Treatment of Laryngeal Hereditary Angioedema

The Journal of Emergency Medicine, Vol. 42, No. 1, pp. 44–47, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

doi:10.1016/j.jemermed.2010.11.032

Clinical Communications: Pediatrics TREATMENT OF LARYNGEAL HEREDITARY ANGIOEDEMA Mark J. Richman, MD, MPH,*† David A. Talan, MD,*† and William R. Lumry, MD‡ *Department of Medicine, DavidGeffen School of Medicine at UCLA, Los Angeles, California, †Department of Emergency Medicine, Olive View-UCLA Medical Center, Sylmar, California, and ‡Department of Internal Medicine, University of Texas Southwestern Medical School-Dallas, Dallas, Texas Reprint Address: Mark Richman, MD, MPH, Department of Emergency Medicine, Olive View-UCLA Medical Center, 14445 Olive View Drive - North Annex, Sylmar, CA 91342

, Keywords—angioedema; hereditary angioedema; HAE; laryngeal; C1 inhibitor

, Abstract—Background: In the emergency department, patients with laryngeal swelling and an inconclusive patient history may receive treatment for allergy-mediated angioedema. Intubation may be necessary if the patient does not respond to treatment. Because angioedema subtypes respond to different interventions, a correct diagnosis is vital. Objectives: Review the differential diagnosis of angioedema and characteristics differentiating subtypes. Discuss therapies for angioedema subtypes. Introduce therapies for prevention and acute treatment of hereditary angioedema (HAE). Case Report: A 10-year-old girl presented with laryngeal swelling unresponsive to diphenhydramine, methylprednisolone, and epinephrine. It was later revealed that she had a family history of HAE, was C1 inhibitor deficient, and enrolled in a clinical study of acute HAE treatment. She was given 1000 units of nanofiltered C1 inhibitor and was able to swallow within 30 min. She was prescribed routine prophylaxis with C1 inhibitor concentrate and has had no subsequent severe HAE swelling attacks. Conclusion: This case illustrates the need for providers to consider HAE in light of available diagnostic testing and recent Food and Drug Administration approval of specific therapies for HAE. Ó 2012 Elsevier Inc.

INTRODUCTION Angioedema is characterized by non-pitting, non-pruritic subcutaneous or submucosal edema in the head/neck, bowel, or extremities that may migrate from one site to another during an attack (1). Hospitalizations from angioedema increased by 35% from 1998 to 2005, and 24% of attacks and hospitalizations were attributed to adverse reactions to antihypertensive or cardiovascular drugs (2). Although often associated with allergic reactions, angioedema also occurs without an immunoglobulin E-mediated histamine release. Bradykinin mediates hereditary angioedema (HAE) due to C1 inhibitor deficiency or dysfunction, angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema, and acquired C1 inhibitor deficiency angioedema. Cytokines mediate episodic angioedema with eosinophilia. Antihistamines, epinephrine, corticosteroids, and allergen avoidance are used to treat allergic and idiopathic angioedema; angioedema mediated by cytokines does not respond to these therapies. This report describes a case of HAE with emphasis on the importance of emergency department (ED) recognition in light of the availability of specific testing and newly available treatments.

Financial support has been provided by ViroPharma Incorporated. Dr. Lumry has received grant support from ViroPharma/Lev, Dyax, and Jerini/Shire; he is on the Advisory Board of ViroPharma/Lev and Dyax, and is on the Speakers Bureau of ViroPharma.

RECEIVED: 21 January 2010; FINAL SUBMISSION RECEIVED: 11 April 2010; ACCEPTED: 1 November 2010 44

