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Disease Summaries

Upper Airway Edema

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Updated: July 2015
Originally Posted: 2004

Updated by:


Professor Jonathan Bernstein, M.D. FAAAAI, FACAAI
Professor, Department of Internal Medicine, Division of Allergy/Immunology
University of Cincinnati College of Medicine
Cincinnati, Ohio

Original author:


Professor Connie Katelaris MB BS PhD FRACP (FAAAAI FACAAI)
Clinical Associate Professor, Dept of Clinical Immunology and Allergy
Westmead Medical Centre
Westmead, Australia

 

Introduction

Angioedema (AE) was first described by Quincke in 1882 related to an infectious cause.[1]  In the present day AE is classified as histaminerigic or non-histaminergic.[2]  The former term implies a similar pathophysiology as urticaria, which affects the epidermis whereas AE extends to the deeper dermis and subcutaneous tissues.[3] The later form, non-histaminergic AE, implies that histamine and other mast cell mediators are not involved and in fact many forms of non-histaminergic AE may be bradykinin mediated.[2, 4]  Angioedema is a condition that is usually well-demarcated and non-pitting.[5]  When associated with urticaria which is evident in 40% of cases, the edema may be associated with pruritus but isolated AE is seldom associated with pruritus.[5]  Histaminergic angioedema most commonly involves the face, tongue, lips and eyelids but for non-histaminergic bradykinin mediated AE the extremities, abdomen, genitalia, larynx and other parts of the body can be involved. Angioedema can be life-threatening when it extend to the posterior pharynx and larynx.[5]

Classification and Causes of Angioedema

Within the spectrum of chronic idiopathic urticaria (CIU) and angioedema, approximately 40% of patients experience both urticaria and angioedema while 40% have urticarial lesions alone, and up to 20% will have angioedema without urticaria.[5] The most common cause of isolated angioedema is typically “idiopathic”, but this is a diagnosis by exclusion. Precipitating factors such as underlying diseases, medications, foods and physical factors can usually be excluded by a careful, thorough history and limited history directed laboratory testing.[3]  Examples of IgE-mediated hypersensitivity reactions that can be associated with AE with or without urticaria include foods (but in reality a rare cause in adults which is frequently implicated and not easily confirmed), drugs, insect stings and inhalants.[3] Non-IgE-mediated sensitivity to drugs, particularly aspirin and other non-steroidal anti-inflammatory drugs and ACE inhibitors also occur but are not histaminergic.[3, 5]  For ASA and NSAIDs the likely cause is over production of leukotrienes due to the irreversible and reversible inhibition of cyclooxygenase, respectively.[3, 5]  For ACE induced angioedema, inhibition of C1 esterase inhibitor (C1-INH) leads to over production of bradykinin.[6-9]  Hereditary AE which is autosomal dominant and associated with a family history approximately 75% of the time, and acquired angioedema (AAE) typically associated with an underlying lymphoproliferative disorder and/or an autoantibody against C1-INH are non-histaminergic bradykinin mediated forms of AE.[2, 5, 10-12] Figure 1 classifies the different types of AE and Table 1 summarizes the different types of AE.

 

Figure 1: Classification of Angioedema (from Cicardi M, et.al. Allergy 2014;69(5):602-16)[2]

 

Table 1: Classification of Angioedema [2]

Hereditary Type 1- C1 esterase inhibitor deficiency; Type 2 – Functional abnormality of C1-INH; Type 3 – a.k.a. HAE with normal complement with or without a genetic mutations
Acquired Angioedema Secondary to underlying lymphoproliferative disorder;Secondary to autoantibody to C1-INH; Overlap of both
Idiopathic  
IgE-mediated (often associated with urticaria) Foods, Drugs, Insect stings; infections
Non-IgE mediated NSAIDs, ASA, Systemic diseases (Thyroid, autoimmune, malignancies)
Physical Vibratory, delayed pressure, cold

 

Hereditary Angioedema (HAE)

 

William Osler first described a patient with five family generations of swelling with what today is referred to as Hereditary Angioedema (HAE).[1] It was not until 1963 that Donaldson and Evans described the biochemical defect which was due to the absence of C1-INH.[13]  Studies in mice by Davis et.al. demonstrated that bradykinin was the putative mediator involved in HAE.[14]

