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Disease Summaries

Upper Airway Edema

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Posted: 2004


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 (A/O) was first described by Quincke in 1882. It is caused by the same pathophysiological factors which produce urticaria, but the reaction occurs deeper in the dermis and subcutaneous tissues. Angioedema is a term used to describe well-demarcated, non-pitting oedema that occurs as large erythematous swollen areas in the subcutaneous tissues. The face, tongue, lips and eyelids are most commonly affected, but it may also involve the hands, feet, genitalia, mucous membranes and other parts of the body. A/O may cause life-threatening respiratory distress if the larynx is involved.

Classification and Causes of Angioedema

Within the spectrum of chronic idiopathic urticaria (CIU) and angioedema, 50% of patients experience both urticaria and angioedema while 40% have urticarial lesions alone, and 10% will have angioedema and no urticaria. Typically, sporadic A/O is idiopathic, however, precipitating factors include physical factors, such as temperature changes and trauma. Other causes include IgE-mediated hypersensitivity to foods, drugs, insect stings and inhalants. Non-IgE-mediated sensitivity to drugs, particularly aspirin and other non-steroidal anti-inflammatory drugs and ACE inhibitors also occur. Hereditary A/O is usually familial, however, acquired forms have also been associated with malignancy, in particular, lymphoproliferative disorders. Table 1 summarises different kinds of Angioedema.

Table 1: Classification of angioedema

Hereditary

Type 1: C1 esterase inhibitor deficiency
Type 2: functional abnormality of C1 esterase inhibitor

Acquired

Idiopathic (most common)
IgE-mediated (most commonly with urticaria)

Drugs
Foods
Stings
Infections (viral - Epstein Barr Virus, Hepatitis A, B, helminthic)

Non IgE mediated

Cyclooxygenase inhibition
ASA, NSAIDS
Angiotensin converting enzyme inhibition
Systemic diseases eg

Systemic Lupus Erythematosis
Hypereosinophilia
Lymphoma: Abnormal antibodies activate complement system

Physical causes

Cold
Cholinergic
Solar
Vibratory

Other

Some contact reactions
Autoantibodies to C1 esterase inhibitor (associated with malignancy, connective tissue diseases)
Unopposed complement activation

Hereditary Angioedema (HAE)

William Osler published a paper in 1888 describing an hereditary form of A/O when he reviewed the cases of individuals of five generations of one family with this disease. It was not until 1963 that Donaldson and Evans described the biochemical defect, an absence of C1 inhibitor.

Classification of Hereditary Angioedema

HAE exists as two subtypes, type 1, which accounts for 85% of HAE and type 2, for 15% of cases. The former is an autosomal dominant quantitative disorder with a mutant gene leading to markedly suppressed C1 esterase inhibitor (C1 inhibitor) protein levels as a result of abnormal secretion or intracellular degradation. Type 2 is also dominantly inherited, typically with a point mutation leading to synthesis of a dysfunctional C1 esterase protein. The C1 esterase level may be normal, therefore, a functional assay is required for diagnosis (2). A third type of HAE with normal biochemical C1-inhibitor function has been described occurring only in women (3).

Epidemiology of HAE

Reliable data on the epidemiology of this condition are lacking. The worldwide incidence ranges from 1:10,000 to 1:150,000. There appears to be no racial or gender predilection.

Clinical manifestations of HAE

Symptoms of HAE typically manifest for the first time during the second decade of life, although attacks may be seen in young children. Oedema may develop in one or several organs or areas of the body. Typical attacks last 2-5 days before spontaneous resolution occurs. Manifestations depend entirely on the site where the swelling occurs. A/O may develop in the subcutaneous tissues of the extremities, genitalia, face or trunk. It may involve the mucous membranes of the upper airway and gastrointestinal tracts.

Submucosal oedema of the larynx or pharynx can cause asphyxiation. Even the first episode of laryngeal oedema may be fatal (4). Therefore, the possibility of airway obstruction and asphyxiation should be discussed with patients and their families. A high degree of awareness is necessary and the need for early presentation to hospital should be stressed. Oedema of the wall of the intestine may mimic the manifestations of an acute abdominal crisis and has inappropriately led to emergency laparotomy (5).

Patients with HAE have an increased incidence of autoimmune diseases. Approximately 2% will also have systemic lupus erythematosis with a strong female preponderance (6). In another study quoted in the same paper, (6) 12% of those with HAE had associated autoimmune disorders.

