HEREDITARY ANGIOEDEMA: AN EMERGENCY NURSING PERSPECTIVE Authors: Jillian Wade, RN, BSN, and Thomas W. Barkley Jr., PhD, ACNP-BC, FAANP, Los Angeles, CA Case Study
24-year-old female patient presents to the emergency department with painful non-pitting, non-pruritic facial swelling, reporting a history of 2 self-resolving episodes of these symptoms. She has no known allergies and no signiﬁcant medical history but does report a positive family history of undiagnosed intermittent facial or extremity swelling. The patient is awake; alert; oriented to person, place, time, and purpose; and able to follow commands. Her lung sounds are clear to auscultation, and her heart sounds have a regular rate and rhythm, with no murmurs, clicks, or rubs. Her abdomen is soft and nontender, with bowel sounds present in all quadrants. The patient’s skin is pink; warm; dry; and free of any rash, redness, or lesions. Her vital signs and laboratory results are all within normal limits. Diphenhydramine, epinephrine, and prednisone are administered, with no improvement in symptoms. The patient is admitted for observation, and an allergist is consulted. Low levels of C1 inhibitor and C4 conﬁrm a diagnosis of type I hereditary angioedema (HAE). HAE is an autosomal dominant disorder that affects between 1 in 10,000 and 1 in 150,000 individuals. 1–3 Acute episodes account for 15,000 to 30,000 ED visits annually, and patients with HAE can be affected for up to 100 days per year. 1 Racial and ethnic backgrounds are not predisposing factors for HAE, whereas sex does have a strong association with type III HAE. 3 Patients with HAE report an average of 26.9 episodes per year, with an average episode lasting longer than 2.5 days. 4
HAE is characterized by repeated episodes, or “attacks,” of localized subcutaneous or submucosal edema. 2,3,5 Angioedema can affect any part of the body, although the most commonly affected areas are the face, extremities, upper respiratory tract, gastrointestinal system, oropharynx, or genitals. 2,6–8 Episodes can be extremely painful and can be life-threatening when they involve the tongue, soft palate, or larynx. 2,9 Several factors can precipitate episodes: minor surgery or trauma, infection, stress, anxiety, menstruation, oral contraceptive use, and pregnancy. Patients also often have idiopathic episodes, showing no obvious precipitating factors. 1–3,10,11
Jillian Wade, Member, Greater Los Angeles County Chapter, is Graduate Student, Adult-Gerontology Acute Care Nurse Practitioner Program, California State University, Los Angeles, CA; and Staff Nurse, Emergency Care Center, St. Joseph Hospital of Orange, Orange, CA. Thomas W. Barkley Jr is Coordinator, Adult-Gerontology Acute Care Nurse Practitioner Program, and Director of Nurse Practitioner Programs, School of Nursing, California State University, Los Angeles, CA. For correspondence, write: Jillian Wade, RN, BSN, California State University, Los Angeles, School of Nursing, 5151 State University Drive, Los Angeles, CA, 90032; E-mail: [email protected]
Generally, HAE can be the result of 1 of more than 200 mutations on the gene controlling C1 inhibitor production on chromosome 11. Most patients with type I and type II HAE have autosomal dominant mutations in the C1 inhibitor gene. 3 Some 20% to 25% of cases occur from spontaneous mutations in individuals who have no known family history of HAE. 1 These mutations result in decreased C1 inhibitor production or dysfunction. The C1 inhibitor protein acts as an inhibitor in complement and contact systems and the kallikrein-kinin cascade, and it plays a minor role in the coagulation and ﬁbrinolysis pathways. 1,12,13 Decreased C1 inhibitor activity causes inappropriate activation of these pathways. 1–3 Increased activation of the contact system and the kallikrein-kinin cascade results in increased kallikrein activation, which increases bradykinin production. Excess bradykinin and complement fragments, in turn, increase vascular permeability, vasodilation, and nonvascular smooth muscle constriction. This leads to interstitial ﬂuid accumulation, causing the characteristic angioedema. 1,3,5 When the C1 inhibitor fails, the resulting angioedema may be severe enough to prompt hospitalization and may even lead to death in cases in which the airways are blocked by swelling.