Classification of Hereditary Angioedema

HAE exists as two subtypes, type 1, which accounts for 85% of cases and type 2, which accounts for 15% of cases.[2] The former is an autosomal dominant quantitative disorder with a mutant gene leading to markedly suppressed C1-INH protein levels as a result of abnormal secretion or intracellular degradation. The type 2 form is also autosomal dominant but is typically due to a point mutation leading to synthesis of a dysfunctional C1-INH protein.[2] For both type 1 and 2, the C1-INH functional level is markedly low.[2]  For type 1 the C1-INH quantitative protein is also low whereas for type 2 the C1-INH level may be normal or even increased.[2]  Therefore, a reliable functional assay to measure C1-INH activity is required for definitive diagnosis.[15] A third type of HAE with normal complement and C1-INH function has also been described with or without a factor XII mutation occurring more commonly but not exclusively in women.[16]

Epidemiology of HAE

Reliable data on the epidemiology for HAE are lacking. However, it is believed the worldwide population prevalence ranges from 1:10,000 to 1:50,000. Data on the incidence of HAE are lacking.  There is no racial or gender predilection.[17]

Clinical manifestations of HAE

Symptoms of HAE can present as early as 6 months but onset typically manifests for the first time between 6-11 years of age.[18, 19]  Swelling may be preceded by a prodrome which may be a wide variety of sensations including a sense of uneasiness, nausea, tingling or by the classic serpiginous rash, Erythema Marginatum.[2, 20] Swelling can develop peripherally, in the abdomen, genitalia, neck, face, lips, tongue and in the most severe cases throat.  It may start in one part of the body and spread to another part and more than one organ system can be involved at a time.  However, the most common attacks locations are peripheral extremities and abdomen.  Once swelling begins, without treatment, it can take several days to resolve.  For example, typical abdominal attacks may last for 2-5 days but in some patients complete resolution can take over a week.  Clinical symptoms depend entirely on the location of the swelling.  Often patients can tell what triggered an attack such as stress, trauma (physical or medical procedure), in women menses but many patients do not know what triggers an attack.[2, 20]

The most ominous presentation of HAE is submucosal edema of the larynx or pharynx which if not managed properly can cause death by asphyxiation. Fifty percent of HAE patients will have a throat swelling episode at some point in their life.[21] Therefore, the possibility of airway obstruction and asphyxiation should be discussed with patients and their families and an action plan including availability of on-demand therapy and going to the nearest emergency department should be emphasized.[22] Edema of the abdomen can mimic the manifestations of an acute abdomen resulting in unnecessary surgical procedures by physicians not knowledgeable about HAE.  Fortunately these situations are becoming less common.[2, 5, 20]  In contrast, HAE patients can still have acute abdominal emergencies that may or may not be related to their HAE such as cholecystitis, appendicitis or ischemic bowel which need to be ruled out especially in situations when the pain is not relieved with on-demand therapy.

Patients with HAE have an increased incidence of autoimmune diseases. Approximately 12% of HAE patients were reported to have an associated autoimmune disorder in one study.[23]

Laryngeal oedema in HAE

Asphyxiation is the commonest cause of mortality in HAE. A retrospective survey 58 HAE patients from 46 families revealed that 23 died from asphyxiation between ages 20-50 due to laryngeal edema over a 10 year period.[24]  They also reported 6 additional cases of asphyxiation due to laryngeal edema where the swelling progressed over 1-14 hours with an average time of 7 hours.  One of these cases was a 9 year old male child who experienced an atypical rapid progression of swelling over 20 minutes. Early symptoms reported by these individuals included a tight sensation in the “throat”, feeling of a lump (globus) in the “throat”, hoarseness, dysphagia and progressive dyspnea.[24]  Of note, most cases of fatal laryngeal edema occur in patients without a prior history of throat swelling.  With the advent of prophylactic (pdC1-INH and androgens) on demand therapies (pdC1-INH, rC1-INH), Icatibant and Ecallantide, mortality from HAE has significantly decreased.[21, 25, 26]

Diagnosis of HAE

HAE patients have low C4 levels during and between attacks whereas C2 levels are typically low during an attack but can normalize between attacks.  For this reason, C4 is considered the best screening test for determining whether a patient presenting with angioedema de novo may have HAE or AAE.[4, 5, 10, 12]  Sometimes the C4 level can be slightly low due to poor laboratory processing or secondary to a heterozygous C4 deficiency.  If the C4 is normal and there is a high suspicion for HAE then it should be repeated during an attack along with C1-INH quantitative and functional levels.[4, 5, 10, 12]  C1Q has been used to differentiate HAE from AAE but only 70% of AAE have a low C1Q and some HAE patients may have a low C1Q as well.[27-29]  Complement 4 levels are low because complement is chronically consumed in the absence of C1-INH.  If there is a known family history of HAE then for undiagnosed family members a C4 along with a C1-INH quantitative level and functional assay should be obtained. All HAE patients should have a decreased functional C1-INH level, depending on the assay, below 40-50%.[4, 5]  Type 1 HAE, which is found in 85% of HAE patients, is characterized by low C4, decreased C1-INH, quantitative and functional levels, whereas Type 2 HAE is characterized by low C4, normal or high C1-INH quantitative levels and low functional C1-INH.[4, 5] In both types of HAE, C1Q will be typically normal.[4, 5]  Table 2 summarizes the complement profiles associated with different types of angioedema.[5] Figure 2 illustrates an algorithmic approach to diagnosis of HAE.[5]

 

Table 2. Complement profiles for different types of angioedema[5]

 

Figure 2.  Diagnostic Algorithm for Angioedema[5]

Pathophysiology of HAE

C1-INH, a member of the serine protease inhibitor family, is a single chain glycoprotein with a molecular weight of 104,000, which circulates in the plasma at a concentration of about 150mcg/ml.[30] It is an important regulatory protein of the complement cascade as it inactivates the C1 esterase complex.[30]  C1-INH regulates the activity of the coagulation, fibrinolytic, kinin and complement systems. The lack of C1-INH or its activity leads to abnormal activation of the classical complement pathway which results in the low C4 and C2 levels.[30]  However, more importantly pathologically, C1-INH regulates the ability of kallikrein to activate high molecular weight kininogen which is cleaved to form bradykinin, the sentinel mediator leading to vasodilation and extravasation of fluid from the blood vasculature. In addition, C1-INH regulates the ability of kalikrein to activate Factor XII which, after converting to Factor XIIa, also regulates the conversion to Factor XI and the ability of Factor XIIa to activate plasma prekallikrein.[30]

Genetics of HAE

HAE has an autosomal dominant pattern of inheritance although in some families this does not always hold true as some families may have 50% affected offspring whereas others may have 25% or 75% affected offspring.[31]  Most HAE patients have mutations in the gene SERPING1 which codes for C1-INH, located in the q12–q13.1 region of chromosome 11, resulting in diminished or non-functional plasma C1-INH activity. All HAE patients inherit one normal and one abnormal SERPING1 gene that is either non-functional and not transcribed (type 1) or codes for the synthesis of normal quantities of an abnormal protein (type 2).[31] It is important to note that greater than 250 different mutations in SERPING1 have been described, ranging from nucleotide substitutions and small insertion deletions to large deletions and duplications, resulting in low functional activity and deficient levels of C1-INH or  normal/high levels of C1-INH protein with low functional activity[32]. Since the SERPING gene is so polymorphic and prone to mutations, approximately 25% of affected patients have de novo mutations and therefore can present clinically without a family history of the disease.[31]

Management of HAE

Management of HAE includes an action plan for acute swelling episodes and a strategy for long-term prophylaxis which will differ in children versus adults.[22] Short term prophylaxis (see below) is very effective in preventing the occurrence of swelling attacks in patients undergoing traumatic head and neck surgery, dental procedures or other invasive medical procedures.[33] HAE patients should be closely monitored over time to determine the frequency, severity and location of attacks and to whether the prescribed therapy(ies) are reducing the frequency and severity of attacks as well as improving quality of life.[34]

Acute HAE Attacks

Since the emergence of a number of on-demand therapies such as plasma derived (Berinert) and recombinant (Ruconest) C1-INH replacement therapies, a bradykinin receptor 2 antagonist (Icatibant) and a kalikrein inhibitor (Ecallantide) the approach to treating acute HAE attacks has dramatically changed.  Each of these therapies have been found in Phase 3 clinical trials to significantly shorten the duration of an attack, especially when administered in the first four hours after the start of an attack.  Table 3 lists the different on demand therapies, how they work, dosing, mechanisms and their advantages and disadvantages.[2, 10]  All patients with HAE should have at least one on-demand therapy available at all times for the treatment of an acute attack.  All attacks are eligible for treatment but whether or not it is treated is often left to the discretion of the patient.[2, 5, 10, 12, 22]

 

Table 3. HAE Specific Treatments[5]

Recently guidelines for the management of acute angioedema attacks involving the airways including HAE attacks have been published.[35]  For any swelling episode above the neck, HAE patients should be advised to self-treat and go to the Emergency Department immediately where they can be monitored for progression of the attack, receive further treatment and if needed be intubated to prevent airway compromise.[35]

Fresh frozen plasma (FFP), which contains C1 esterase inhibitor, has previously been used to treat acute attacks in the past, but paradoxical exacerbation can occur because of the added substrate and there is also an increased risk of viral transmission.[5, 36]

