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Treatment of 193 Episodes of Laryngeal Edema With C1 Inhibitor Concentrate in Patients With Hereditary Angioedema
Konrad Bork, MD;
Sven-Erik Barnstedt, MD
Arch Intern Med. 2001;161:714-718.
ABSTRACT
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Background Hereditary angioedema (HAE) is an autosomal dominant disease (Mendelian Inheritance in Man 106100) caused by an inherited
deficiency of C1 inhibitor (C1-INH) function. The clinical symptoms include
skin swelling, abdominal pain, and life-threatening episodes of upper airway
obstruction. We evaluated the efficacy of C1-INH concentrate for treating
sudden airway compromise.
Methods A series of 95 patients with HAE and a functional deficiency of C1-INH
belonging to 59 families underwent screening for laryngeal edema. Double-blind
treatment of randomized patients was not justifiable because of the life-threatening
nature of this condition. Efficacy was evaluated by determining the interval
from injection of C1-INH concentrate to the beginning of resolution of symptoms.
The mean duration of episodes of laryngeal edema was compared in treated and
untreated patients. Clinical information was obtained from emergency department
physicians, the hospitals involved, reports of the general practitioners,
and patients and their relatives.
Results Forty-two patients had 517 episodes of laryngeal edema. Eighteen patients
received 500- or 1000-U injections of C1-INH concentrate in 193 episodes.
The C1-INH concentrate was effective in all laryngeal edemas. The interval
from injection to interruption in progress of symptoms ranged from 10 minutes
to 4 hours (mean ± SD, 42.2 ± 19.9 minutes). The mean ±
SD duration of laryngeal edema was 15.3 ± 9.3 hours in patients who
received C1-INH concentrate and 100.8 ± 26.2 hours in those who did
not.
Conclusions Injected C1-INH concentrate is highly and rapidly effective in the treatment
of laryngeal edema of HAE. Relief and resolution of symptoms begins 30 to
60 minutes after injection, and duration of the upper airway obstruction is
substantially reduced.
INTRODUCTION
HEREDITARY angioedema (HAE), first described clinically by Osler in
1888,1 is a well-defined autosomal dominant
disease (Mendelian Inheritance in Man 1061002) caused by an inherited deficiency of functional C1-esterase
inhibitor (C1-INH). Donaldson and Evans3 discovered
the defect in 1963. The defective C1-INH gene produces
no C1-INH (type I HAE [HAE I]) or a dysfunctional C1-INH (type II HAE [HAE
II]). In HAE I, which represents 85% of patients, plasma levels of C1-INH
are 5% to 30% of normal values. In HAE II, levels of C1-INH are normal or
elevated. Both forms are clinically indistinguishable. Until now, more than
100 different C1 INH gene mutations have been described
in HAE, including missense and nonsense mutations, large deletions, and frame-shift
and splice-site mutations.4-5
The exact prevalence of HAE is unknown; current estimates suggest that the
disease affects between 1 in 10 000 and 1 in 50 000 persons.6 The clinical features of the disease are recurrent
transient episodes of skin swelling and intestinal and laryngeal edema. These
transient episodes of edema last 2 to 5 days, after which they regress spontaneously.
The episodes of intestinal wall edema may be accompanied by transient ascites.7 Asphyxiation due to obstruction of the upper airways
is the most common cause of death.8 Upper airway
obstruction is usually due to laryngeal and glottal edema. In some patients,
however, laryngeal edema may extend into lower parts of the airway, and some
patients may have pulmonary edema also. Since this is rare, we use the term laryngeal edema. The unexpected occurrence of laryngeal
edema associated with the risk for asphyxiation is the most important feature
of this disease.
Treatment of HAE includes the following: (1) long-term prophylaxis to
prevent skin swelling, abdominal attacks, and predominantly laryngeal edema;
(2) short-term prophylaxis before elective surgical procedures; and (3) treatment
of acute attacks.
Long-term prophylactic treatment may include attenuated androgens, tranexamic
acid, and C1-INH concentrate. Attenuated androgens, such as danazol or stanozolol,
reduce the number of HAE attacks considerably.9-11
However, a number of adverse effects may limit their use, including weight
gain, menstrual irregularities, and arterial hypertension.12-13
Recently, hepatocellular adenoma has been reported in 3 patients with HAE
who took danazol for more than 10 years.14
Furthermore, a hepatocellular carcinoma has also been observed with long-term
use of attenuated androgens.15 Therefore, despite
the proven efficacy in preventing HAE attacks, treatment with attenuated androgens
cannot be recommended routinely to all patients. Continuous prophylactic treatment
of HAE is also possible with tranexamic acid, an antifibrinolytic agent. Its
efficacy, however, is lower than that of androgens.10
Furthermore, antifibrinolytic agents bear the risk for thromboembolic events.