J Emerg Nurs ■. 0099-1767
Types of HAE
Copyright © 2015 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jen.2015.02.001
There are 3 types of HAE. Type I HAE is caused by a mutation that results in truncated or misfolded C1 inhibitor
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proteins. 14 Type I is characterized by low levels of C1 inhibitor and low levels of C4. 1–3 Overall, approximately 85% of individuals with HAE have type I. 3 Type II HAE is characterized by a mutation that results in a dysfunctional C1 inhibitor protein and low level of C4. 1–3,14 Type III HAE is sometimes also called “HAE with normal C1 inhibitor” and is more common in women. 1,3 With type III, the C1 inhibitor has normal levels and functionality. Estrogen may play a role in triggering angioedema in patients with type III HAE by inﬂuencing the contact system through increasing factor XII, prekallikrein, kallikrein, and bradykinin levels. 3,10 The exact cause of angioedema in type III HAE is not completely understood. Approximately 25% of patients with type III HAE have a mutation for the factor XII gene, which promotes kinin production. 3,9,14
Signs and Symptoms
Patients with HAE have episodes of non-pitting, nonpruritic swelling of the extremities, abdomen, face, or upper airway. 1 In a typical episode, the swelling severity gradually increases over the ﬁrst 24 hours and then gradually decreases over the next 48 to 72 hours. Swelling can begin in one location and progress to another location before beginning to resolve. 1,3 Abdominal episodes can be especially distressing for the patient. These episodes can cause abdominal pain, distension, cramping, colic, nausea, vomiting, or diarrhea. 1,3,15 Such episodes can be extremely disabling and disruptive to activities of daily living. 2 Between 70% and 90% of patients with HAE have abdominal episodes at least once. 1,2 Abdominal episodes can induce acute pancreatitis if the angioedema causes obstruction of the pancreatic duct, although this is a rare occurrence. 11 Unfortunately, these episodes are often misdiagnosed, resulting in unnecessary surgery, such as exploratory laparotomy, or periods of unnecessary hospitalization. 2 Laryngeal edema is also of particular concern, given that the incidence of death with untreated laryngeal episodes is as high as 40%. 5 However, it is very rare (constituting b 1% of episodes); nevertheless, approximately 50% of patients with HAE have a laryngeal episode at least once in their lifetimes. 2,5 Normally, laryngeal edema presents later in the course of the disease, usually in the second or third decade. 2 A cardinal feature of HAE is the lack of urticaria with repeated angioedema episodes. 3,16 It should be noted that although HAE is not associated with urticaria, some patients may have the prodromal symptom of erythema marginatum (ie, a rash characterized by wavy edges). 1,3
In the diagnosis of HAE, it is important to obtain a thorough history and perform a thorough physical examination, in addition to several key blood tests. 1,3 Three key clinical features that are highly suggestive of HAE are episodic angioedema that is slow to peak and triggered by some stressor or trauma, recurrent abdominal pain, and a family history (present in approximately two-thirds of patients). 17 Tests of C1 inhibitor level, C1 inhibitor function, and C4 level should be performed. C4 levels are useful in HAE diagnosis because they decrease with uncontrolled complement and contact system activation. Type I HAE is characterized by a low C1 inhibitor level, low C1 inhibitor function, and a low C4 level. Type II HAE presents with a normal C1 inhibitor level, low C1 inhibitor function, and a low C4 level. Type III HAE presents with a normal C1 inhibitor level, normal C1 inhibitor function, and a normal C4 level. There are no deﬁnitive tests or criteria for the diagnosis of type III HAE, and the diagnosis is made on the basis of symptoms and patient history. 18 At the time of diagnosis, several laboratory studies are recommended: complete blood count; urinalysis; creatinine kinase level; lactic dehydrogenase level; hepatic function tests; renal function tests; serum lipid levels; pregnancy testing (if applicable); and possibly, abdominal imaging. 3,9 In patients with abdominal episodes, an abdominal ultrasound or abdominal computed tomography scan may be used to assess for bowel edema (or ascites in later stages of an episode). Patients also often have leukocytosis during episodes because of hemoconcentration caused by third spacing. 11 Pharmacology PHARMACOLOGY IN ACUTE EPISODES