Long-term management of HAE: Attenuated androgens

The 17 α-alkylated androgens (danazol and stanozolol) have been the long standing prophylactic treatment of HAE. Androgens have been demonstrated to increase C1-INH levels as well as C4 and C2 levels.  However, they are associated with a number of side effects including weight gain, cholestasis, liver toxicity, fatty liver or hepatic neoplasms, hypertension and hyperlipidemia which can lead to atherosclerosis.[4, 5, 22]  Increased hair growth, weight gain, deepening of the voice, menstrual irregularities, decreased breast size and changes in libido are all potential side effects in females. It is recommended to see HAE patients who are taking androgens at least every 6 months to monitor liver function tests, lipid profiles, CPK levels and urinalysis.[37]  An ultrasound of the liver should be obtained once a year to assess for hepatic structural abnormalities. Patient’s taking doses greater than 200mg a day are at greater risk for these side effects.[4, 5, 22]

The availability of plasma derived C1-INH replacement therapy (Cinryze) for prophylactic treatment of HAE patients has provided additional options for the clinician and patient.  This treatment has been shown in clinical studies to reduce the attack frequency by at least 50% and has an excellent safety profile (Table 3).[38]

The decision to treat with prophylactic therapy depends on several factors including the frequency of attacks (i.e., > 1 attack per month), severity of attacks (i.e., recurrent abdominal attacks) and the location (i.e., throat swelling) but should also take into consideration patient preferences and safety of the treatment.[4, 5, 22]

Antifibrinolytic agents, tranexamic acid and ε-aminocaproic acid, have been used as prophylactic therapy for adults and children but are not as effective as androgens and C1-INH therapy.  As no approved prophylactic therapies have been approved for children as of yet, tranexamic acid has been found to be well tolerated and fairly effective with low toxicity in children with HAE.[39] Side effects such as muscle weakness, myalgias, myonecrosis, elevation of CPK levels, vascular thrombosis, hypotension and fatigue should be monitored in patients taking these medications especially when they are being used at higher doses.[5, 20, 22]

Short-term Prophylaxis of HAE

Prophylactic therapy is usually necessary before any high risk invasive surgical or dental procedures. C1-INH administered as 1000-2,000 units one to two hours before the procedure has been found to be very effective in preventing a swelling episode.[26, 33]  Less information about the effectiveness of Icatibant (Firazyr) or Ecallantide (Kalbitor) or Ruconest as short-term prophylaxis is available.[26, 33]  Patients on oral attenuated androgens have had their dose increased several days before the procedure and this has also been found to be effective if C1-INH is not available.[5, 12]

Other precautions in HAE

ACE inhibitors and estrogen based oral contraceptives should be avoided with HAE since both may precipitate attacks. Prophylactic therapy is indicated before using intravenous radiocontrast media, streptokinase or plasminogen activator because they may decrease levels of C1-INH which can result in angioedema.[5, 20, 22]

When attacks remain unresponsive to treatment, investigation of other underlying disorders or contributing factors should be investigated. For example, a chronic underlying infection or ongoing emotional stress may increase the frequency and severity of attacks significantly.[5, 20, 22]

Genetic counselling for HAE

Genetic counselling for HAE patients thinking about conceiving is recommended.[40]

Acquired Angioedema (AAE)

The terminology of AAE is in a state of flux.  Previously, Type 1 AAE referred to patients with rheumatologic or an underlying B cell lymphoproliferative disorder resulting in increased complement consumption and ensuing C1-INH deficiency whereas Type II AAE referred to those patients with an antibody directed against C1-INH which renders it ineffective at regulating the complement, contact, plasmin and fibrinolytic pathways. However, it has been found that many AAE patients have an underlying lymphoproliferative disorder and an autoantibody against C1-INH making the old terminology outdated.[27, 41]  As mentioned, a decreased C1Q level is used to differentiate AAE from HAE (Table 2).[5]

Treatment of AAE

Treatment of the underlying disease can potentially cure Type I AAE.  For Type 2 AAE, treatment to eliminate the blocking antibody with plasmapheresis, cyclophosphamide and rituximab have been reported to be successful.[42-44]  For long term treatment tranexamic acid 2-3 grams a day has been found to be very effective for the treatment of AAE regardless of whether they have an underlying disease or autoantibody.[27]  C1-INH replacement therapy has not been reported to be as effective a treatment for AAE and, for the Type 2 form, could theoretically act as a substrate for producing more autoantibody.  On demand therapy with Icatibant and Ecallantide, although not approved for AAE, has been reported to be effective at stopping attacks.[45, 46]

Angiotensin Converting-Enzyme (ACE) Inhibitors and AAE

ACE-inhibitor-induced AE occurs in up to 2% of the population taking these agents but the incidence varies depending on the population studied.[5, 9] There is a much greater risk for ACE induced AE among blacks vs. Caucasians but there is no gender difference.[5, 9]  Most attacks involve the lips, tongue and pharynx but rarely can involve the abdomen.  ACE induced AE can occur at any time after the onset of taking the medication.  After discontinuation of the medication, recurrent attacks have been reported to persist for several weeks or months.