Treatment of Hereditary Angioedema

CASE REPORT A 10-year-old girl presented to the ED complaining of inability to swallow. Her symptoms began 2 h before presentation. She reported awaking with a feeling of fullness in her throat that progressed to scratchiness on her tongue. Her mother, seeing nothing unusual in her daughter’s mouth, assumed she was having postnasal drainage from seasonal allergies and gave her diphenhydramine. An hour later, the girl was spitting saliva in a cup, complaining of a tight throat and inability to swallow. The mother brought her to the ED. Initial questioning indicated the patient had not had insect bites or taken new medications or foods in the prior 24 h. She had no history of similar events. The patient took antihistamines as needed and a multivitamin. She had a history of seasonal allergic rhinitis with typical symptoms, but no history of food or drug allergies. She had been seen in the ED 2 months prior with intractable vomiting 6 h after being hit in the stomach by a soccer ball. Her blood pressure was 100/66 mm Hg, heart rate 100 beats/min, respiratory rate 20 breaths/min, oxygen saturation on room air 90%, and she was afebrile. Physical examination revealed that her voice was hoarse and her head tilted forward. The posterior pharynx and uvula were edematous. Inspiratory stridor was heard over the trachea. No facial, tongue, lip, or neck swelling, or cervical adenopathy or tenderness was noted. On arrival, the patient received oxygen supplementation, intravenous (i.v.) diphenhydramine HCl 50 mg, and i.v. methylprednisolone 60 mg. Epinephrine (1:1000) 0.3 cc was given intramuscularly. Her symptoms did not change with these maneuvers. Laboratory evaluation included a normal complete blood count, chemistry panel, and chest X-ray study. Soft tissue lateral neck film revealed straightening of the cervical spine with edema of the epiglottis and upper airway. The patient’s mother subsequently revealed a family history of attacks of throat swelling and episodic hand and foot swelling and abdominal pain. Both mother and maternal aunt were diagnosed with HAE in their teen years, and the patient had recently been found to have C1 inhibitor deficiency consistent with a diagnosis of HAE, although she had not had any apparent swelling attacks. After the family history HAE was revealed, the mother’s physician was called. It was learned the child was already enrolled in a clinical study for treatment of acute HAE attacks and open-label study drug was provided by her physician. The patient was given 1000 units of nanofiltered C1 inhibitor concentrate via i.v. push over 10 min. Within 30 min, she was able to swallow. After 4 h in the ED, the patient was discharged in stable condition. Because it was late in the day and the patient lived 5 h

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away, her physician had her admitted to the hospital for overnight observation. She did not require further treatment for the HAE attack. In light of this potentially life-threatening laryngeal HAE, the child’s physician prescribed routine prophylaxis with C1 inhibitor concentrate. The patient receives infusions of 1000 units of nanofiltered C1 inhibitor concentrate every 3 to 4 days. She has experienced no severe HAE swelling attacks since beginning prophylactic therapy 1 year ago. DISCUSSION Quick and accurate assessment of a swelling attack involving the face or mouth is critical to identify potentially life-threatening laryngeal involvement. In the absence of corrective action, airway closure and asphyxiation may ensue. In this case, airway involvement was recognized. When accepted treatment for acute allergic angioedema was unsuccessful, alternative diagnosis and treatment was sought. The child had no prior episodes of peripheral swelling, but had previously been found to have C1 inhibitor deficiency. The initial patient history did not reveal her diagnosis, and the ED clinicians did not consider HAE as a possible cause of her angioedema. The patient and her mother were not directly questioned about a family history of HAE before ineffective interventions were administered. This lack of investigation and resulting lag in effective treatment highlights the need for both patient education and increased clinician awareness. Patients’ histories should include questions about a family history of angioedema, episodes of unexplained abdominal pain, and laryngeal edema. The history may suggest the symptoms of HAE: recurrent angioedema without urticaria, a family history of episodic swelling, first attack early in life, and worsening at puberty (1,3). HAE symptoms typically emerge in the second decade of life. Many patients with HAE experience a prodromal syndrome (eg, exhaustion, mood change, tingling) before swelling begins (1,4,5). Angioedema affecting the bowel may be confused with endometriosis, acute gastroenteritis, peritonitis, bowel obstruction, appendicitis, and other causes of acute abdominal pain. Clinicians should consider angioedema in patients with multiple visits for acute abdominal pain, particularly if there is a family history of unexplained abdominal pain or angioedema. HAE symptoms overlap with symptoms of other causes of angioedema, and the location and severity of attacks are variable and unrelated to the extent of C1 inhibitor dysfunction (6,7). Only 39% of patients can identify the trigger of their first HAE attack (8). Known triggers

Bradykinin Possibly bradykinin/ histamine/ other? Normal Normal

HAE = hereditary angioedema; ACE-I = angiotensin-converting enzyme inhibitor. Adapted with permission from Elsevier.

Normal Normal Normal Normal Normal Normal Normal Normal ACE-I induced Idiopathic

Bradykinin Low Normal/ Low Low Low

< 30%

Unknown (possibly bradykinin) Normal Normal Normal Normal

Normal

< 30% Normal/ Elevated

Low

Normal

Normal

Bradykinin

Acute  C1 inhibitor concentrate  Kallikrein inhibitor Prophylaxis  Danazol  C1 inhibitor concentrate  Antifibrinolytics Acute  C1 inhibitor concentrate Prophylaxis  Treat underlying disease  Antifibrinolytics  Attenuated androgens  Withdraw ACE-Is  Antihistamines  Epinephrine  Corticosteroids  Allergen avoidance Bradykinin Normal Normal Low < 30% < 30%