Laryngeal oedema in HAE

Asphyxiation is the commonest cause of mortality in HAE. A German study (4) evaluated several patients who died from laryngeal oedema over the previous 10 years and reported retrospectively on 58 patients with HAE. Most who asphyxiated did so between the 20th and 50th years of life although asphyxiation was also reported in children. One male child died at 9 years of age. Time for onset of swelling to death was dramatically short for this boy (20 minutes) while the interval for others was between 1-14 hours (mean, 7 hours). Early symptoms reported by those affected include a tight sensation in the “throat”, feeling of a lump in the “throat”, hoarseness, dysphagia and progressive dyspnoea. In 5 of the 6 fatalities in a paper published in 2000, covering a ten year period, no episodes of airway obstruction had occurred before the fatal event. From this and other reported series (7, 8), there seems to be an increased risk of fatal complications within certain families, but the explanation for this remains unknown. Mortality from HAE has significantly decreased since the advent of long-term prophylactic treatment with attenuated androgens. In a report of 86 patients receiving such long term treatment, none died of asphyxiation (9).

Diagnosis of HAE

C4 and C2 levels are dramatically decreased and are useful confirmatory tests to obtain during an acute presentation of HAE. C4 levels are persistently low in most patients, while C2 levels are more variable because complement is chronically consumed, even between episodes. Quantitative and functional assays of C1 inhibitor can be obtained in those suspected of having HAE or for screening family members. Decreased levels of C1 inhibitor will be found in type 1 HAE while the level may be normal or supranormal in type 2 with an abnormal functional assay. Measurement of C1q will help distinguish HAE from the acquired form (see below). Those with acquired angioedema (AAE) versus those with HAE will not only have a marked decrease in C1 inhibitor levels but also will have decreased C1q levels (6).

Pathophysiology of HAE

C1 inhibitor, 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. It is an important regulatory protein of the complement cascade in that it inactivates the C1 esterase complex.

C1 inhibitor regulates the activity of four closely inter-related cascades, the coagulation, fibrinolytic, kinin and complement systems. The lack of C1 inhibitor or its activity leads to abnormal activation of the classical complement pathway, which in turn reduces C4 and C2 plasma levels. C2 fragments produced during complement activation generate vasoactive, kinin-like mediators. Also, following tissue damage, the Hageman factor induces the formation of kallekrein from prekallekrein and bradykinin is released from high-molecular weight kininogen. These mediators enhance capillary permeability and are presumed to be jointly responsible for precipitating attacks of oedema (2, 10).

Genetics of HAE

HAE is autosomally inherited although approximately 25% of affected patients have no prior family history of the disease. This probably results from spontaneous mutations.

All patients described are heterozygotes. Therefore, affected individuals inherit one normal and one abnormal 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). More than 100 different mutations have been reported. The variable effect of these on C1 inhibitor synthesis and function may explain the different clinical presentations.

The gene encoding C1 inhibitor is cloned, located on chromosome 11q11-q13.1, has 7 exons and approximately 7 introns, and contains multiple Alu repeat sequences (9,11-14).

Management of HAE

Management of HAE includes an action plan for acute episodes and a strategy for long-term prophylaxis and will differ in children versus adults. Short term prophylaxis (see below) may be prescribed for patients with HAE undergoing head and neck surgery or dental procedures. Close and regular follow up is essential to monitor efficacy of treatment and to screen for side effects from long term therapy.

Acute attacks of HAE

C1 esterase inhibitor concentrate, 500-1000U, infused intravenously, is the treatment of choice for acute attacks of HAE and AAE. The dose is the same for adults and children (6). Treatment results in a rapid increase of C1 inhibitor level, followed by a slower increase in C4 (2-24 hours later). Acute attacks responded within 30 minutes in 69% patients in one study (15) and almost all responded within 4 hours compared to 12% who responded to placebo. Eighteen patients in another study (16) received C1 inhibitor concentrate, (500-1000U) for each of 193 episodes. The concentrate was effective in all laryngeal oedema episodes. The time from injection to interruption in progress of symptoms ranged from 10 minutes to 4 hours, and the mean duration of laryngeal oedema was 15.3 versus 100.8 hours, respectively, for those treated versus those not treated. No long term side effects or autoantibodies were reported. C1 esterase inhibitor concentration is available in Europe and Australia but not in the USA.

Intubation and respiratory support may be necessary for episodes characterised by respiratory compromise because of laryngeal oedema, especially where C1 inhibitor concentrate treatment is not available. In mild cases of airway oedema, careful observation and oxygen therapy may suffice. When the oedema is progressive, intubation or tracheostomy may be necessary. If asphyxiation is imminent, an emergency cricothyrotomy should be performed without delay (16).

Fresh frozen plasma (FFP), which contains C1 esterase inhibitor, has been used to treat acute attacks in the past, but paradoxical exacerbation can occur because of the added substrate. 

