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Acquired C1 inhibitor deficiency: Management and prognosis

Author: Sarbjit Saini, MD
Section Editor: Bruce S Bochner, MD
Deputy Editor: Anna M Feldweg, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2020. | This topic last updated: Feb 13, 2020.

INTRODUCTION

Acquired angioedema due to deficiency of C1 esterase inhibitor, also called acquired angioedema
and abbreviated C1INH-AAE, is a rare syndrome of recurrent episodes of angioedema, without
urticaria, which is associated with B cell lymphoproliferative disorders in some patients [1].
Angioedema typically affects the skin or mucosal tissues of the upper respiratory and
gastrointestinal tracts. The swelling is self-limited, although laryngeal involvement may cause fatal
asphyxiation. Clinically, this disorder is very similar to hereditary angioedema (HAE), although
acquired angioedema develops in older patients and is frequently associated with underlying
disease, whereas the hereditary disorder presents in younger patients who are otherwise healthy [2].

This topic review will discuss the management and prognosis of C1INH-AAE. The clinical
manifestations, epidemiology, pathogenesis, and diagnosis of this disorder are reviewed elsewhere.
(See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and
diagnosis".)

HAE, which is caused by mutations in the gene for C1INH, is discussed separately. (See "Hereditary
angioedema: Pathogenesis and diagnosis" and "Hereditary angioedema: Epidemiology, clinical
manifestations, exacerbating factors, and prognosis" and "Hereditary angioedema: Acute treatment
of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care
and long-term prophylaxis".)

OVERVIEW OF MANAGEMENT

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The management of a patient with acquired angioedema involves several components [3]:

● Educating the patient about the potential triggers and early recognition of angioedema attacks
and ensuring that the patient understands that there is a real risk of fatal asphyxiation with
attacks involving the upper airway. (See 'Patient education about laryngeal edema' below and
'Avoidance of exacerbating factors' below.)

● Providing the patient with written instructions about treatment of acute attacks, which can be
given to other providers in the emergency setting (form 1). (See 'Written treatment plan' below
and 'Airway management in laryngeal edema' below.)

● Prescribing appropriate "on-demand" therapies for attacks of angioedema and ensuring that the
patient is either trained to self-administer these treatments or has access to appropriate
medications at the hospitals nearest to the patient's home. (See 'Pharmacologic treatment of
acute attacks' below.)

● Managing associated diseases, if present, or if none is initially found, monitoring for the
development of an associated disease. (See 'Associated disorders' below.)

● Evaluating the need for prophylaxis to prevent angioedema attacks. (See 'Prophylaxis to prevent
angioedema episodes' below.)

PREPARATION FOR ACUTE ANGIOEDEMA EPISODES

Laryngeal attacks are the most dangerous type of attack in acquired angioedema because edema
can lead to fatal airway obstruction. Upper airway angioedema usually progresses over hours,
although it can occur precipitously. Intubation may become very difficult due to distortion of the
anatomy of the upper airway. Because of the dangers associated with laryngeal attacks, it is
important to make sure that patients are prepared to respond effectively to the development of
symptoms near or in the throat.

Angioedema may also affect the gastrointestinal tract, causing colicky abdominal pain, nausea,
vomiting, and/or diarrhea. Episodes of abdominal angioedema are often debilitating but are not life-
threatening. Angioedema affecting the skin is temporarily disfiguring but rarely dangerous unless it
affects the mouth or lips, since it can compromise the airway in these situations. The approach to
treating abdominal and cutaneous attacks is similar to that used in patients with hereditary
angioedema (HAE), which is reviewed in detail separately. (See "Hereditary angioedema: Acute
treatment of angioedema attacks", section on 'Gastrointestinal attacks' and "Hereditary angioedema:
Acute treatment of angioedema attacks", section on 'Cutaneous attacks'.)