HAE type I (85% of HAE) HAE type II (15% of HAE) Inherited angioedema with normal C1 inhibitor (< 1% of HAE) Acquired C1 inhibitor I/II

Mediator C1q Level C3 Level C4 Level C1 Inhibitor Function C1 Inhibitor Level Angioedema Type

Table 1. Laboratory Studies and Treatment Approaches for Different Causes of Angioedema (5,10–16)

include physical trauma (including surgical and dental procedures); mechanical pressure (typing, prolonged standing); infection; emotional stress; and medications such as ACE-Is and estrogens (3,7–9). Patients with C1 inhibitor deficiency or dysfunction cannot regulate C1 inhibitor-dependent pathways (contact, complement, fibrinolytic). When these pathways are activated, dysregulation leads to an increased production of bradykinin with subsequent vasodilation and increased vascular permeability, which leads to angioedema. Therefore, trauma, medical/surgical procedures, infection, or other conditions triggering these pathways may initiate angioedema attacks. Spontaneous genetic mutations are responsible for one-quarter of HAE cases. Without a known family history of HAE, spontaneous cases and first presentations will be indistinguishable from acquired, idiopathic, or medication-induced cases. In this situation, HAE can be distinguished from other types of angioedema with readily available laboratory studies (Table 1) (5,10–16). Acquired angioedema associated with C1 inhibitor deficiency usually presents later in life, is not familial, and usually is associated with a low C1q level or antiC1 inhibitor antibodies (5). Idiopathic angioedema occurs at least three times per year with no apparent cause and is accompanied by urticaria in half of patients (10). Histamine-responsive idiopathic angioedema responds to treatment with antihistamines, corticosteroids, or epinephrine (17). ACE-I-induced angioedema occurs in 0.1% to 2.2% of patients receiving ACE-Is (18). The most commonly affected sites are the lips, tongue, and face (11). This condition generally emerges in the first month of treatment, but can occur after years of therapy (11). The symptom pattern for ACE-I-induced angioedema closely resembles that of HAE when it affects the face, lips, or tongue. Patients with suspected ACE-I-induced angioedema should have tests to rule out HAE or acquired angioedema. A switch to angiotensin receptor blockers is safe in most patients; however, clinicians should be aware that a small percentage of patients may develop angioedema episodes after a switch (18,19). Laboratory assessment can help distinguish between angioedema types (Table 1). This patient had C4 level, C1 inhibitor level, and C1 inhibitor function test results consistent with a diagnosis of type I HAE. Food and Drug Administration (FDA)-approved agents for prophylactic therapy include the attenuated androgen, danazol, and the nanofiltered C1 inhibitor concentrate, CINRYZEÔ (Lev Pharmaceuticals; New York, NY) (13,14). Antifibrinolytic agents (e.g., epsilon aminocaproic acid) have been used off-label. Danazol is more effective than antifibrinolytics in reducing the frequency and severity of attacks, but both agents have

M. J. Richman et al.

Treatment

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Treatment of Hereditary Angioedema

significant side effects that may limit their use (1). The availability of nanofiltered C1 inhibitor via intravenous infusion provides an effective, well-tolerated therapy (13). CINRYZEÔ was recently approved for patient self-administration for routine prophylaxis. The plasma-derived C1 inhibitor (human), BerinertÒ (CSL Behring LLC; Kankakee, IL), was recently approved by the FDA for treatment of acute abdominal and facial HAE attacks (15). The FDA has also recently approved the kallikrein inhibitor, KALBITORÒ, for the treatment of acute HAE attacks in patients 16 years and older (16). In the event that these approaches are not available and an off-label approach is implemented, care must be exercised. Fresh frozen plasma (FFP), which contains C1 inhibitor, has reported efficacy for acute HAE attacks, but is controversial because the contact system proteins in FFP may promote bradykinin production and exacerbate the attack (1). There are some reports that epinephrine may provide benefit if given early and probably should be administered to anyone presenting with airway angioedema (1). Due to delayed onset of action, androgens and antifibrinolytics are not useful for acute HAE attacks (1). CONCLUSION Episodes of angioedema can be frightening for patients and perplexing for clinicians. This case of HAE underscores the role of patient and family history and the need to consider non-allergic types of angioedema in the differential diagnosis. With the recent availability of FDA-approved therapies for prophylaxis and acute treatment, and accurate testing methods, it is now critically important for emergency physicians to consider an HAE diagnosis to guide acute treatment of angioedema attacks and their long-term management. Acknowledgments—Lynne Isbell, PHD, and Innovative Strategic Communications provided assistance in the preparation of the manuscript and other editorial support.

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