Sudden upper airway obstruction in patients with hereditary angioedema

doi:10.1016/j.transci.2003.08.007

Transfusion and Apheresis Science

Volume 29, Issue 3, December 2003, Pages 235-238

https://doi.org/10.1016/j.transci.2003.08.007 Get rights and content

Abstract

Hereditary angioedema (HAE) is clinically characterized by recurrent and self-limiting skin, intestinal, and life-threatening laryngeal edema. This study describes the age at which laryngeal edema first occurred, the time between onset and full development, and the effectiveness of therapy and prophylaxis in 123 HAE patients. 61 (49.7%) patients experienced a total of 596 laryngeal edema episodes. The ratio of laryngeal edema episodes to skin swellings and abdominal pain attacks was approximately 1:70:54 in patients who had laryngeal edema. The mean (SD) age at the first laryngeal edema was 26.2 (15.3) years. Nearly 80% of the laryngeal edemas occurred between age 11 and 45. The mean interval between onset and maximum development of laryngeal edema was 8.3 hours. A total of 354 laryngeal edemas cleared spontaneously without treatment and 208 laryngeal edemas were successfully treated with C1 inhibitor concentrate. Despite long-term prophylactic treatment with danazol, 6 patients developed subsequent laryngeal edemas. Laryngeal edema may occur at any age, although young adults are at greatest risk. In adults, the interval between onset of symptoms and acute risk of asphyxiation is usually long enough to allow for use of appropriate emergency procedures. It is essential to instruct patients and their relatives about the first signs of laryngeal edemas and the necessary procedures to follow.

Introduction

Classical hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is clinically characterized by relapsing, self-limited episodes of edema at various body sites––most often the subcutaneous tissue, wall of the intestine, and larynx. The recurrent edema attacks therefore appear as skin swellings, abdominal pain attacks with or without ascites, and episodes of upper airway obstruction. Other clinical features are rare and include episodes of tongue edema and swelling of the soft palate. In patients with HAE, upper airway obstruction is usually a result of laryngeal edema; if patients with HAE die from their disease, laryngeal edema is the usual cause of death. The unforeseen and unexpected occurrence of laryngeal edema associated with the risk of asphyxiation is the most important feature of this disease. In patients with undiagnosed HAE, mortality has been reported in up to 30% to 50% [1], [2]. Recently, 6 patients with HAE who asphyxiated as a result of laryngeal edema were described [3]. Laryngeal edema in HAE always bears the risk of asphyxiation; however, it is a rare event in HAE. The aim of this study is to provide information on the frequency of episodes of laryngeal edema compared with edema episodes at other sites, the age at which episodes of laryngeal edema first occur compared with the age of onset of the other clinical symptoms, the age at which laryngeal edema occurs most frequently, the interval between onset and maximum development of the laryngeal edema (i.e., the period when emergency measures can be performed), the triggers of laryngeal edema, and the efficacy of treatment and prophylaxis.

Section snippets

Patients and methods

A total of 123 patients with HAE due to C1-INH deficiency were surveyed in the angioedema outpatient service at the Department of Dermatology, University of Mainz, Germany, from 1973 to 2001. Diagnosis of HAE was made on the basis of patient history, clinical examination, and laboratory results, including deficiency of functional C1-INH and C4 in plasma. Protein levels of C1-INH antigen, C4, and C1q were assayed by radial immunodiffusion, and C1-INH activity was determined using the chromogenic

Results

The clinical signs of laryngeal edema were dysphagia; the sensation of a lump in the throat; a feeling of tightness in the throat; voice changes, including hoarseness and roughness; and dyspnea. In patients with progressed laryngeal edema, mostly fear of asphyxiation and aphonia also occurred. Some patients reported only minimal dysphagia and hoarseness; a full-blown laryngeal edema, however, could not be verified. Such events were difficult to classify and therefore not considered here.

Discussion

HAE due to C1-INH is a potentially life-threatening disease. Although the most frequent symptoms––i.e., relapsing attacks of skin swelling and abdominal pain––are not life-threatening, sudden airway obstruction may lead to asphyxiation [2], [3]. Even the first episode of laryngeal edema may be fatal [3]. The fact that HAE may be associated with upper airway obstruction and death by asphyxiation has been known since Quincke’s and Osler’s descriptions of the disease [4], [5]. Table 1 summarizes

Conclusions

It can be concluded that laryngeal edema is a life-threatening condition in HAE that may occur at any age and that most commonly affects young adults. In adults, the interval between symptom onset and acute risk of asphyxiation is usually long enough to allow for appropriate emergency procedures, but this interval may be considerably shorter in children. Education of patients and their relatives about the first signs of laryngeal edema, which is usually unforeseen, and about the necessary

