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Allergy. 2022;77:1961–1990.
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1961wileyonlinelibrary.com/journal/all
Received: 16 September 2021
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Revised: 22 November 2021
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Accepted: 8 December 2021
DOI: 10.1111/all.15214
GUIDELINES
The international WAO/EAACI guideline for the management
of hereditary angioedema— The 2021 revision and update
Marcus Maurer1,2 | Markus Magerl1,2 | Stephen Betschel3| Werner Aberer4|
Ignacio J. Ansotegui5| Emel Aygören- Pürsün6| Aleena Banerji7| Noémi- Anna Bara8|
Isabelle Boccon- Gibod9| Konrad Bork10 | Laurence Bouillet9|
Henrik Balle Boysen11| Nicholas Brodszki12| Paula J. Busse13| Anette Bygum14,15|
Teresa Caballero16 | Mauro Cancian17| Anthony Castaldo11| Danny M. Cohn18|
Dorottya Csuka19 | Henriette Farkas19 | Mark Gompels20| Richard Gower21|
Anete S. Grumach22| Guillermo Guidos- Fogelbach23| Michihiro Hide24,25|
Hye- Ryun Kang26 | Allen Phillip Kaplan27 | Constance Katelaris28|
Sorena Kiani- Alikhan29| Wei- Te Lei30 | Richard Lockey31| Hilary Longhurst32|
William R. Lumry33| Andrew MacGinnitie34 | Alejandro Malbran35|
Inmaculada Martinez Saguer36| Juan José Matta37| Alexander Nast38 |
Dinh Nguyen39| Sandra A. Nieto- Martinez40| Ruby Pawankar41 |
Jonathan Peter42,43 | Grzegorz Porebski44 | Nieves Prior45| Avner Reshef46 |
Marc Riedl47| Bruce Ritchie48| Farrukh Rafique Sheikh49| William B. Smith50|
Peter J. Spaeth51| Marcin Stobiecki44| Elias Toubi52| Lilian Agnes Varga19 |
Karsten Weller1,2 | Andrea Zanichelli53| Yuxiang Zhi54 | Bruce Zuraw55|
Timothy Craig56
1Institute of Allergology, Charité— Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin,
Germany
2Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, G ermany
3University of Toronto, Toronto, ON, C anada
4Depar tment of Dermatology, Medical University of Graz, Graz, Austria
5Depar tment of Allergy & Immunology, Hospital Quironsalud Bizkaia, Bilbao, Spain
6Center for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
7Division of Rheumatolog y, Allerg y and Immunolog y, Massachusetts General Hospital, Boston, Massachusetts, USA
8Romanian Hereditary Angioedema Exper tise Centre, Mediquest Clinical Research Center, Sangeorgiu de Mures, Romania
9National Reference Center for Angioedema (CREAK), Angioedema Center of Reference and Excellence (ACARE), Grenoble A lpes University Hospital,
Grenoble, France
10Department of Dermatolog y, University Medical Center, Johannes Gutenberg University, Mainz, Germany
11HAE International (HAEi), Skanderborg, Denmark
This is an open access article under the terms of the Creat ive Commo ns Attri butio n- NonCo mmerc ial- NoDerivs License, which permit s use and distribution in
any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made.
© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
Marcus M aurer, Markus Magerl, Ste phen Betschel and Ti mothy Craig cont ributed equally.
Important: As this i s an internation al guideline, n o information is provided regarding th e licensing of the d rugs mention ed for the treatm ent of HAE. It is in th e duty of the tre ating
physici an to adhere to the r elevant local r egulations.
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M AURER Et Al .