AE symptoms resolve within 24-48 hours after discontinuing the drug and will reoccur if a different ACE inhibitor is initiated.  AE to ARBs can occur but due to a different mechanism as there is no cross reactivity with ACE inhibitors.[47]  Risk factors which have been reported for ACE induced AE include marked obesity, prior face or neck surgery and prior endotracheal intubation. Although it is not entirely clear as to why only a few patients taking ACE inhibitors develop AE, investigators have demonstrated that those patients with impairment in kininase 1, an enzyme important for bradykinin degradation, are more susceptible to bradykinin accumulation once ACE activity is inhibited.[7, 8] As patients with HAE are at increased risk of having their underlying disease worsen when taking an ACE inhibitor, this class of anti-hypertensive medications is contraindicated.[5]

Pathophysiology of ACE induced angioedema

Angiotensin-converting enzyme acts to cleave angiotensin1 and bradykinin, rendering them inactive. Therefore ACE inhibitors which inhibit ACE can lead to bradykinin accumulation resulting in AE secondary to vasodilatation and fluid extravasation.[48]

Management of ACE induced angioedema

A patient on an ACE inhibitor presenting with AE should have this medication immediately stopped and an alternative drug from a different group of anti-hypertensive drugs should be started.[5, 35] Conventional therapies with H1/H2 antagonists, oral corticosteroids and epinephrine are generally not effective.  Although there are no approved therapies for ACE induced AE, Icatibant has been found to be effective in preventing the progression of an attack and Phase 3 trials are ongoing.[49, 50]  Ecallantide also appears promising for this indication.[51]  Use of Fresh frozen plasma has been previously reported to successfully arrest the attack if no other therapies are available.[52, 53]  Regardless, these patients need close monitored to make sure the swelling does not progress to the extent where the airway is compromised.  Patients can be monitored in the ED and either intubated, admitted to an ICU or monitoring floor or discharged home based on the progression of disease using an AE scoring system.[35]  As mentioned even after treatment and resolution of the initial AE episode, patients should be carefully observed over several weeks or months as rebound swelling can occur.[54]

References

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2.   Cicardi, M., et al., Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy, 2014. 69(5): p. 602-16.

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6.   Boxer, M., Accupril- and Cozaar-induced angioedema in the same patient. J Allergy Clin Immunol, 1996. 98(2): p. 471.

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40. Caballero, T., et al., International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol, 2012. 129(2): p. 308-20.

41. Zingale, L.C., et al., Acquired deficiency of the inhibitor of the first complement component: presentation, diagnosis, course, and conventional management. Immunol Allergy Clin North Am, 2006. 26(4): p. 669-90.

42. Dreyfus, D.H., et al., Successful rituximab B lymphocyte depletion therapy for angioedema due to acquired C1 inhibitor protein deficiency: association with reduced C1 inhibitor protein autoantibody titers. Isr Med Assoc J, 2014. 16(5): p. 315-6.

43. Kaur, R., et al., Rituximab therapy in a patient with low grade B-cell lymphoproliferative disease and concomitant acquired angioedema. J Asthma Allergy, 2014. 7: p. 165-7.

44. Donaldson, V.H., et al., Angioneurotic edema with acquired C1- inhibitor deficiency and autoantibody to C1- inhibitor: response to plasmapheresis and cytotoxic therapy. J Lab Clin Med, 1992. 119(4): p. 397-406.

45. Zanichelli, A., et al., Treatment of acquired angioedema with icatibant: a case report. Intern Emerg Med, 2011. 6(3): p. 279-80.

46. Patel, N.S., et al., Ecallantide for treatment of acute attacks of acquired C1 esterase inhibitor deficiency. Allergy Asthma Proc, 2013. 34(1): p. 72-7.

47. Haymore, B.R., et al., Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol, 2008. 101(5): p. 495-9.

48. Hoover, T., et al., Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors. Clin Exp Allergy, 2010. 40(1): p. 50-61.

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