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Patient education about laryngeal edema — All patients with C1INH-AAE must be counseled about
the earliest signs of an attack affecting the upper airway, which typically includes the sensation of a
lump or feeling of tightness in the throat or swallowing difficulties. Patients should also have a plan
to get prompt and appropriate treatment. Any patient with throat symptoms should seek emergency
care immediately. The patient should not attempt to manage early laryngeal attacks at home,
although if therapy for self-administration is available and can be given quickly, the patient can
initiate therapy and then call for an ambulance to take him/her to the nearest emergency
department. It is important to discuss that even if the treatment has worked well in the past, the
patient should always proceed immediately to an emergency care setting when the throat is involved
because all of the first-line therapies take approximately 30 minutes or more to begin working. In rare
circumstances, acute treatment, particularly with plasma-derived C1INH (pdC1INH), can be less
effective than in hereditary C1INH deficiency, thus a second dose is occasionally required. In
contrast, abdominal angioedema or cutaneous angioedema can often be managed by patients at
home if they have access to acute treatments. The emergency treatments that are appropriate for
administration at home are discussed elsewhere. (See "Hereditary angioedema: Acute treatment of
angioedema attacks", section on 'Initiating acute treatment of HAE attacks at home'.)

Written treatment plan — C1INH-AAE is a rare disorder, and few emergency department providers are
familiar with the treatment. Patients can be equipped with a document that briefly explains their
diagnosis, outlines the indicated treatment for acute attacks, and provides contact information for
the supervising clinician (form 1).

Airway management in laryngeal edema — Assessment and protection of the upper airway is the
first and most important management issue in the patient with an acute attack involving any part of
the airway because none of the available therapies including C1INH concentrate, icatibant, and
ecallantide can be considered universally effective in all cases. In addition, these agents take time to
work, and the patient's airway must be protected in the interim. Asphyxiation remains an important
and preventable cause of death in patients with this disorder, even in settings with appropriate
medications available. (See 'Prognosis' below.)

Intubation should be performed immediately if stridor or signs of respiratory arrest are present. A
clinician trained in difficult airway management should be summoned if possible because failed
attempts can lead to fatal obstruction. Emergent cricothyroidotomy may be required in rare cases.
(See "Approach to the anatomically difficult airway in adults outside the operating room" and
"Emergency cricothyrotomy (cricothyroidotomy)".)

Once the patient is assessed and either intubated or deemed stable, additional therapies can be
considered. Transfer to the intensive care unit should be arranged. Frequent and meticulous

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monitoring of airway status should continue throughout the course of the attack until complete
resolution, and patients should not be discharged until all airway symptoms have resolved.

Pharmacologic treatment of acute attacks — There are several medications available for acute
treatment of episodes of angioedema due to genetic C1INH deficiency that can be used for C1INH-
AAE. None of these drugs are registered/approved specifically for C1INH-AAE, and availability varies
around the world (table 1):

● C1INH concentrate, derived from human plasma (pdC1INH) (see 'C1 inhibitor concentrate'
below)
● Recombinant human C1INH (rhC1INH, conestat alfa) (see 'Recombinant C1 inhibitor' below)
● Icatibant, a synthetic bradykinin B 2-receptor antagonist (see 'Icatibant' below)
● Ecallantide, a recombinant plasma kallikrein inhibitor (see 'Ecallantide' below)
● Human plasma, either solvent/detergent-treated plasma (S/D plasma) or fresh frozen plasma
(FFP) (see 'Plasma' below)

The therapy with which there is most experience is pdC1INH, followed by icatibant. A clinical
response should be evident within two hours with pdC1INH, icatibant, or ecallantide. Each
medication is discussed in detail below, including mechanism of action, dosing, availability, efficacy
data, and adverse effects.

The treatment of C1INH-AAE is extrapolated from that of HAE [2,4,5]. No controlled studies have
been performed in patients with C1INH-AAE, and no therapies are specifically registered/approved
for treatment of this condition. Based on clinical experience, there appears to be some differences in
the response of these two disorders to the available therapies, as discussed in this section.

C1 inhibitor concentrate — The most widely used therapy for acute laryngeal edema is pdC1INH,
which is available as Cinryze or Berinert (brand names). pdC1INH became available in the United
States in 2009 but has been available in Europe for decades. Observational studies indicate that
pdC1INH is effective in the majority of patients with C1INH-AAE, reducing the average attack
duration by 60 percent or more [6].

Based on the controlled studies performed in C1INH-HAE, an initial dose of 20 units/kg is suggested.
The dosing, administration, and adverse effects of pdC1INH are reviewed elsewhere. (See "Hereditary
angioedema: Acute treatment of angioedema attacks", section on 'First-line agents: Dosing, efficacy,
and adverse reactions'.)

Resistance — A small percentage of patients with C1INH-AAE become less responsive to

pdC1INH over time, requiring higher doses to control symptoms [7,8]. As an example, one of the
author's patients required multiple infusions totaling 12,000 units of pdC1INH (the usual initial dose

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is 1500 units) over a period of two hours to control laryngeal edema. The newer therapies for
bradykinin-mediated angioedema, ecallantide and icatibant, offer alternatives for the treatment of
patients who become resistant to pdC1INH, and we would suggest trying these if resistance is
suspected. (See 'Ecallantide' below and 'Icatibant' below.)

The mechanism by which resistance to pdC1INH develops appears to involve extremely rapid
catabolism of the inhibitor protein, although this has not been formally demonstrated. In blood
samples collected from the patient described above, no significant increase of C1INH function could
be detected at any point during the multiple infusions, while C1INH antigen normalized due to the
increase in cleaved C1INH. These data suggest that the infused C1INH was rapidly bound by the
autoantibodies and converted in its cleaved inactive form upon interaction with target proteases. The
patient described above had high levels of anti-C1INH antibodies in serum.

Recombinant C1 inhibitor — There are limited data regarding the efficacy of recombinant human
C1INH (rhC1INH) (Ruconest [brand name]) in C1INH-AAE. rhC1INH has a shor ter half-life than
pdC1INH. This is a theoretical disadvantage in treating C1INH-AAE, which is characterized by
increased C1INH consumption, although no published data are available to confirm. The dosing and
adverse effects of this agent are discussed elsewhere. (See "Hereditary angioedema: Acute
treatment of angioedema attacks", section on 'Recombinant C1 inhibitor'.)

Icatibant — Icatibant (Firazyr [brand name]) is an antagonist of the bradykinin B 2-receptor, which

has also been successful in treating a small number of patients not responsive to C1INH concentrate
[9,10]. It became available in the United States in 2011.

The author has successfully used icatibant to treat angioedema episodes, including laryngeal
edema, in several C1INH-AAE patients, some of whom were not responsive to C1INH [9,10]. Because
icatibant does not depend on C1INH catabolic rate, the author prefers it to C1INH concentrate in his
own practice.

The dosing, administration, and adverse effects of icatibant are reviewed elsewhere. (See "Hereditary
angioedema: Acute treatment of angioedema attacks", section on 'Bradykinin B2-receptor
antagonist'.)

Plasma — Plasma has been used in the treatment of acute laryngeal attacks and severe
abdominal attacks in both acquired and hereditary angioedema, although the efficacy has not been
formally investigated. Where available, S/D plasma is preferred because the risk of disease
transmission is theoretically lower. If not available, FFP may be given. Plasma contains an array of
complement components, including C1INH.

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Two units is the usual initial dose for treatment of angioedema. This dose can be repeated every two
to four hours until there is clinical improvement. Once the attack begins to subside, further plasma is
not usually required. If a patient has comorbid conditions that increase the risk for volume overload,
then dosing of 10 to 15 mL per kg body weight is recommended instead, with monitoring of volume
status and cardiopulmonary function.

The administration, infection risks, and adverse effects of plasma are reviewed elsewhere. (See
"Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Plasma'.)

Ecallantide — Ecallantide (Kalbitor [brand name]) is an inhibitor of plasma kallikrein that has been
effective in a small number of case reports of patients with C1INH-AAE [11,12]. Kallikrein is the
enzyme that releases bradykinin, the mediator of angioedema, from high molecular weight
kininogen. Ecallantide is approved by the US Food and Drug Administration (FDA) for acute
angioedema attacks in patients with HAE [13]. It is only available in the United States.

During the first open-label trial, the author's group used this drug in two patients with C1INH-AAE,
one of them resistant to pdC1INH, and observed a prompt resolution of symptoms [11]. Both patients
developed a relapse of angioedema within 12 hours, but the symptoms were mild and resolved
spontaneously without need for further treatment.

The dosing, administration, and adverse effects of ecallantide are reviewed elsewhere. (See
"Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Kallikrein inhibitor
(United States only)'.)

Ineffective therapies — Our and others' experience support the view that antihistamines,
glucocorticoids, and epinephrine are not effective in acute treatment of C1INH-AAE [14]. There are no
trials that directly evaluate the use of these therapies in acquired or hereditary angioedema. We
strongly recommend not relying on these drugs to treat angioedema in patients with C1INH
deficiency. In one review of 22 patients, investigators concluded that "in the acute setting, high-dose
glucocorticoids with or without subcutaneous epinephrine seem to be effective, depending on the
severity of symptoms" [15]. However, they did not provide the data to support the statement, and this
conclusion is not consistent with our clinical experience. On the other hand, these therapies should
be considered if there is any uncertainty about the patient's diagnosis because allergic forms of
angioedema do respond to these therapies.

AVOIDANCE OF EXACERBATING FACTORS

Factors that exacerbate or precipitate attacks include physical or psychological stress and certain
medications.

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Medications that can increase the frequency and/or severity of attacks in acquired angioedema
(C1INH-AAE) include the following:

● Estrogen-containing medications, such as hormone replacement therapy and contraceptives

[16].

● Tamoxifen, a selective estrogen receptor modulator (SERM) that has mixed agonist/antagonist
actions on the estrogen receptor. In one reported case, a patient with hereditary angioedema
(HAE) who developed increased episodes on tamoxifen was successfully treated with the
aromatase inhibitor letrozole [17]. If tamoxifen or another SERM is essential to the patient's
therapy, then worsening symptoms of C1INH-AAE may need to be managed by increasing
therapy to prevent angioedema episodes, rather than discontinuing the SERM.

● Angiotensin-converting enzyme (ACE) inhibitors [18]. In contrast, the experience of the author is
that angiotensin II receptor blockers (ARBs) are well-tolerated.

ASSOCIATED DISORDERS

Monitoring for development — If no associated condition is identified initially, we monitor patients by

performing all age-appropriate cancer screening and repeating studies for B cell malignancies
annually. Specifically, we obtain a complete physical examination, a complete blood count (CBC) with
differential, a serum protein electrophoresis and immunofixation, a chest radiograph, and an
abdominal ultrasound. Although there are limited published data regarding the rate at which
disorders are detected over time, the author has personally followed one patient with no apparent
associated disease for over a decade.

Management of identified disorders — Successful treatment of lymphoproliferative disorders that

are identified in a patient with acquired angioedema usually results in reduction of attacks of
angioedema. Two independent case series provide evidence that partial or complete clinical and/or
biochemical remission of acquired angioedema occurs upon treatment of associated
lymphoproliferative diseases [19,20]. The effect of treating other associated disorders is informed by
single case reports [21-23].

In patients with lymphoma, a variety of therapies, including surgery, chemotherapy, and biologic
agents, such as rituximab, have been reported to be helpful in reducing episodes of angioedema
[19,20]. Responses to treatment range from partial to complete (and apparently stable) remission.
However, treatment of the underlying disorder is not indicated in every case, and the risk-benefit
balance should be considered in each patient. It would not be prudent to risk potential adverse
effects to treat a lymphoproliferative disorder that had a very mild course for the sole purpose of

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controlling angioedema attacks, since the latter can often be managed with the therapies discussed
in this review.

Alterations in complement abnormalities are variable following treatment for lymphoma in patients
with acquired angioedema. C1INH levels, C1q, and C4 levels may normalize in concert or
independently. Disappearance of autoantibodies can also occur. We have observed a wide range of
changes in complement studies and autoantibody levels in the patients we manage following
treatment for lymphoma, although we have not detected a consistent pattern [19]. One of the author's
patients had complete reversal of clinical and complement abnormalities but persistence of anti-
C1INH autoantibodies. Such findings highlight the uncertainties regarding the pathogenesis of
acquired angioedema. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology,
pathogenesis, and diagnosis", section on 'Pathogenesis'.)

Monitoring MGUS — Patients with acquired angioedema who are found to have monoclonal
gammopathy of undetermined significance (MGUS) must be followed and evaluated regularly, as
MGUS can transform to a more serious disorder at a rate of approximately 1 percent per year. The
author has followed patients with stable MGUS for over 20 years. It is not known if treatment of
MGUS prior to transformation would impact the patient's outcome. The recommendations for
monitoring are reviewed separately. (See "Clinical course and management of monoclonal
gammopathy of undetermined significance".)

PROPHYLAXIS TO PREVENT ANGIOEDEMA EPISODES

Short-term prophylaxis should always be administered if intubation, oral surgery, or general surgery
is planned. It is often administered prior to lesser dental procedures. Other minimally traumatic
procedures not involving the oral cavity, such as a colonoscopy, may not require prophylaxis,
although it is best to provide prophylaxis if the patient's tolerance to a procedure is unknown. The
approach is identical to that for patients with hereditary angioedema (HAE). Only a few case reports
describe short-term prophylaxis in patients with acquired angioedema specifically, and these have
used either plasma-derived (pdC1INH) or recombinant human C1INH (rhC1INH) concentrates [24,25].

The indications for long-term prophylaxis in patients with acquired angioedema are not well-defined,
and guidelines remain vague. The author's approach is to initiate prophylactic therapy in patients
who cannot control symptoms by "on-demand therapy" and experience several days of disability
each month. The author also administers prophylaxis to patients in whom "on-demand therapy" is
not entirely or consistently effective.

The options for prophylactic therapy in patients with acquired angioedema are the same as those
used in HAE [7,21,26-28]:
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● Antifibrinolytic agents (ie, tranexamic acid [TA])
● Attenuated androgens
● Regular infusions of C1INH concentrate

However, we have concerns about the use of C1INH concentrate for prophylaxis because acquired
angioedema patients sometimes become resistant to it (possibly due to anti-C1INH antibodies), and
we prefer to reserve it for treating acute attacks. Whether regular C1INH infusion increase the levels
of anti-C1INH autoantibody worsening disease course has not been proven, but such possibility
should be considered [29]. (See 'Resistance' above.)

It is the author's approach to start with TA (3 grams daily) [2]. If the patient's episodes of angioedema
stop occurring, the dose of TA may be gradually lowered, although some patients have recurrent
symptoms when this is attempted and need to remain on the full dose indefinitely. If the attacks do
not decrease in number and severity on full-dose TA, the author then changes to danazol (200 mg
daily), adjusting to the lowest effective dose.

Antifibrinolytics — TA is well-tolerated by most patients with acquired angioedema and is available in

many countries [30]. It became available in the United States in oral form in 2009. TA reduces the
frequency and severity of attacks in the majority of patients [2]. As an example, of 13 patients treated
with TA in one series, 8 responded very well and 4 responded partially [7]. Use of TA for the
prevention of angioedema, including dosing and monitoring, is discussed in more detail separately.
(See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term
prophylaxis", section on 'Antifibrinolytics'.)

It is debated whether or not antifibrinolytics carry an increased risk of thrombosis, particularly in

patients with associated malignancies. Until this question is conclusively answered, we coadminister
antithrombotic therapy only to patients with other reasons for increased risk of thromboembolism
(eg, those with malignancies, coronary heart disease, or history of thromboembolic stroke) who also
need long-term TA for acquired angioedema [31]. We have observed thrombotic events in four
patients on antifibrinolytic agents, and the treatment was discontinued. In three of these patients, the
frequency and severity of angioedema recurrences increased substantially after withdrawal of TA
and could not be controlled by on-demand treatment alone or with danazol. Therefore, after complete
recovery from the acute thrombotic events, antifibrinolytic treatment was resumed with concomitant
oral anticoagulants. No further thrombotic events have occurred in these three patients using this
approach for over 10 years [10].

Androgens — Attenuated androgens, such as danazol, stanozolol, and others, control symptoms in

approximately one-half of patients in our clinical experience [7,21,27,28]. Those who respond well to
this therapy sometimes achieve control of symptoms with very low doses and remain on this agent

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for years. However, in the remaining patients, androgens either do not work from the outset or
become ineffective after a period of time [7]. Use of androgens for the prevention of angioedema is
discussed in more detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency):
General care and long-term prophylaxis", section on 'Attenuated androgens'.)

PROGNOSIS

There are no published studies that provide information about the long-term prognosis of patients
with C1INH-AAE. Among the 77 patients the author has followed since 1975, 16 patients have died
since diagnosis [10]. Eleven deaths were not related to C1INH-AAE, and one patient died of laryngeal
edema. Three patients died from complications of the associated lymphoproliferative disease, and
one died due to hemorrhagic complication of hepatitis C virus cirrhosis, possibly acquired during
treatment with plasma-derived C1INH (pdC1INH) in the 1970s (when viral controls for plasma
products were not available).

The risk of asphyxiation due to upper airway closure remains a real and immediate risk for patients
with acquired angioedema because of the limited knowledge of this condition on the part of
clinicians. In the patient who died due to laryngeal edema, an infusion of 1000 units of C1INH
concentrate was started but too late to prevent progression of the swelling to airway closure.
Attempts at endotracheal intubation failed because of massive laryngeal edema, and permanent
anoxic brain damage was already established by the time a tracheotomy was performed. Our overall
experience with 983 patients diagnosed in Italy since 1974 with C1INH-HAE indicates that 63 died, 5
of them for laryngeal edema.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding
hereditary angioedema)".)

SUMMARY AND RECOMMENDATIONS

● Acquired angioedema due to deficiency of C1 inhibitor (C1INH-AAE) is a rare syndrome of

recurrent episodes of angioedema, without urticaria, which is associated with B cell
lymphoproliferative disorders in some patients.

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● Patients should be educated about the risk of fatal laryngeal attacks and instructed on how to
proceed should swelling in the throat develop. Because so few clinicians are familiar with this
disorder, equipping the patient with information about proper treatment is critical. A printable
form is provided (form 1). (See 'Patient education about laryngeal edema' above and 'Written
treatment plan' above.)

● Patients with laryngeal attacks require immediate assessment of the airway. If respiratory
distress or stridor is present, preparations to intubate should be made because even the first-line
therapies take approximately 30 minutes or more to begin working. An expert should manage
the airway, if possible. (See 'Airway management in laryngeal edema' above.)

● For treatment of severe angioedema in patients with C1INH-AAE, we suggest plasma-derived

C1INH (pdC1INH) concentrate (Grade 2C). There is more experience with this therapy than with
any other. Other agents that may be effective based on case reports include the following (table
1):

• Icatibant, a bradykinin B2-receptor antagonist (available in the United States, Europe, and
other countries).

• Ecallantide, a kallikrein inhibitor (available in the United States).

• Recombinant human C1INH (rhC1INH) (available in most of Europe and the United States).

• Plasma (fresh frozen or solvent-detergent treated).

Patients should either be trained to self-administer one of these treatments or have access to
appropriate treatments at the hospitals nearest to the patients' homes. (See 'Pharmacologic
treatment of acute attacks' above.)

● Patients with acquired angioedema can become resistant to C1INH concentrate over time. For
patients with acute angioedema who do not improve in response to an initial dose of C1INH
concentrate, we suggest administering ecallantide or icatibant instead (Grade 2C).

● If an underlying disorder is identified, treatment of that disorder usually reduces the frequency of
angioedema episodes. (See 'Associated disorders' above.)

● We suggest prophylactic therapy for patients with recurrent episodes of laryngeal edema or
angioedema symptoms affecting the gastrointestinal tract or skin, who despite the availability of
on-demand therapies, experience several days of disability per month (Grade 2C). The primary
agents for prevention of attacks are antifibrinolytic agents or attenuated androgens. (See
'Prophylaxis to prevent angioedema episodes' above.)

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ACKNOWLEDGMENT

We are saddened by the death of Marco Cicardi, MD, who passed away in August 2019. UpToDate
wishes to acknowledge Dr. Cicardi's past work as an author for this topic.

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 8110 Version 18.0

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GRAPHICS

Instructions for emergency care of acquired angioedema

Graphic 57664 Version 18.0

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Treatment of acute episodes of angioedema in acquired angioedema (also known as acquired C1 inhibitor
deficiency)

Medication Availability Dosing Precautions

C1 inhibitor concentrate
(plasma-derived)
(Berinert, Berinert P, Cinryze)
In United States: 20 units per kg body weight Do not shake solution, because
Berinert given intravenously over 10 protein will denature. Cinryze is
Cinryze minutes. Symptoms usually not FDA-approved for acute
stabilize in 30 minutes. Second attacks but has efficacy.
Other countries:
dose uncommonly needed but
Berinert P
may be given 30 minutes to 2
Cinryze hours after first dose.

Recombinant C1 inhibitor
Conestat alfa (Ruconest,
Rhucin)
Europe, United States, some
other countries.
50 units per kg body weight for
patients <84 kg. 4200 units (two
vials) for those ≥84 kg. Second
dose rarely needed.
Patients should be screened for
rabbit allergy prior to receiving
with rabbit-specific IgE
immunoassay and should not
receive drug if positive.

Bradykinin B 2 -receptor United States and many other 30 mg slow subcutaneous Caution in patients with
antagonist countries. infusion (because of volume) in unstable angina. Mild injection
Icatibant (Firazyr) Approved in the United States abdominal area. Second dose site reactions are common.
for individuals over the age of needed in about 10% of patients

18 years. and can be given 6 hours after

first dose. Maximum of three
doses in 25 hours.

Kallikrein inhibitor United States only. 30 mg (three doses of 10 mg Rare allergy reaction reported
Ecallantide (Kalbitor) Approved in the United States each) given at three separate usually in <1 hour. Should be

for individuals over the age of sites subcutaneously in administered by a clinician or

16 years. abdomen, upper arm, or thigh nurse in a medical facility
and away from site of equipped to treat anaphylaxis.
angioedema.

Plasma Solvent detergent-treated
plasma (S/D plasma)
(preferred)
Fresh frozen plasma (FFP)
2 units initially. Can be repeated
every 2 to 4 hours, if needed.
Monitor for volume overload in
patients with underlying
conditions predisposing to
volume overload. Theoretical
risk of transmission of blood-
borne pathogens.

The use of the therapies in the table for acquired angioedema (ie, acquired C1 inhibitor deficiency) is extrapolated from hereditary
angioedema. Evidence supporting the use of the agents in the acquired forms of the disease is limited to case reports and clinical
experience. Plasma-derived C1 inhibitor concentrate is the agent with which there is the most clinical experience.  

FDA: US Food and Drug Administration; IgE: immunoglobulin E.

Graphic 99435 Version 9.0

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