Icatibant is sometimes used in treating acute episodes. This agent is a bradykinin β2 receptor antagonist, blocking bradykinin from binding to β2 receptors and preventing edema. 2 It has been approved in the United States for subcutaneous self-administration. However, in addition to icatibant self-administration, patients should seek care from a provider, given the potential for laryngeal edema. 19 Injection-site reactions occur after administration in almost all patients, up to 97%. 19 It is important to note that icatibant interacts with angiotensin-converting enzyme inhibitors and may attenuate antihypertensive effects, placing the patient at risk of hypotension. 19 Ecallantide is also used to treat acute episodes. Ecallantide is a selective reversible kallikrein inhibitor because it decreases kallikrein-mediated bradykinin production. 4,5,20
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Because of the risk of hypersensitivity reactions to ecallantide, it must be administered under the supervision of a health care provider. 5 Ecallantide has proved to be very effective during acute HAE episodes. In a systematic review, use of ecallantide improved laryngeal edema in most HAE patients; 80% of patients had consistent improvement, and 63% had either complete or nearly complete symptom resolution within 4 hours of initial dosing. This response in patients was improved or maintained at 24 hours as well. 5 C1 inhibitor concentrates are an integral part of treating HAE. Three forms are used: C1 esterase inhibitor, C1 inhibitor (human), and recombinant analogue of human C1 inhibitor conestat alfa. Only C1 inhibitor (human) has been approved for both short- and long-term prophylaxis. C1 inhibitor concentrates have been shown to decrease the severity, duration, and frequency of HAE episodes, as well as decrease the need for rescue therapy during an episode. 13 In facilities that do not have C1 inhibitor concentrates, icatibant, or ecallantide available, fresh-frozen plasma (FFP) or solvent-/detergent-treated plasma (SDP) can be used for acute episodes. These blood products both contain active C1 inhibitor proteins that can help replace deﬁcient or dysfunctional C1 inhibitor proteins. However, blood products should not be a ﬁrst-line choice. Although research does support the effectiveness of FFP and SDP in reducing symptoms, they should only be used if ﬁrst-line therapy is unavailable. 9,21 Whereas both FFP and SDP contain C1 inhibitor proteins, which can alleviate some HAE symptoms, they also contain the same proteins that are activated in the cascades that lead to angioedema. Although it is uncommon, blood products have the potential to worsen HAE episodes and can also increase the patient’s risk of blood-borne infectious diseases associated with blood transfusions, such as hepatitis or human immunodeﬁciency virus. 22 Baseline testing should be performed for hepatitis B, hepatitis C, and human immunodeﬁciency virus. 3,9 In addition, it is recommended to ensure that patients have been vaccinated for and have immunity to hepatitis B, in case that they may need blood transfusions in the course of their treatment. Although the emergency nurse’s ﬁrst priority during a patient’s acute HAE episode is to ensure airway patency and administer medications that decrease angioedema, it is also important to consider pain management and control of nausea or vomiting. Angioedema is most often very painful for the patient, and nausea and vomiting are often present during abdominal episodes. In cases with acute abdominal episodes, volume replacement may be necessary because of third spacing or ﬂuid loss due to vomiting or diarrhea. 3 It is important to emphasize that HAE is not caused by a histamine reaction and, therefore, does not respond to
medications used for histamine-mediated allergic reactions. Antihistamines, prednisone, and epinephrine are not effective treatments for this type of angioedema because HAE is noninﬂammatory and nonvascular. 5 Emergency nurses play a key role in distinguishing HAE from histamine-mediated allergic angioedema, which is essential in avoiding inappropriate therapy and preventing recurrent episodes. 23 PHARMACOLOGY OF HAE PROPHYLAXIS