12Department of Pediatric Immunology, Childrens Hospit al, Skåne University Hospital, Lund, Sweden
13Icahn School of Medicine at Mount Sinai, New York, NY, USA
14Clinical Institute, University of Southern Denmark, Odense, Denmark
15Depar tment of Clinical Genetics, Odense University Hospital, Odense, Denmark
16Allergy Department, Hospital Universitario La Paz, IdiPaz, CIBERER U754, Madrid, Spain
17Depar tment of Systems Medicine, University Hospital of Padua, Padua, Italy
18Depar tment of Vascular Medicine, Amsterdam UMC/University of Amsterdam, Amsterdam, The Netherlands
19Depar tment of Internal Medicine and Haematology, Hungarian Angioedema Center of Reference and Excellence, Semmelweis University, Budapest, Hungar y
20Clinical Immunology, North Bristol NHS Trust, Bristol, UK
21Marycliff Clinical Research, Principle Research Solutions, Spokane, Washington, USA
22Clinical Immunology, Centro Universitario FMABC, Sao Paulo, Brazil
23Instituto Politécnico Nacional SEPI- ENMH, Mexico City, Mexico
24Department of Dermatology, Hiroshima Citizens Hospit al, Hiroshima, Japan
25Department of Dermatology, Hiroshima University, Hiroshima, Japan
26Depar tment of Internal Medicine, Seoul National Universit y College of Medicine, Seoul, Korea
27Division of Pulmonary, Critical Care, Allerg y and Immunology, Medical university of South C arolina, Charleston, South Carolina, USA
28Depar tment of Medicine, Campbelltown Hospital and Western Sydney Universit y, Sydney, NSW, Australia
29Department of Immunology, Bar ts Health NHS Trust, London, UK
30Division of Allergy, Immunology, and Rheumatolog y, Department of Pediatrics, Mackay Memorial Hospital, Hsinchu, Taiwan
31Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, Universit y of South Florida, Tampa, Florida, USA
32Depar tment of Immunology, Auckland District Health Board and Department of Medicine, University of Auckland, Auckland, New Zealand
33Internal Medicine, Allergy Division, University of Texas Health Science Center, Dallas, Texas, USA
34Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
35Unidad de Alergia, Asma e Inmunología Clínica, Buenos Aires, Argentina
36Pediatrics, Haemophilia Centre Rhine Main (HZRM), Moer felden- Walldorf, Germany
37H. Especialidades C.M.N.SX XI, I.M.S.S., México City, Mexico
38Department of Dermatology, Venereolog y and Allergology, Division of Evidence- Based Medicine Charité - Universitätsmedizin Berlin, corporate member of
Free University of Berlin, Humboldt Universit y of Berlin, and Berlin Institute of Health, Berlin, Germany
39Respiratory, Allergy and Clinical Immunology Unit, Internal Medicine Department, Vinmec Healthcare System, College of Health Sciences, V inUniversit y,
Hanoi, Vietnam
40Genetic Unit of Nutrition, National Institute of Pediatrics, Mexico City, Mexico
41Depar tment of Pediatrics, Nippon Medical School, Tokyo, Japan
42Division of Allergy and Clinical Immunology, University of Cape Town, Cape Town, South Africa
43Allerg y and Immunology Unit , University of Cape Town Lung Institute, Cape Town, South Africa
44Department of Clinical and Environment al Allergology, Jagiellonian University Medical College, Krakow, Poland
45Allergy, Hospit al Universitario Severo Ochoa, Madrid, Spain
46Angioderma Center, Barzilai University Medical Center, Ashkelon, Israel
47Division of Rheumatology, Allergy and Immunology, University of California San Diego, L a Jolla, California, USA
48Department s of Medicine and Medical Oncology, University of Alber ta, Edmonton, AB, Canada
49Section of Adult Allergy & Immunolog y, Depar tment of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
50Clinical Immunology and Allergy, Royal Adelaide Hospital, Adelaide, SA, Australia
51Institute of Pharmacology, University of Bern, Bern, Switzerland
52Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Affiliated with Rappaport Faculty of Medicine, Technion- Israel Institute of Technology,
Haifa, Israel
53Depar tment of Internal Medicine, ASST Fatebenefratelli Sacco, Ospedale Luigi Sacco- University of Milan, Milan, Italy
54Department of Allerg y and Clinical Immunology, Bejing Union Medical College Hospit al & Chinese Academy of Medical Sciences, Bejing, China
55University of C alifornia, San Diego, San Diego, C alifornia, USA
56Depar tment s of Medicine and Pediatrics, Penn State University, Hershey, Pennsylvania, USA
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MAURER Et A l.
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Hereditary angioedema (HAE) is a rare genetic disease that mani-
fests with episodes of cutaneous or submucosal edema, most com-
monly affecting the skin, the abdomen, and the upper respiratory
tract. HAE is a serious global health problem, for patients and their
families. Evidence- based recommendations are needed to inform
and guide clinical decision makers.
The most common cause of HAE involves either a deficiency
(type 1) or dysfunction (type 2) of C1 inhibitor (C1- INH),1,2 which
leads to the overproduction of bradykinin and activation of bradyki-
nin B2 receptors. This increases vascular permeability and results in
angioedema attacks.3
This is the second revision and update of the international
guideline for the diagnosis and management of HAE,4,5 which
was developed by the World Allergy Organization (WAO) in col-
laboration with the European Academy of Allergy and Clinical
Immunology (EAACI). This revised and updated WAO/EAACI
guideline on the diagnosis and management of HAE differs from
previous versions and other guidelines, consensus reports, and po-
sition papers6– 12 in th a t it builds on th e mos t rece ntl y pu b lish ed ev -
idence on HAE and the expertise and experience of a global panel
of experts. Published evidence was identified by a structured and
incremental review and assessed systematically and transparently
for its quality, considering the Appraisal of Guidelines Research
and Evaluation (AGREE II) Instrument and the methods suggested
by the Grading of Recommendations Assessment, Development
and Evaluation (GRADE) working group.13 In line with the GRADE
approach, this revision and update of the guideline acknowledges
that evidence alone is insufficient to guide treatment decisions,
and it incorporates values and preferences as well as clinical cir-
cumstances and expertise.
A global and diverse panel of expert clinicians, scientists, HAE
patients and patient advocates was assembled for the development
of this update and revision of the guideline. The expert panel com-
position reflects the global nature of this guideline, with geographi-
cal and gender balance of its members. