Angioedema: differential diagnosis and acute management

ABSTRACT

A clinical vignette illustrates a typical presentation of a patient seeking help for acute angioedema. Despite the risks of SARS-CoV-2 (COVID-19) exposure, it is critical to evaluate patients with acute angioedema in person, because there is always the potential for angioedema to progress to the head, neck, or lungs, which can rapidly compromise the airways and require immediate intervention to avoid potential asphyxiation. There are three mediators of angioedema, histamine, leukotriene, or bradykinin, each requiring different management. This article provides clinicians essential information for differentiating between these types of angioedema, including an overview of the underlying pathogenies of angioedema, and the subjective and objective findings that are useful in differentiating between angioedema types. The article ends with the appropriate management for each type of acute angioedema, including the medications approved by the FDA for on-demand treatment of an HAE attack.

KEYWORDS:

• Angioedema
• asphyxiation; bradykinin
• hereditary angioedema
• swelling

1.0 Introduction

1.1 Clinical vignette

An adolescent girl presented in her pediatrician’s office with an extremely swollen upper lip and adjacent facial area, which she noticed upon awakening that morning, along with a lacy, erythematous nonpruritic rash and a lump in her throat that worsened over the past several hours. She was not having breathing difficulties. Epinephrine was administered without effect, and the patient was referred to the local emergency department (ED). She was monitored in the hospital and the swelling resolved over 3 days without intervention or need for intubation. Lab studies revealed low levels of C4, C1 inhibitor (C1INH), and C1INH function, supporting a diagnosis of type I hereditary angioedema.

2.0 Body

2.1 Brief overview of angioedema

Angioedema, self-limited subcutaneous or submucosal swelling caused by a localized increase in microvascular permeability, is not rare; the US lifetime prevalence is about 25% [1,2]. Of the three main categories of angioedema (histamine-, leukotriene-, and bradykinin-mediated), bradykinin-mediated angioedema is less common but highly clinically relevant given its potential to progress unpredictably to life-threatening laryngeal swelling and its general unresponsiveness to traditional therapies (antihistamines, corticosteroids, epinephrine) [1,3]. Without effective treatment, bradykinin-mediated angioedema has an estimated mortality rate of 30% [4–6].

It is important to recognize that during the SARS-CoV-2 (COVID-19) pandemic, angioedema patients may wait until swelling is severe before seeking emergency management. Data from the Centers for Control and Prevention of Disease noted a decrease in monthly ED visits for conditions such as nonspecific chest pain and acute myocardial infarction during 2020 relative to 2019 (month-on-month), suggesting that some patients could be delaying care for conditions that might result in additional mortality if left untreated [7]. Given the risk for rapid progression to fatal asphyxia, it is recommended that head/neck angioedema episodes undergo immediate treatment and should not be addressed by telemedicine. To minimize the need for a risky ED visit during this COVID-19 pandemic, every effort must be made to encourage medication compliance while anticipating the need for both long-term prophylaxis (LTP) and rescue medication prescription renewals before a dangerous gap in therapy occurs. During every encounter, clinicians should ask patients about the medications they have on-hand, when they are scheduled to expire, and encourage compliance.

2.2 Underlying pathophysiology of angioedema

The underlying pathophysiology of angioedema differs for each mediator of vascular permeability. Histamine-mediated angioedema is triggered by mast cell degranulation and histamine release, either by an allergic reaction that increases immunoglobulin E (IgE) production, or mast cell degranulation independent of IgE [8,9].

Leukotriene-mediated angioedema is triggered by hypersensitivity to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). This NSAID-induced urticaria/angioedema drug reaction is mediated by inhibition of cyclooxygenase-1 that shifts metabolism of arachidonic acid, generating proinflammatory cysteinyl leukotrienes [8,10,11].

Bradykinin-mediated angioedema is caused by localized excess bradykinin, due to either activation of the plasma kallikrein-kinin system, or decreased bradykinin degradation [3,8,9,12]. There are three main forms of bradykinin-mediated angioedema: HAE, angiotensin-converting enzyme inhibitor (ACE-I)-induced, and acquired angioedema (AAE).

HAE is a rare genetic condition affecting approximately 1:50,000 people in the US. It occurs as one of three main types: HAE-C1INH-I, caused by low levels of C1INH; HAE-C1INH-II, caused by dysfunctional C1INH; and HAE with normal levels of C1INH (HAE-nl-C1INH). HAE-C1INH-I and HAE-C1INH-II are caused by autosomal dominant mutations of the SERPING1 gene that codes for the C1INH protein. The cause of HAE-nl-C1INH is not fully understood [2,3,13], although several different genetic variants have been discovered, suggesting this very rare HAE type is due to a variety of defects in the contact-kallikrein system.

Pathophysiology of HAE-C1INH-I and HAE-C1INH-II begins with decreased activity of the serine protease inhibitor C1INH, leading to excess bradykinin activity. C1INH regulates bradykinin production by inhibiting the activity of both FXII and plasma kallikrein [3,8].

Angiotensin-converting enzyme plays two major roles, conversion of angiotensin I to angiotensin II and bradykinin degradation. When activity of ACE is inhibited by ACE-I, the enzyme aminopeptidase P (APP) metabolizes bradykinin. In individuals who have subnormal APP activity due to genetic variant, bradykinin is not degraded and accumulates. This can develop in individuals regardless of the length of exposure to ACE-Is [8].

The pathogenesis of HAE is especially relevant today with the pandemic circulation of COVID-19, which has a pathogeny shown to include an imbalance in the renin-angiotensin system, with reduced expression of the angiotensin-converting enzyme as well as increased expression of angiotensin-converting enzyme 2, renin, renin-angiotensin system receptors, kininogen, and kallikrein [14].

In AAE, a non-genetic deficiency in C1INH activity, the underlying pathophysiology is often due to a lymphoproliferative process or autoimmunity. Some patients have lymphoproliferative disease associated with an expansion of B-cell clones producing C1INH autoantibodies [8,15]. Some cases of bradykinin-mediated (non-histaminergic) AAE are idiopathic with normal levels of C1INH [16].

2.3 Differential diagnosis of angioedema

Differentiating angioedema types relies on clinical, laboratory, and medical history distinctions (Table 1). A major distinguishing hallmark of histamine-mediated angioedema is urticaria/wheals. A thorough medical history is needed to reveal potential allergen exposure, to determine if angioedema is IgE-mediated. While examination for urticaria/wheals is helpful, their presence or absence is not a conclusive differentiator between the three mediators of angioedema. The face and neck are the most common sites of histamine-mediated angioedema. Histamine-mediated angioedema may be idiopathic, requiring determination by a response to high-dose antihistamine treatment (up to 4x recommended dosage) [1,3,8,14].

Table 1. Differential Diagnosis of Angioedema [1,2,8–10,15,16,18]

Clinical Features
Sign/Symptom	Histamine-Mediated		Leukotriene-Mediated		Bradykinin-Mediated
					HAE		ACE-I		Acquired
Timing of symptom onset	Minutes		Hours		Hours		Hours		Hours
Time to symptom resolution	Minutes-hours		Variable		Days		Days		Days
Age at onset (first onset or manifestation)	Any		Any		Often 1^st, 2^nd decade (40% by age 5)		Adults, elderly		≥40 years
Predominant location of angioedema	Face (eyelids, lips), neck		Periorbital, airways		Face, extremities, upper airways, GItract		Face, neck, lips, tongue, upper airways		Face, tongue, upper airways most common
Family history	No		Unknown		Yes^a		No		No
Common triggers	Allergens (IgE); opioids (non-IgE); can be idiopathic/ spontaneous		Aspirin, NSAIDs (COX-1 inhibitors)		Physical exertion or trauma, emotional stress; infection; estrogen^b		ACE-I therapy in susceptible patients		Lympho-proliferative disease, anti-C1INH autoantibodies^c; drugs (ACE-I, ARB, gliptins, sacubitril); can be idiopathic^d
Laboratory Evaluations
Type of Angioedema		C1INH Level		C1INH Function		C4 Level		C1q		Tryptase Level^e
Histamine-mediated
Allergic		Normal		Normal		Normal		Normal		Normal/Elevated
Idiopathic		Normal		Normal		Normal		Normal		Normal
Leukotriene-mediated
NSAID-induced		Normal		Normal		Normal		Normal		Normal
Bradykinin-mediated
HAE-I		Low		Low		Low		Normal		Normal
HAE-II		Normal/High		Low		Low		Normal		Normal
HAE-nl-C1INH		Normal		Normal		Normal		Normal		Normal
ACE-I-induced		Normal		Normal		Normal		Normal		Normal
Acquired		Low or Normal^f		Low		Low		Low (majority of cases)		Normal

ACE-I=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; C1INH=C1 inhibitor; COX-1=cyclooxygenase-1; IgE=immunoglobulin E; GI=gastrointestinal; HAE=hereditary angioedema; HAE-nl-C1INH=HAE with normal C1INH; NSAID=nonsteroidal anti-inflammatory drug

^a25% of all HAE is attributed to de novo genetic mutations

^bEspecially in females with HAE-nl-C1INH caused by FXII genetic mutation

^cAutoantibodies likely due to underlying autoimmune disorder or lymphoproliferative malignancy

^dAlso known as nonhistaminergic idiopathic angioedema; role of bradykinin not confirmed with certainty

^eSerum specimen obtained within 4–6 hours of symptom onset

^fNormal in acquired idiopathic bradykinin-mediated (nonhistaminergic) angioedema

Recent use of an analgesic, such as an NSAID, raises the possibility of leukotriene-mediated angioedema. Up to 60% of patients with NSAID-induced urticaria/angioedema have a history of atopic disease (e.g., rhinitis, asthma) [10]. Among patients with chronic urticaria, approximately one-third may demonstrate NSAID hypersensitivity [17]. The typical cutaneous presentation includes urticarial wheals developing within 30–90 minutes of ingestion, ranging in severity from transient to severe anaphylaxis [10,17]. Leukotriene-mediated angioedema is usually periorbital, but can also affect the airways.

Some key hallmarks of bradykinin-mediated angioedema attacks that differentiate them clinically from histamine-mediated attacks include an absence of urticaria/wheals, a more gradual onset (days versus minutes/hours), longer duration of symptoms (days versus minutes/hours), greater severity of swelling, and typically unilateral distribution of angioedema.

Defining characteristics specific to HAE are initial episodes at an early age and a family history of angioedema, although up to 25% of patients have de novo SERPING1 mutations. A complete medical history may reveal recent activities that can trigger an HAE episode, perhaps heralded by a prodrome or aura, including physical trauma, emotional stress, or recent infection. Increased plasma estrogen can exacerbate HAE, especially in women with HAE-nl-C1NH [18]. Despite the possibility that contracting a COVID-19 infection could increase the risk of an attack, it has been noted that the incidence of a COVID-19 infection was low among HAE patients who had good disease control with LTP treatment [19]. Common HAE attack sites include the face (tongue, lips), larynx/upper airways, extremities, genitals, and abdomen. Relevant laboratory tests (C1INH level, C1INH function, C4, C1q, tryptase) are outlined in Table 1 [1,12].

A clinical history of angioedema without hives while on an ACE-I may suggest ACE-I-induced angioedema. There is a 4-to-5-fold greater prevalence of ACE-I-induced angioedema in Black patients. A patient with AAE may present with constitutional B symptoms indicative of a lymphoproliferative disease, or an autoimmune disorder like systemic lupus erythematosus or dermatomyositis [3,8,15,16]. Onset of angioedema after the age of 40 combined with a low C1q supports a diagnosis of AAE.

2.4 Management of angioedema

Histamine-mediated angioedema may be managed with a nonsedating antihistamine at standard or higher doses, alone or in combination with omalizumab. Presumptive treatment for histamine-mediated angioedema should be administered when the medical history is inconsistent with leukotriene- or bradykinin-mediated angioedema. Monitor for ≥4–6 h after angioedema symptoms begin to resolve. Hospital admission or 24-h observation is recommended for patients treated with epinephrine [1,3].

For leukotriene-mediated angioedema, NSAIDs and aspirin should be avoided, however the use of a selective cyclooxygenase-2 inhibitor may be appropriate. Alternative antihypertensive agents should be found when bradykinin-mediated angioedema is induced by an ACE-I. Diagnosis and treatment are recommended to manage the underlying cause of acquired HAE [10].

Management of HAE-C1INH-I or HAE-C1INH-II attacks requires acute (“on-demand“) treatment with HAE-specific medications to limit attack progression and potentially fatal laryngeal swelling [4,18]. Intubation is risky as the mechanics of intubation can trigger bradykinin-mediated swelling but should be considered early if there is evidence of airway obstruction. When required, nasopharyngeal or endotracheal procedures are recommended and should be performed by an experienced team [2]. Onset of effect following early treatment with the on-demand agents listed in Table 2 is usually within 30–120 minutes. Individual need for LTP should weigh multiple patient factors (medical/physical; quality of life; access to emergency treatment; severity of attacks). Short-term prophylaxis is recommended prior to events which might trigger an attack (e.g., medical/dental procedures; stressful events) [18]. Table 2 lists FDA-approved agents for prophylaxis; these should not be used to treat attacks. Continuity of care for patients diagnosed with HAE-I or HAE-II includes evaluation of their need for LTP and genetic counseling [1,18]. The reader is referred to recent guidelines for complete HAE management recommendations, including nuances of treating non-HAE-C1INH types [18].

Table 2. FDA-Approved Medications for On-Demand Treatment or Prophylaxis of Attacks in HAE-C1INH [18]

On-Demand Treatment of HAE Attacks
	BERINERT® (plasma-derived C1INH)	FIRAZYR® (icatibant)	KALBITOR® (ecallantide)	RUCONEST® (recombinant human C1INH)
US indication	Children, adults^a	≥18 years old	≥12 years old	Adolescents, adults
Self-administration	Yes	Yes	No^b	Yes
Dosing	20 IU/kg IV	30 mg SC	30 mg SC	50 U/kg IV up to 4200 U/kg IV
MOA	Replacement of missing C1INH functional activity	Bradykinin B2 receptor antagonist	Inhibits plasma kallikrein	Replacement of missing C1INH functional activity
Potential AEs	Anaphylaxis (rare); transmission of infectious agent (theoretical)	Injection site discomfort (common)	Anaphylaxis (2.7%) [20]	Anaphylaxis (uncommon)
Prophylaxis of HAE Attacks
	CINRYZE® (plasma-derived C1INH)	HAEGARDA® (plasma-derived C1INH)	TAKHZYRO^TM (lanadelumab-flyo)	ORLADEYO^TM (berotralstat)	DANOCRINE® (danazol)
US indication	≥6 years old	≥12 years old	Adolescents, adults	≥12 years old	Adults
Self-administration	Yes	Yes	Yes	Yes	Yes
Dosing	LTP, adults: 1000 U IV (up to 2500 U if necessary) every 3–4 days LTP, children 6–11): 500 U IV (up to 1000 U if necessary) every 3–4 days STP: single dose 20 IU/kg IV 1–12 hours before the stressor event	LTP: 60 IU/kg SC twice weekly	LTP: 300 mg SC every 2 weeks (every 4 weeks can be considered if well-controlled for >6 months)	LTP: 150 mg/day orally^c	LTP: Minimal effective dose (100 mg every other day to 200 mg TID orally) STP: 400–600 mg/day for 5–7 days prior to the stressor event and continued for 2–5 days afterward
MOA	Replacement of missing C1INH functional activity	Replacement of missing C1INH functional activity	Inhibits plasma kallikrein	Inhibits plasma kallikrein	Unknown
Potential AEs	Anaphylaxis (rare); transmission of infectious agent (theoretical)	Anaphylaxis (rare); transmission of infectious agent (theoretical)	Anaphylaxis (rare); injection site reactions (common)	Abdominal pain, vomiting, diarrhea, back pain, GERD (common)	Weight gain, virilization, acne, altered libido, muscle pains/cramps, headaches, depression, fatigue, nausea, constipation, menstrual abnormalities, increase in liver enzymes, hypertension, and alterations in lipid profile (common)