HAE patients may choose to self-administer their medication. Home-care support programs are becoming more widely available. Both C1 inhibitor concentrates and icatibant have been approved for self-administration. The prescribing physician or nurse practitioner must approve selfadministration of C1 inhibitors, and a specialist nurse must provide training to the patient on intravenous administration. 7,24 For treatment with icatibant, the patient must be trained on subcutaneous administration. Even if episodes are controlled with self-administration, each episode, no matter the severity, should be reported to track frequency and treatment efﬁcacy. 7,14 Methods for managing HAE generally focus on the restoration of the C1 inhibitor deﬁciency and the prevention of bradykinin accumulation. 2,25 There are 2 preventative approaches: short-term and long-term prophylaxis. Short-term prophylaxis is used for preprocedural prevention. Because trauma can trigger acute episodes, patients undergoing medical or surgical procedures are prescribed short-term prophylaxis. In a recent study, physicians testing plasma-derived C1 inhibitors for short-term prophylaxis reported excellent outcomes; in all but 1 case in which short-term prophylaxis was administered before a procedure or operation, postoperative episodes were avoided. 26 The C1 inhibitor should be infused about 1 hour before intubation or another major medical procedure. 3 For minor procedures, prophylactic treatment is unnecessary if a C1 inhibitor is immediately available to the patient should the need arise. If not, the patient should receive prophylaxis 5 days before the procedure and 2 days after. Long-term prophylaxis is used in routine prevention. It may be used for patients with swelling episodes more than once a month or patients who have severe or life-threatening episodes. 3,25 Because C1 inhibitors have a short half-life, frequent dosing is required. Some patients may require central venous catheter placement for their treatment. 3 Recommended long-term prophylaxis for type I or type II HAE includes C1 inhibitor concentrates and androgens. Androgens have been shown to be effective in treating HAE by reducing the frequency of episodes by up to 84%. 14 However, androgens also present with multiple side effects and contraindications and have been associated with serious
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adverse effects. Examples include virilization in women, hypertension, liver neoplasms, and erythrocytosis. 14 Pregnancy is an absolute contraindication for androgen therapy. A C1 inhibitor concentrate can be used during pregnancy for the treatment of an acute episode or prophylaxis, and it is the only medication for HAE that has been shown to be safe while breast feeding. 7,9,10
For most emergency nurses, care for HAE patients generally occurs during acute episodes of angioedema. Administering a C1 inhibitor as quickly as possible during an acute episode is important. 3,13 Some patients can intravenously self-administer a C1 inhibitor concentrate in a non–health care setting for faster symptom relief. Patients who self-administer C1 inhibitor concentrates have less severe episodes, fewer ED visits, less narcotic use, and fewer days of work missed than those who receive treatment in a health care setting. 14 Health care providers should assess whether self-administration is feasible and practical for their patients because it can decrease the amount of critical care time during which patients would be treated in a hospital or prevent the need to present to an acute care facility at all. In cases of airway edema, ensuring airway patency is the emergency nurse’s primary concern. Up to 10% of patients with laryngeal edema may require an emergency airway intervention, such as intubation, cricothyrotomy, or tracheostomy. 5 Patients should be warned of the unpredictable nature of acute episodes. 1–3 The frequency and intensity of HAE exacerbation vary widely among individuals; some have episodes several times a week, whereas others rarely have them. 27 In addition, the frequency of episodes can vary for the same individual over time. 10 Thus patients should be informed of the necessity of carrying medical-alert identiﬁcation cards and a copy of their speciﬁc treatment plan, especially if traveling. 3 Patients should also be able to identify facilities close to home for urgent or emergent needs. 28 In addition, all patients should be taught the importance of early identiﬁcation of triggers. 3 Avoiding activities that can cause trauma, especially facial trauma, should be emphasized, and if such trauma occurs, patients should be advised to seek prompt treatment for infections. Patients should also be educated about the HAE resources at their disposal. Examples of such resources include the Hereditary Angioedema Association (HAEA, www.haea.org) and the National Organization for Rare Disorders (NORD, www.rarediseases.org). Because HAE is uncommon, HAEA has a scientiﬁc registry for patients diagnosed with HAE should they be willing to
participate in clinical studies or research, which can be found on their Web site. For women with HAE whose episodes are aggravated by estrogen, estrogen-containing oral contraceptives and hormone replacement therapy are not recommended. Alternative contraceptive methods include barriers such as condoms or cervical caps, progestin-only contraceptives, and copper intrauterine devices. Progestins are generally well-tolerated and have even been shown to decrease the frequency of episodes in some women. 10
Providing Compassionate Care
Patients with HAE face signiﬁcant social, psychological, and economic burdens because of the cost of treatment, as well as the unpredictable nature of the condition and the impact it has on quality of life. 4,29 To manage their disease process, this patient population requires education, training, and longterm monitoring. HAE patients also face signiﬁcant psychological burdens, experiencing an increased incidence of depression and anxiety. 29,30 Patients often have fatigue, depression, and decreased productivity after an episode, further exacerbating psychosocial issues. These patients face decreased quality of life and a signiﬁcant economic burden. 5,8 Moderate to extreme cases of insomnia have also been reported and may exacerbate depression and anxiety. 30 Many patients deal with anxiety due to the fear of upper airway edema. 2,29,30 They can be assured that upper airway edema is relatively rare, but they still ought to be warned that it has a mortality rate of up to 40%, and proper precautions should be emphasized. 2 Furthermore, in many cases, anxiety may be ameliorated by a deﬁnitive diagnosis, treatment, and training of patients by nurses on what to do during an episode or on medication self-administration. 30 Although the timing of individual episodes associated with HAE is unpredictable, the disease itself is manageable with pharmacologic therapy. HAE episodes are often misdiagnosed by practitioners, leading to expensive and unnecessary hospital stays and even needless operations. Thus it is important that emergency nurses, nurse practitioners, physicians, and other health care providers are familiar with HAE signs and symptoms and treatment regimens. Equally important is the task of training HAE patients to care for themselves; when patients are trained to self-administer certain treatments, hospital stays become fewer and symptoms less severe. Modern treatments allow HAE to be managed on a prophylactic basis rather than only an emergent basis, and health care providers have access to tools that help prevent HAE from interrupting patients’ daily lifestyles as often as it did in the past.
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24. Symons C, Rossi O, Magerl M, Andritschke K. Practical approach to self-administration of intravenous C1-INH concentrate: a nursing perspective. Int Arch Allergy Immunol. 2013;161(Suppl 1):17-20. 25. Craig T, Aygören-Pürsün E, Bork K, et al. WAO guideline for the management of hereditary angioedema. World Allergy Organ J. 2012;5(12):182-199. 26. Nanda MK, Singh U, Wilmot J, Bernstein JA. A cross-sectional questionnaire assessing patient and physician use of short-term prophylaxis for hereditary angioedema. Ann Allergy Asthma Immunol. 2014;113(2):198-203. 27. Walford HH, Zuraw BL. Current update on cellular and molecular mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112(5):413-418. 28. Riedl MA. Creating a comprehensive treatment plan for hereditary angioedema. Immunol Allergy Clin North Am. 2013;33(4):471-485. 29. Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329-336. 30. Fouche AS, Saunders EFH, Craig T. Depression and anxiety in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112(4):371-375.
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