Long-term management of HAE: Attenuated androgens

The 17 α-alkylated androgens (danazol and stanozolol) can prevent attacks of HAE. Androgens increase levels of C1 inhibitor, C4 and C2. All patients should be considered for long term prophylactic treatment since a previous history does not negate a subsequent serious attack. Once exacerbations are controlled, the dose of stanozolol or danazol should be gradually tapered to the lowest effective dose. Danazol can be effective used every 2nd or 3rd day at a dose of 200mg/day. Increased hair growth, weight gain, deepening of the voice, menstrual irregularities, decreased breast size and changes in libido may be problematic in females, but for the most part, few side side-effects occur. Microhaematuria, cholestasis, hepatic necrosis or neoplasms, hypertension and possibly increased atherogenesis are potential problems (6). Therefore, physician visits every six months are recommended by some physicians to monitor liver function tests, CK levels, urinalysis and periodic abdominal ultrasound to check for hepatic abnormalities (5).

Antifibrinolytic agents, tranexamic acid and ε-aminocaproic acid, are used in children as first line prophylaxis because of the concern associated with the use of attenuated androgens. Tranexamic acid is better tolerated than ε-aminocaproic acid which often causes abdominal discomfort. Muscle weakness, myalgias, myonecrosis, elevation of CK levels, vascular thrombosis, hypotension and fatigue may occur associated with the use of high doses.

Farkas et al (5) reviewed the clinical data of 26 pediatric patients with HAE ages 2.5 to 15 years. Not all required prophylactic therapy. Anti-fibrinolytic agents were given for long term prophylaxis in 11 patients. Complete remission was achieved in 3 females maintained on tranexamic acid, 1-2 grams/day, but was ineffective in the other 8 patients. These were treated with danazol, 100-200mg/day, with complete elimination of serious attacks of swelling. After six months without exacerbation, the dosage interval of danazol, 100mg, was increased to 2-3 day intervals. The intermittent regimen was successful in 4 of the 8 patients. When prodromal symptoms or mild episodes occurred, doubling the daily dose for several days aborted full blown attacks in all others. A similar protective effect occurred in patients exposed to an upper respiratory infection or mechanical trauma. These pediatric patients were followed for long term side-effects from attenuated androgens. Bone age, skeletal growth and weight development did not differ from age-specific averages. The time of appearance of secondary sexual characteristics and the onset of puberty were also similar in 7 children. Menarche was delayed and menstruation irregular in one female. Hirsuitism was not observed. There were no abnormal blood counts, CK levels, or liver function tests in the 11 children and abdominal ultrasound revealed no abnormalities. There were significant increases in C4 and C1inhibitor concentrations.

Short-term Prophylaxis of HAE

Prophylactic therapy is necessary before any high risk surgical or dental procedures. C1 esterase inhibitor concentrate, FFP, or oral attenuated androgens may be used prophylactically to prevent angioedema. For those maintained on danazol or stanozolol, increasing the dose daily for several days prior to the procedure is usually effective.

Other precautions in HAE

ACE inhibitors and 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 inhibitor.

When attacks remain unresponsive to treatment, investigation of other contributing factors may be helpful. Chronic infection and ongoing emotional stress are two instances where the condition may remain unstable.

Genetic counselling for HAE

Genetic counselling for affected individuals, their siblings and parents and screening of relatives is indicated remembering that up to 25% of cases of HAE occur because of spontaneous mutations.

Acquired Angioedema (AAE)

There are two types of AAE. Type 1 occurs in patients with rheumatologic and B cell lymphoproliferative disorders. It is hypothesized that immune complexes, continuously formed between anti-idiotypic antibodies and immunoglobulins on cell surfaces, activate C1. C1 inhibitor is consumed, activating these large quantities of C1, and ultimately, synthesis of C1 inhibitor cannot keep pace with consumption and levels decline.

The second form of AAE is caused by autoantibodies directed against C1 inhibitor. These autoantibodies bind at the active site on the molecule causing inactivation. Patients with AAE have significantly decreased serum levels of the classic components of complement, particularly C1q, C2 and C4. Decreased C1q levels distinguish AAE from HAE where C1q is usually normal (17, 18).

Treatment of AAE

Treatment of the underlying disease may result in resolution of the AAE. C1 inhibitor concentrate should be used for acute attacks, however, it may not be as effective as it is for HAE because of the large amounts of anti-C1nh antibodies which rapidly inactivate the infused product.

Type 1 AAE may respond to androgen therapy whereas type 2 AAE does not. Tranexamic acid or ε-aminocaproic acid may produce better results in AAE for long term prophylaxis. Autoantibody production in type 2 AAE may be suppressed with immunosuppressive therapy, such as cyclophosphamide and glucocorticosteroid therapy. Symptomatic improvement has been reported for type 2 AAE using pulse methylprednisolone, 500mg-1000mg daily (19).