AE=adverse events; HAE-C1INH=hereditary angioedema due to C1INH deficiency; GERD=gastroesophageal reflux disease; IU=international units; IV=intravenous; LTP=long-term prophylaxis; MOA=mechanism of action; SC=subcutaneous; STP=short-term prophylaxis; TID=three times a day; U=units

^aDrug of choice for children, pregnant women [3]

^bKALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and HAE

^cDosage adjustments recommended in patients with moderate-severe hepatic impairment, patients with chronic administration of P-gp or BCRP inhibitors, and patients with persistent gastrointestinal reactions; refer to ORLADEYO prescribing information for full recommendations

Note: some information sourced from product labeling

Transparency

Declaration of funding

Funding for writing and editorial support was provided by CSL Behring; CSL had no role in the development of manuscript content.

Declaration of financial/other relationships

RT has served as a speaker and consultant for BioCryst Pharmaceuticals, CSL Behring, Pharming Group, Sanofi/Regeneron, and Shire/Takeda Pharmaceutical Company. He has served as a speaker for Grifols and GSK. DJ has served on a speakers’ bureau and as a consultant/advisor for Aimmune Therapeutics, CSL Behring, Pharming Group, and Shire/Takeda Pharmaceutical Company; he has served on a speakers' bureau for Pfizer and Nutricia North America; he has served as a consultant/advisor for Allakos, BioCryst Pharmaceuticals, REGENXBIO, and DBV Technologies. A reviewer on this manuscript has disclosed that they have received speaking fees from Takeda; another reviewer has disclosed that they have been involved with both research and teaching with both CSL Behring and Shire/Takeda; a third reviewer has declared no conflict of interest regarding this manuscript; however, they have been a speaker for Shire/Takeda and CSL Behring, they also participated in advisory boards for Takeda and CSL Behring and that they have received a grant of researcher initiative from Takeda.

Biographical Note

Raffi Tachdjian, MD, MPH, is Associate Clinical Professor of Medicine and Pediatrics at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). He is also the past president of the Los Angeles Society of Allergy, Asthma and Clinical Immunology. He received his medical degree from Morehouse School of Medicine in Atlanta, Georgia, followed by an internship and residency in Pediatrics at Harvard Medical School in Boston, Massachusetts, with a fellowship in adult and pediatric Allergy & Immunology at the David Geffen School of Medicine at UCLA.

Dr. Tachdjian’s research focuses on immune dysfunction, asthma, and allergic inflammation, and he has served as primary or co-investigator of over 25 NIH and other grant-funded research studies. He was voted one of the UCLA Health System’s Best Doctors and was selected to receive the Editors’ Choice Award by the Journal of Allergy and Clinical Immunology.

Dr. Tachdjian completed an internship at the Centers of Disease Control & Prevention, where he led the outbreak investigations and epidemiologic studies on Pertussis (whooping cough). He is credited with helping to understand the waning immunity of the pertussis vaccine, which led to current booster dosing in adolescents and adults.

Dr. Johnston is an allergist/immunologist at Carolina Asthma & Allergy Center in Charlotte, NC and assistant professor of medicine at Edward Via College of Osteopathic Medicine in Spartanburg, SC. He received his medical degree from New York College of Osteopathic Medicine in Old Westbury, New York, completed his residency in Internal Medicine at NYU/Winthrop University Hospital in Mineola, New York and received fellowship training in Allergy and Immunology at the University of Alabama at Birmingham.

Dr. Johnston has served as chair of the Allergic Skin Disease Committee of the AAAAI, Urticaria/Angioedema subcommittee, and has served as a principal investigator for many HAE therapeutics used today and has been published in the Journal of Allergy and Clinical Immunology, Allergy, Annals of Allergy Asthma, Clinical Immunology, JAMA, and the New England Journal of Medicine. He has been activity involved with the education of children with HAE in collaboration with the HAEA and continues to learn from his patients each day.

Acknowledgments

The authors acknowledge the writing assistance of Carol Gorman, MS (Churchill Communications; Maplewood, NJ), funded by CSL Behring.