Concentrate of C1-INH is effective in preventing and treating acute attacks
of HAE, and it has also been tried for long-term prophylaxis for HAE.16 However, since the available preparations are concentrates
from pooled human plasma, the risk of transmission of infectious agents cannot
totally be excluded. Furthermore, the concentrate is expensive and not available
in all countries. These drawbacks limit the use of these drugs as a life-long
prophylactic standard treatment. Short-term prophylaxis before surgery, especially
dental surgery, may be achieved with C1-INH concentrate or with attenuated
androgens.6
Acute attacks of abdominal pain and skin swelling have been treated
successfully with C1-INH concentrate. Information about the efficacy of C1-INH
concentrate in the treatment of sudden upper airway obstruction in patients
with HAE is sparse because of the rarity and unforeseen occurrence of these
episodes and the limited number of patients who have been treated with C1-INH
concentrate.
This study evaluates the efficacy of C1-INH concentrate in the treatment
of laryngeal edema of HAE in 18 patients with HAE I who received C1-INH concentrate
for 193 episodes of upper airway obstruction. Because of the life-threatening
nature of this condition, a study of double-blind treatment of randomized
patients was not justifiable ethically. Laryngeal edema occurs rarely and
is usually unforeseen, and another method of evaluating efficacy had to be
used. Therefore, efficacy was evaluated by determining the interval between
the injection of C1-INH concentrate and the start of relief and resolution
of symptoms. In addition, the duration of laryngeal edema was compared between
treated and untreated episodes of laryngeal edema in the same patients, as
well as between patients who received C1-INH concentrate and a control group
of patients with HAE who did not receive C1-INH concentrate.
PATIENTS AND METHODS
PATIENTS
A series of 95 patients with HAE from 59 unrelated kindreds have been
followed up at the angioedema service of the Department of Dermatology of
the University of Mainz, Mainz, Germany, for up to 20 years. The patients
were from various regions of Germany. Deficiency of C1-INH was confirmed for
all 95 patients; 92 had HAE I, and 3 had HAE II. All patients had the typical
clinical symptoms of HAE, ie, relapsing attacks of skin swelling and abdominal
pain. Forty-two of the patients had 1 or more episodes of sudden airway obstruction;
18 of them, all with HAE I, received C1-INH concentrate for sudden airway
obstruction. Information about the patients with laryngeal edema is given
in Table 1.
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Table 1. Clinical Features of 42 Patients With Hereditary Angioedema
Who Had 1 or More Episodes of Laryngeal Edema*
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C1-INH CONCENTRATE
The C1-INH concentrate used (Berinert HS; Aventis Behring, Liederbach,
Germany) is derived from pooled plasma of healthy donors seronegative for
hepatitis B surface antigen, anti–human immunodeficiency virus 1 (HIV-1),
anti–HIV-2, and anti–hepatitis C virus (HCV). Furthermore, all
donations were tested for the absence of hepatitis A virus (HAV), hepatitis
B virus (HBV), HCV, and HIV-1 as well as high titers of Parvovirus B 19 by
means of polymerase chain reaction (PCR) analysis. In addition, a plasma pool
for fractionation is only released for further processing if results of a
sensitive and selective PCR are nonreactive for HBV DNA, HCV RNA, and HIV-1
RNA. Therefore, the high virus reduction capacity of the manufacturing procedure
of Berinert HS is facilitated by the starting material, nonreactive for transfusion-relevant
viruses on PCR findings. Important steps in the production procedure included
heat treatment in aqueous solution at 60°C for 10 hours (pasteurization).
One clinical study showed that Berinert HS does not transmit HIV-1 infections,17 and another (which followed the International Committee
on Thrombosis and Haemostasis protocol) found no transmission of HBV or non-HAV/HBV.18
METHODS
At the beginning of the study, all 95 patients received a vial containing
500 U of C1-INH concentrate and stored it in their refrigerators at home.
When patients experienced an episode of laryngeal edema, they received an
injection from this vial administered by their general practitioner or at
the nearest hospital. If the general practitioner gave the injection, the
patient was admitted to the nearest hospital, where immediate intubation,
tracheostomy, cricothyrotomy, or other emergency procedures were possible
if the laryngeal edema progressed rapidly and asphyxiation threatened. If
the symptoms of laryngeal edema did not resolve within 30 to 60 minutes of
the injection or had progressed further by that time, an additional 500-U
injection of C1-INH concentrate was administered in the hospital. If this
was necessary in 3 consecutive episodes of laryngeal edema in the same patient,
the patient received 1000 U of C1-INH instead of 500 U initially for all subsequent
episodes. The efficacy was evaluated by determining onset of symptom resolution.