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The increased vascular permeability results from bradykinin overproduction.2,4 When edema formation involves the upper airways,5 death may occur owing to asphyxia.1,6 Patients suspected of having HAE should be evaluated by measuring C4 and C1 inhibitor (C1-INH) levels, and C1-INH function.4,7
Hereditary angioedema (HAE) is known for mortality when it is not treated properly. Many advances have occurred over the past decades that affected patients’ lives. However, not all patient populations have access to the same diagnosis and treatment resources.
To evaluate mortality from HAE in a large cohort in a reference center in Brazil. Furthermore, the research intended to describe patients’ life span, the asphyxia evolution, and factors related to the fatal outcome.
A cohort of 433 patients from 46 families was evaluated in this prospective and retrospective study. Families were organized in clusters and were given a verbal autopsy to arrange data collection for the deaths and analyze symptoms during life. Causes of death were classified as deaths from laryngeal edema (LE) or other causes.
Of 433 patients evaluated, 254 were not given the diagnosis of HAE. A total of 75 fatal events were evaluated. Only 10 of 75 patients were given the diagnosis of HAE before death, and the HAE diagnosis was made after death in 65 of 75 patients using verbal autopsy. The final cause of death after the investigation was asphyxiation owing to LE in 39 of 75 (52%) and deaths owing to other causes in 36 of 75 (48%). Ten deaths had occurred in the past decade. Time from onset of symptoms to seeking medical assistance was a median of 4 hours, and the time to death was a median of 8 hours. Three patients received fresh-frozen plasma and none received medications specific to HAE attacks. Throat pain or discomfort was the most common symptom, experienced by 71.8% of patients. The most common mistaken diagnosis at the original death certificate was allergy or anaphylaxis. The life span of patients who died of LE was reduced by 20 years compared with those who died of other causes.
Hereditary angioedema remains a threat to life in the studied population. The large number of patients who do not receive a diagnosis makes the situation even more severe and is responsible for most deaths. Death analyses add knowledge to an understanding of the diseases and their impact on patients’ lives, improving the targeting of public health efforts.
Hereditary Angioedema
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Isolated swelling of the genitals may be the only manifestation of an HAE attack.31,32 Any structure in the oropharynx and deeper upper respiratory tract may show signs of edema, and up to 50% of patients with HAE will experience laryngeal edema at some point.33 The risk of asphyxiation is higher in patients with undiagnosed HAE than in those that have correctly been diagnosed.34
Hereditary Angioedema: Insights into inflammation and allergy
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Laryngeal, nasal and sinus edema can lead to airway collapse and dead by suffocation. Laryngeal edema occurs at least once in the lifetime in 50% of patients and, if undiagnosed, mortality due to airway obstruction can reach 30% to 40% (Bork and Ressel, 2003). AAE-C1INH is caused by the presence of autoantibodies targeting and depleting C1INH as a consequence of underlying malignant or autoimmune diseases (Cicardi and Zanichelli).
Hereditary Angioedema (HAE) is a rare autosomal recessive bradykinin (BK)-mediated disease characterized by local episodes of non-pitting swelling. Initially considered a complement-mediated disease, novel pathogenic mechanisms uncovered in the last decade have revealed new HAE-associated genes and tight physiological relationships among complement, contact, coagulation, fibrinolysis and inflammation. Uncontrolled production of BK due to inefficient regulation of the plasma contact system, increased activity of contact and coagulation factors or a deficient regulation of BK receptor-triggered intracellular signalling are on the basis of HAE pathology. In this new scenario, HAE can result from different mechanisms that may generate distinct clinical phenotypes of the disease. This review focuses in the recent advances and unsolved challenges in our comprehension of this ever increasingly complex pathology.
Death due to obstruction of the upper airways caused by edema of the laryngeal mucosa in the course of hereditary angioedema
2015, Forensic Science International
A rare case of death of a young man due to airway obstruction in the course of angioedema (Quincke's edema). Type I hereditary angioedema due to C1 esterase inhibitor deficiency had been diagnosed in the man while he was alive. The information concerning the man's health state was given in the Public Prosecutor's decision ordering medico legal autopsy, which was extremely helpful in recognizing the cause of death.
Upper airway edema in 43 patients with hereditary angioedema
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For most patients, UAE began in the second to fourth decades of life. This finding is similar to that in a previous study in Germany.18 Compared with other involved sites in HAE (eg, skin and abdomen), UAE is relatively rare, occurring in approximately 1% of attacks.13
Upper airway edema (UAE) occurs infrequently in hereditary angioedema (HAE), but still results in significant morbidity and mortality.
To assess patients with HAE and UAE to determine whether unique features exist that can predict the risk of UAE.
Clinical, laboratory, and genetic data were compared between 43 patients with HAE and 743 UAE attacks and those without UAE and normal controls after ethics committee approval.
Most patients had their first episode of UAE in the second (25.6%), third (27.9%), and fourth (23.3%) decades of life, and the mean age at onset was 27.3 years. Evolution of UAE from initial to maximum symptoms was 4.6 hours on average, and most cases (69.8%) progressed within 4 hours. Dyspnea was the most frequent manifestation in per-episode (92.2%) and per-patient (97.7%) analyses. Men developed more asphyxiation attacks (19 vs 2) and underwent more tracheotomies (12 vs 2) than did women. UAE was associated with facial edema in half the studied patients. Patients with a positive family history of UAE had a high risk of UAE attacks.
Symptoms limited to the upper airway should be taken seriously. Dyspnea may be the only manifestation of UAE. UAE attacks most commonly start spontaneously and usually progress rapidly, as quickly as 30 minutes, from awareness of symptoms to maximum airway involvement. Patients with a positive UAE family history are predisposed to UAE attacks, and men appear to be more apt to develop asphyxiation than women.

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Sudden upper airway obstruction in patients with hereditary angioedema

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Conclusions

J. Allergy Clin. Immunol.

Am. J. Med. Sci.

Mayo. Clin. Proc.

Ann. Allergy Asthma Immunol.

Über akutes umschriebenes Hautödem

Monatsh Prakt Dermatol.

Hereditary angioneurotic edema

Am. J. Med. Sci.

Replacement therapy in hereditary angioedema: successful treatment of acute episodes of angioedema with partly purified C1 inhibitor

N. Engl. J. Med.

Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate

N. Engl. J. Med.