Angiotensin Converting-Enzyme (ACE) Inhibitors and AAE

ACE-inhibitor-induced A/O occurs in 0.1% to 0.5% of subjects who take these drugs (20). There is no gender difference, except that gastrointestinal involvement has been reported only in females. A report suggests a threefold increase of A/O in black versus white Americans suggesting genetic factors are important (21). Angioedema, as an early or late complication of ACE inhibitor therapy, is described most commonly with captopril and enalapril but has been reported with all drugs in this class.

The onset of A/O may occur within a week or as long as 2-3 years after initiating treatment. Symptoms resolve within 24-48 hours after discontinuing the drug and recur if rechallenged with a different ACE inhibitor. While the most common site for swelling is the face and lips, laryngeal oedema has been reported and may be more likely if there has been upper airway trauma or instrumentation. Jain et al (22) identified a number of risk factors which include marked obesity, prior face or neck surgery and prior endotracheal intubation. It is unclear as to why only a few individuals on ACE inhibitor therapy develop this potentially serious complication. Those who do may have an impairment in kininase 1 which degrades bradykinin, allowing for its accumulation once ACE activity is blocked (6). Patients with HAE and idiopathic urticaria/angioedema are also at increased risk for ACE inhibitor triggered attacks, so alternative antihypertensive therapy is indicated in such cases. 

Pathophysiology of AAE

Angiotensin-converting enzyme has two main substrates, angiotensin1 and bradykinin, which it cleaves into smaller molecules, inactivating these molecules. ACE inhibitors may also induce A/O in susceptible individuals by causing bradykinin accumulation with vasodilatation, capillary leakage and angioedema.

Management of AAE

If angioedema occurs in a patient on an ACE inhibitor it should be stopped and an alternative drug from a different group of anti-hypertensive drugs should be used for therapy. Treatment for ACE induced acute angioedema is variable. In some, epinephrine, corticosteroids and antihistamines may suffice. Therapy for progressive angioedema should be aggressive and, where necessary, an airway should be secured with oral or nasal intubation. A tracheotomy is rarely necessary since the oedema usually subsides within 24-48 hours. Careful observation and monitoring is necessary after successful treatment since rebound swelling can occur some time later.

References

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3. Bork K, Barnstedt S, Koch P et al. Hereditary angioedema with normal C1 inhibitor activity in women. Lancet 2000; 356:213-217.

4. Bork K, Siedlecki K, Bosch S et al. Asphyxiation by laryngeal oedema in patients with hereditary angioedema. Mayo Clin Proc 2000; 75:349-354.

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10. Nielsen EW, Johansen HT, Hogasen K et al. Activation of the complement, coagulation, fibrinolytic and kallekrein systems during attacks of hereditary angioedema. Immunopharmacology 1996; 33:359-360.

11. Theriault A, Whaley k, McPhaden AR et al. Regional assignment of the human C1 inhibitor gene to 11q11-q13.1. Hum Genet.1990; 84:477-479.

12. Carter PE, Dunbar B, Fothergill JE. Genomic and cDNA cloning o fthe human C1 inhibitor:intron-exon junctions and comparison with other serpins. Eur J Biochem. 1988; 173:163-169.

13. Eck SL, Morse JH, Janssen DA et al. Angioedema presenting as chronic gastrointestinal symptoms. Am J Gastroenterol.1993; 88:436-439.

14. Zuraw BL, Herschbach BA. Detection of the C1 inhibitor mutations in patients with hereditary angioedema. J Allergy Clin Immunol. 2000; 105:541-546.

15. Waytes AT, Rosen FS, Frank MM.Treatment of hereditary angioedema with a vapour-treated C1 inhibitor concentrate.N Engl j Med 1996;334:1630-1634.

16. Bork K, Barnstedt SE. treatment of 193 episodes of laryngeal oedema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med.2001;161:714-718.

17. Markovic SN, Inwards DJ, Frigas Ea et al. Acquired C1 esterase deficiency. Ann Int Med 2000; 132:144-150.

18. Csepregi A, Nemesanksky E. Acquired C1 esterase inhibitor deficiency. Ann Int Med 2000; 133:838-839.

19. Laurent J, Guinnepain MT. Angioedema associated with C1 inhibitor deficiency. Clin Rev Allergy Immunol 1999; 17:513-523.

20.Slater EE, Merrill D, Guess H et al. Clinical profile of angioedema- associated with angiotensin converting- enzyme inhibition. JAMA 1988; 260:967-970.

21. Brown N, Ray WA, Snowden M et al. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther 1996; 60:8-13.

22. Jain M, Armstrong l, Hall J. Predisposition to and late onset of upper airway obstruction following angiotensin-converting enzyme inhibitor therapy. Chest 1992; 102:871-874.

23. Roberts JR, Wuerz RC. Clinical characteristics of angiotensin-converting enzyme inhibitor-induced angioedema. Ann Emerg Med 1991; 20:555-558.