Symptoms included dyspnea, fear of asphyxiation, feeling of tightness in the
throat, dysphagia, and voice changes (including hoarseness, roughness, and
aphonia). The time from injection of C1-INH concentrate to the first signs
of symptom resolution or the end of the symptom progression was determined,
as well as the duration of laryngeal edema from the first symptoms (feeling
of a lump in the throat, dysphagia, or voice changes) to the end of the involutional
period and attainment of normality. The duration of laryngeal edema was compared
with the duration of a previous episode that was not treated with C1-INH concentrate
in the same patient. Furthermore, the duration of laryngeal edema in patients
treated with C1-INH concentrate was compared with the duration in a control
group of patients with HAE who had never received C1-INH concentrate. The
medical histories are based on reports by the general practitioners, emergency
department physicians, and hospitals involved. Additional information was
obtained from the patients and their relatives.
Unless otherwise indicated, data are given as mean (±SD).
RESULTS
From 1970 to 1999, 42 of the 95 patients with HAE experienced 1 or more
episodes of laryngeal edema. Forty of the patients had HAE I, and 2 had HAE
II. The patients experienced a total of 517 episodes of laryngeal edema; 24
patients who experienced 172 episodes of laryngeal edema had never received
C1-INH concentrate because HAE and the causal C1-INH deficiency had not yet
been diagnosed or because the C1-INH concentrate was not available on the
market. The 18 patients who had received C1-INH concentrate experienced a
total of 345 episodes of laryngeal edema. These patients were treated with
C1-INH concentrate for 193 episodes of laryngeal edema. The other 152 episodes
occurred before the C1-INH concentrate was available or before the C1-INH
deficiency had been diagnosed.
In 48 episodes of laryngeal edema in 12 patients, only 500 U of C1-INH
was needed for treatment. In 21 additional episodes in 8 patients, a second
injection of 500 U was warranted after the first 500 U. Two patients with
124 episodes of laryngeal edema started therapy with 1000 U of C1-INH concentrate.
Four of the 18 patients received 500 U alone or, in other laryngeal edemas,
1000 U of C1-INH concentrate. None of the patients needed more than 1000 U.
The C1-INH concentrate was effective in all episodes of laryngeal edema in
all patients. None of the patients who received C1-INH concentrate required
additional emergency procedures such as tracheostomy and cricothyrotomy.
In all patients, difficulty breathing and fear of asphyxiation were
the first symptoms that resolved. Dysphagia, the sensation of a lump in the
throat, and voice changes took longer to resolve completely. All patients
experienced onset of relief within 4 hours after injection of C1-INH concentrate.
In most patients, symptoms started to resolve between 30 and 60 minutes after
administration of C1-INH concentrate (Figure
1). The therapeutic effect began within 1 hour in 17 patients with
192 episodes of laryngeal edema. In only 1 patient with 1 episode of laryngeal
edema, resolution of symptoms did not start until 4 hours after administration
of C1-INH concentrate. The mean interval between injection of C1-INH concentrate
and the reversal of development of symptoms was 42.2 (± 19.9) minutes.
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Figure 1. Onset of efficacy after injection
of C1 inhibitor concentrate in 192 episodes of laryngeal edema in 17 patients
with hereditary angioedema. In an 18th patient, resolution of symptoms in
another episode did not begin until 4 hours after the injection.
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The mean duration (beginning of symptoms to resolution of last symptoms)
of the 324 untreated episodes of laryngeal edema in the 24 patients who had
never received C1-INH concentrate and in untreated episodes of laryngeal edema
in the 18 patients who had received C1-INH concentrate for other episodes
was 100.8 hours (± 26.2 hours) or 4.2 days (Figure 2). In the 18 patients, the mean duration of the 193 treated
episodes of laryngeal edema was 15.3 hours (± 9.3 hours) and therefore
was significantly lower than the duration of the untreated episodes of laryngeal
edema of all patients (P<.001).
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Figure 2. Mean duration of 193 episodes
of laryngeal edema treated with C1 inhibitor concentrate and 324 episodes
of untreated laryngeal edema.
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Among the 18 patients treated with C1-INH concentrate, 8 also had episodes
that were not treated with C1-INH concentrate because it was not yet available
for treatment of HAE or the C1-INH deficiency had not yet been diagnosed.
The duration of the 144 episodes of laryngeal edema treated with C1-INH concentrate
was significantly shorter than the duration of the 152 episodes that were
not treated with C1-INH concentrate in the same 8 patients (Wilcoxon test, 
= .05; P = .01; highly significant) (Table 2).
