Acquired Angioedema


Article Author:
Terrell Swanson


Article Editor:
Bhupendra Patel


Editors In Chief:
Sisira Reddy
Joseph Nahas


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
4/9/2019 8:46:14 PM

Introduction

Angioedema is characterized by one or more areas of well-demarcated, non-pitting edema of deep subcutaneous tissues. Although known primarily to involve the face and intra-oral area, it can also involve the genitals, distal extremities, and intraabdominal gastrointestinal mucosa[1]. Immediate identification of angioedema is of the utmost importance due to the potential for rapid development and progression of life-threatening airway compromise due to either intraoral and/or laryngeal edema.

Etiology

There are several etiologies of angioedema, most notably angiotensin-converting enzyme inhibitor (ACEI) use. With tens of millions of people taking ACEIs, the incidence of ACEI angioedema is rising[2]. African Americans are at a much higher risk for ACEI angioedema, possibly due to lower endogenous bradykinin and increased sensitivity to ACEI-mediated increases in bradykinin.

Other etiologies include IgE-mediated allergic reactions (such as to food, drug, or environmental triggers), nonsteroidal anti-inflammatory drug (NSAID) use (including aspirin), and chemically-induced histamine release (most commonly opiates, highly cationic antibiotics, and muscle relaxants)[1]. A less common cause is hereditary angioedema (HAE) and acquired angioedema (AAE), both caused by a C1-inhibitor (C1-INH) deficiency.

HAE and AAE are rare. AAE is due to an acquired deficiency of (C1-INH), caused by either consumption (type 1) or inactivation (type 2)[3]. This increased catabolism can be related to an autoimmune disorder (e.g., systemic lupus erythematous) or a malignant tumor (e.g., lymphoma)[4]. Angioedema recurs unpredictably, lasting from two to five days. It not only presents with edema of the areas mentioned above, but it can also cause severe abdominal pain due to gastrointestinal mucosa edema. AAE recurrence is associated with various conditions such as different forms of lymphoproliferative disorders[5].

Epidemiology

Less than 1% - 2% of angioedema cases are characterized as either HAE or AAE, with HAE having been noted to be about ten times more common than AAE. While the prevalence of AAE is difficult to estimate due to its rarity and potential lack of recognition, some estimate it to be between 1:100,000 and 1:500,000. Specific triggers include trauma, medical procedures, emotional stress, menstruation, oral contraceptives, infections, and drugs, although flare-ups are unpredictable.

Other specific notable factors include more than 90% of patients developing AAE after 40 years of age, and that those suffering from AAE exacerbations have abdominal pain less than 50% of the time as compared to those with HAE having abdominal more than 80% of the time.

Pathophysiology

Angioedema’s underlying pathophysiology involves increases in vascular permeability and vasodilation that is histamine, bradykinin or complement-mediated, resulting in fluid extravasation into interstitial tissues. Active C1-INH is decreased through catabolism or binding that renders it inactive. The decrease of C1-INH causes deregulation of the complement pathway, leading to increased vascular permeability, mast cell degranulation, and increased bradykinin levels. Neutralizing autoantibodies to C1-INH are present in the majority of patients.

History and Physical

It is of utmost importance to obtain medication, food, and environmental exposure history with special attention to ACEIs and NSAIDs as possible causative factors. Also, find out if prior similar events have happened in the patient or family members. If no factors can be identified, then HAE/AAE should be considered. Distinguishing AAE from HAE can be challenging. However, there are characteristics in the patient’s history that can help distinguish HAE from AAE. Unlike HAE, AAE can be late onset (older than 40 years old). There will also be no family history of HAE, and there may be signs and symptoms that suggest an underlying malignancy[6]. Determination of C1 esterase and C4 levels allow differentiation of HAE and AAE from other causes of angioedema.

On physical exam, the hallmark of angioedema is localized, well-demarcated, non-pitting edema that most commonly involves the lips, tongue, face, and eyelids. It may also involve the larynx, genitals, and distal extremities. Urticaria may also be present. Angioedema can also cause recurrent, severe abdominal pains mimicking a surgical abdomen, which can lead to partial bowel resection[7].

It is always important to consider other possible diagnoses, like infection, a local reaction to insect bites, congestive heart failure, and renal or liver disease. Characteristics that suggest angioedema include rapid onset, an asymmetric distribution of edema, and absence of symptoms that point to other possible diagnoses.

Evaluation

Rapid assessment of the airway is critical. In one study, patient age as well as edema involving the oral cavity and/or the oropharynx, were predictive of the need for airway intervention while involvement of other sites, etiology and sex were not[8]. In another study, voice change, hoarseness, stridor, or dyspnea were highly predictive of impending airway compromise, and fiber-optic nasopharyngoscopy was shown to identify laryngeal involvement[9].

If definitive airway management is needed, direct laryngoscopy may be difficult or even impossible due to the inevitable distorted airway anatomy, making awake fiberoptic intubation an attractive alternative. Providers may consider preserving the patient’s respiratory effect during intubation with only mild sedation and no paralysis since the intubation has a high probability of being difficult. Because of this, advance preparation for cricothyrotomy is key in case airway securement becomes impossible.

Treatment / Management

Because initially, the cause of angioedema is likely to be unknown, the mainstays of initial medical management include supplemental oxygen, a parenteral H-blocker, a parenteral steroid, and intramuscular epinephrine. Unfortunately, in AAE standard regimens of epinephrine, corticosteroids and antihistamines do not have much effect and are not recommended for AAE. Administration of plasma-derived or recombinant C1-INH can resolve acute attacks, but some patients will become non-responsive[5].

Icatibant, a bradykinin B2 receptor antagonist, has been shown to provide symptoms relief in AAE and was well tolerated[10]. Ecallantide, a potent bradykinin pathway inhibitor, has also shown promise in the treatment of AAE, providing another alternative in the treatment of patients with resistance to C1-INH replacement[11]. If neither treatment is available, fresh frozen plasma (FFP) may be used. Although effective (at least in HAE), it at times will lack efficacy or even cause a sudden worsening of the patient’s symptoms. There is also the risk of viral transmission to consider[12]. Rituximab efficacy has been shown to be inconstant in AAE[13]. It is also important to consider that treatment of an underlying causative condition can result in improvement of AAE[4].

The emergency department course is varied and clinical evolution may reflect the natural course of the illness rather than an actual response to medical management. Therefore, frequent re-evaluation is essential to monitor for any sudden deterioration in clinical status. If a patient has persistent involvement of the tongue, intraoral cavity, or throat, if they have persistent or recurring airway edema, or if they have persistent signs and symptoms of anaphylaxis (e.g., hypotension, cardiovascular compromise, altered mental status) then they require admission to the hospital in an intensive care setting. However, if the angioedema is limited to the face and lips or there is localized tongue involvement with a fully visible soft palate, patients may be observed in the emergency department for four to six hours before discharge home if they are reliable with a good support system at home.

Pearls and Other Issues

Symptoms of angioedema include angioedema of the face, laryngeal edema leading to difficulty with breathing, edema of the extremities and genitalia. Abdominal pain and bloating may occur together with hypotension.

Angioedema in the absence of urticaria indicates a bradykinin-mediated mechanism, most commonly C1-INH deficiency and may be hereditary or acquired.

Acquired angioedema may have underlying autoimmune connective tissue disease or a lymphoproliferative disorder.

 

Enhancing Healthcare Team Outcomes

The diagnosis and management of angioedema is best done with a multidisciplinary team that includes the emergency department physician, nurse practitioner, anesthesiologist, allergist, pharmacist and an intensivist. Time is of essence as the condition can rapidly lead to respirtaory distress.

Because initially, the cause of angioedema is likely to be unknown, the mainstays of initial medical management include supplemental oxygen, a parenteral H-blocker, a parenteral steroid, and intramuscular epinephrine. Unfortunately, in AAE standard regimens of epinephrine, corticosteroids and antihistamines do not have much effect and are not recommended for AAE. Administration of plasma-derived or recombinant C1-INH can resolve acute attacks, but some patients will become non-responsive[5]. Once the patient is stabilized, the cause of angioedema should be determined. The outcomes depend on the cause.


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Acquired Angioedema - Questions

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A patient is given intravenous iodinated contrast for a CT scan. Thirty minutes later the patient presents with diffuse swelling of his face and arms. Contrast-related angioedema is suspected. Which of the following symptoms is of greatest concern?



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Complement levels are abnormal in which one of these four types of angioedema?



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Which of these is untrue of the manifestations of hereditary angioedema?



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A 54-year-old male who does not take any medications and has no family history of angioedema presents with significant tongue and lip swelling as well as a scratchy throat. He has not eaten any new foods nor has he taken any new medications, over the counter, or otherwise. What are some characteristics of acquired angioedema (AAE) that differentiate it from hereditary angioedema (HAE)?



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A 33-year-old female with no past medical history and no known drug or food allergies presents to the emergency department with swelling of her lips associate with severe diffuse abdominal pain. You suspect angioedema of unknown etiology. Which of the following is the pathophysiology for the abdominal pain associated with angioedema?



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Acquired Angioedema - References

References

Angioedema of the tongue due to acquired C1 esterase inhibitor deficiency., Dobson G,Edgar D,Trinder J,, Anaesthesia and intensive care, 2003 Feb     [PubMed]
Angioedema: 5 years' experience, with a review of the disorder's presentation and treatment., Megerian CA,Arnold JE,Berger M,, The Laryngoscope, 1992 Mar     [PubMed]
Predictors of airway intervention in angioedema of the head and neck., Zirkle M,Bhattacharyya N,, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery, 2000 Sep     [PubMed]
The role of fiberoptic nasopharyngoscopy in the management of the acute airway in angioneurotic edema., Bentsianov BL,Parhiscar A,Azer M,Har-El G,, The Laryngoscope, 2000 Dec     [PubMed]
Acquired angioedema., Cicardi M,Zanichelli A,, Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology, 2010 Jul 28     [PubMed]
Chapter 22: Hereditary and acquired angioedema., Georgy MS,Pongracic JA,, Allergy and asthma proceedings, 2012 May-Jun     [PubMed]
Acquired deficiency of the inhibitor of the first complement component: presentation, diagnosis, course, and conventional management., Zingale LC,Castelli R,Zanichelli A,Cicardi M,, Immunology and allergy clinics of North America, 2006 Nov     [PubMed]
"Surgical" abdomen in a patient with chronic lymphocytic leukemia: a case of acquired angioedema., Jung M,Rice L,, Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 2011 Dec     [PubMed]
Icatibant treatment for acquired C1-inhibitor deficiency: a real-world observational study., Zanichelli A,Bova M,Coerezza A,Petraroli A,Triggiani M,Cicardi M,, Allergy, 2012 Aug     [PubMed]
Ecallantide for treatment of acute attacks of acquired C1 esterase inhibitor deficiency., Patel NS,Fung SM,Zanichelli A,Cicardi M,Cohn JR,, Allergy and asthma proceedings, 2013 Jan-Feb     [PubMed]
Fresh frozen plasma for the treatment of hereditary angioedema., Prematta M,Gibbs JG,Pratt EL,Stoughton TR,Craig TJ,, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 2007 Apr     [PubMed]
Acquired C1-inhibitor deficiency: 7 patients treated with rituximab., Branellec A,Bouillet L,Javaud N,Mekinian A,Boccon-Gibod I,Blanchard-Delaunay C,Oksenhendler E,Ollivier Y,Dunogué B,Amarger S,Ponard D,Drouet C,Mouthon L,Thomas M,Fain O,, Journal of clinical immunology, 2012 Oct     [PubMed]
Drug-induced, life-threatening angioedema revisited., Thompson T,Frable MA,, The Laryngoscope, 1993 Jan     [PubMed]

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