIa, C1s, and C1r.4 Pathogenesis of HAE involves the kallikrein–kinin and complement pathways, with activated factor XII initiating a cascade that produces bradykinin, the primary mediator of swelling via the enhancement of vascular permeability.2,3 HAE is an autosomal dominant disease, and roughly 75% of patients with HAE have a positive family history of angioedema.5 Three important subtypes of HAE have been recognized: type I, type II, and HAE with normal C1-INH (HAE-nC1 INH). More than 275 different mutations have been identified and are responsible for these diseases.2 Type I HAE involves a mutation in the C1-INH gene, SERPING1, resulting in a truncated or misfolded protein that is not secreted, accounting for about 85% of patients with HAE.2,3 Type II HAE is caused by a missense mutation, resulting in a normal C1-INH level but defective function. Finally, HAE-nC1 INH is due to either an increased activity of factor XII or is through an unidentified cause. In addition to the symptoms and signs previously described, HAE-nC1 INH may also include hemorrhage at the site of edema.4 In 20% of HAE-nC1 INH patients, the diagnosis can be made through identification of two known mutations in the factor XII gene; otherwise, it is a diagnosis of exclusion.6 We chose Icatibant for this patient for two reasons. First, it has been proven effective in acute attacks for HAE type II, due to its antagonistic effect on bradykinin receptors. Second, it is readily available in 3-mL prefilled syringes that can be administered subcutaneously at home without risk of anaphylaxis. Patients can give themselves up to three doses in a 24-h period if needed to reduce edema. Conclusion This case presentation is unique because of the extremely late diagnosis of type II HAE. There are other reports present in the literature of patients with recurrent abdominal pain resulting from HAE but having a delay in their diagnosis. Patients with recurrent abdominal pain may be misdiagnosed with a disease of primary gastrointestinal pathology, such as irritable bowel syndrome, recurrent pancreatitis, appendicitis, or colon intussusception, with an eventual diagnosis of HAE.7 Individualized treatment plans for patients of all ages should address preventive, home, and emergency measures for disease management, including long-term prophylaxis and on-demand medication with HAE identification and instructions.6 To best accomplish this, several general HAE guidelines have been published and are available; examples include the World Allergy Organization Guideline for the Management of Hereditary Angioedema3,8 and the US Hereditary Angioedema Association Medical Advisory Board 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 Inhibitor Deficiency.9 The World Allergy Organization (WAO) in collaboration with the European Academy of Allergy and Clinical Immunology (EAACI) recently proposed new guidelines in 2017 for the management of hereditary angioedema. Specifically, they recommend that attacks are treated as early as possible and HAE attacks are treated with either C1-INH, Ecallantide, or Icatibant. If these three agents are not available, then soluble detergent plasma or fresh frozen plasma can be given. The new guidelines recommend that patients have sufficient medication for on-demand treatment of two attacks and patients should carry this medication at all times. The advantages of using an on-demand medication are shorter time to resolution of symptoms and shorter total attack duration. The following is a review of currently available options. Plasma-derived C1-INH concentrate is available in intravenous formulation (Cinryze) and subcutaneous formulation (Haegarda); however, both have been associated with anaphylactic adverse reactions. Ruconest is the only available recombinant human C1-INH (rhC1-INH) and is only available in intravenous formulation, which is not ideal for on-demand home treatment. Ecallantide (a kallikrein inhibitor) can be used on demand in the United States; however, 3–4% of patients have reported hypersensitivity reactions to include anaphylaxis. This makes Icatibant (a bradykinin receptor antagonist) a more practical option as it can be given at home subcutaneously and the main adverse reaction is local injection site irritation according to the safety data. The authors see three potential solutions to prevent future extremely delayed diagnosis. First, increasing physician awareness of the signs and symptoms of HAE may lead to a timelier diagnosis and reduce patient suffering. Two, once the diagnosis has been made, provide family screening. In this case, our patient had a niece diagnosed with HAE; however, our patient remained undiagnosed until an extended abdominal flare led to further workup and referral to an allergy specialist. As evident with the presented case, clinical suspicion for HAE in later stages of life is a paramount to prevent unnecessary patient suffering and potential serious and preventable disease manifestations. Third, consider referral to an allergist or immunologist once the diagnosis has been made for definitive treatment. References 1 Jose J, Zacharias J, Craig T: Review of select practice parameters, evidence-based treatment algorithms, and International Guidelines for Hereditary Angioedema. Clinic Rev Allerg Immunol  2016; 51: 193. doi:10.1007/s12016-016-8546-7. Google Scholar CrossRef Search ADS   2 DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995. Record No. 114672, C1 inhibitor deficiency; [updated 2017 Apr 05, cited May 9, 2017]; [about 18 screens]. Available from http://search.ebscohost.com.ezproxy.hsc.usf.edu/login.aspx?direct=true&db=dnh&AN=114672&site=dynamed-live&scope=site. 3 Craig T, Pürsün EA, Bork K, et al.  : WAO guideline for the management of hereditary angioedema. World Allergy Organ J  2012; 5( 12): 182– 99. Google Scholar CrossRef Search ADS PubMed  4 LoVerde D, Files DC, Krishnaswamy G: Angioedema. Crit Care Med  2017; 45( 4): 725– 35. doi:10.1097/CCM.0000000000002281. Google Scholar CrossRef Search ADS PubMed  5 Zuraw BL, Bernstein JA, Lang DM, et al.  : A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol  2013; 131( 6): 1491– 3. doi:10.1016/j.jaci.2013.03.034. Google Scholar CrossRef Search ADS PubMed  6 Bouillet L, Boccon‐Gibod I, Launay D, et al.  : Hereditary angioedema with normal C1 inhibitor in a French cohort: clinical characteristics and response to treatment with icatibant. Immun Inflamm Dis  2017; 5( 1): 29– 36. doi:10.1002/iid3.137. Google Scholar CrossRef Search ADS PubMed  7 Patel N, Suarez LD, Kapur S, Bielory L: Hereditary angioedema and gastrointestinal complications: an extensive review of the literature. Case Rep Immunol  2015; 2015: 925861. doi:10.1155/2015/925861. 8 Maurer M, Markus M, Ignacio A, et al.  : The international WAO/EAACI guideline for the management of hereditary angioedema – the 2017 revision and update. Allergy  2018. doi:10.1111/all.13384. 9 Zuraw BL, Banerji A, Bernstein JA, et al.  : US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol Pract  2013; 1( 5): 458– 67. doi:10.1016/j.jaip.2013.07.002. Google Scholar CrossRef Search ADS PubMed  Author notes The views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, US Navy, US Air Force, the Department of Defense, or the US Government. Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Journal

Military MedicineOxford University Press

Published: Mar 26, 2018

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