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Table 2. Duration of Episodes of Laryngeal Edema Not Treated and Treated
With C1-INH Concentrate in the Same Patients*
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In a subset of 3 patients with laryngeal edema, plasma concentration
of C1-INH was determined by means of radioimmunodiffusion (reference range,
0.15-0.35 g/L) before and 1, 24, and 72 hours after administration of 500
U of C1-INH concentrate. The mean values were 0.03 ± 0.01 g/L before
injection of C1-INH, 0.07 ± 0.01 g/L at 1 hour, 0.05 ± 0.01
g/L at 24 hours, and 0.03 ± 0.01 g/L at 72 hours.
Two patients received 500 U of C1-INH concentrate prophylactically 30
minutes before dental surgery and another patient, before 3 abdominal operations.
No laryngeal edema or angioedema at other sites developed in these patients.
There were no clinical signs of adverse drug reactions in any patients who
had received C1-INH concentrate.
COMMENT
Hereditary angioedema is a potentially life-threatening disease. Although
the most frequent symptoms, ie, relapsing attacks of skin swelling and abdominal
pain, are not life threatening, sudden airway obstruction may lead to asphyxiation.
Six asphyxiation-related deaths of patients with HAE have been reported recently.8 Even the first episode of laryngeal edema may be fatal.8 The possibility of sudden airway obstruction and asphyxiation
must be emphasized in discussions with the patients and their relatives, and
attending physicians should have a high degree of awareness of this aspect
of HAE. Because of the danger of asphyxiation due to laryngeal edema, the
2 most important aims of treatment are interruption of an acute attack of
laryngeal edema and prevention of laryngeal edema by means of long-term prophylaxis.
Patients' early recognition of the beginning of an episode of laryngeal edema
is crucial. For this purpose, patients should be carefully educated to recognize
the first symptoms of upper airway obstruction such as dysphagia, sensation
of a lump in the throat, feeling of tightness, and voice changes, including
hoarseness and roughness. Dyspnea, fear of asphyxiation, and aphonia are features
of a fully developed episode of laryngeal edema. In choosing treatment for
laryngeal edema, consideration should be given to the degree of the airway
obstruction.19-20 In mild cases
of airway edema, careful observation of the patient in the hospital may be
sufficient, and oxygen therapy may be provided. When the edema progresses
and dyspnea occurs, ventilation via mask and further emergency procedures,
including intubation or tracheostomy, may become necessary. If no other treatment
is possible and asphyxiation is imminent, an emergency cricothyrotomy should
be performed without delay.
Replacement therapy with purified C1-INH preparation has proved to be
effective in treating relapsing skin swelling and acute attacks of abdominal
pain in patients with HAE.9, 21-24
Information about treatment of laryngeal edema with C1-INH concentrate, however,
is sparse. Gadek et al21 reported 2 attacks
of laryngeal edema treated with a partly purified C1-INH. The times from infusion
to resolution of symptoms were 7 hours and 1 hour in these patients. Agostoni
and Cicardi with others9, 25-27
reported on the treatment of 67 episodes of laryngeal edema in 23 patients
with HAE with infusions of C1-INH concentrate. Resolution of symptoms started
after 30 to 60 minutes. Kunschak et al23 reported
on the treatment of acute attacks of edema with C1-INH concentrate in 11 patients
with acute edema. Among the 70 attacks in patients treated with C1-INH, there
were only 4 episodes of difficult breathing or swallowing and no episodes
of swelling of the respiratory tract. The number of patients who experienced
these 4 episodes was not reported. Visentin et al24
described 7 patients who received C1-INH transfusions. One of these patients
was treated for 3 or 4 episodes of laryngeal edema. In this patient, the mean
duration of the episodes of laryngeal edema treated with C1-INH concentrate
was 71 minutes.
Because of the risks and adverse effects of long-term prophylactic treatment
with attenuated androgens, antifibrinolytic agents, and C1-INH concentrate,
having an appropriate treatment available for acute life-threatening events
is very important. The present study shows, in a large number of laryngeal
edemas in patients with HAE, that the administration of C1-INH concentrate
is extremely helpful. Relief of the symptoms begins, on average, 42 minutes
after the injection, and the course of the laryngeal edema is considerably
shortened. Acute treatment must be administered early enough in the episode
to interrupt its progression, and all steps must be discussed with the patient
in detail.
CONCLUSIONS
Concentrate of C1-INH is rapidly effective (average, 42 minutes) in
relieving and resolving symptoms of life-threatening laryngeal edema of HAE.
The duration of the upper airway obstruction is significantly reduced.
AUTHOR INFORMATION
Accepted for publication September 18, 2000.
Corresponding author and reprints: Konrad Bork, MD, Universitäts-Hautklinik,
Langenbeckstr. 1, 55131 Mainz, Germany (e-mail: bork{at}hautklinik.klinik.uni-mainz.de).
From the Department of Dermatology, University of Mainz, Mainz, Germany.
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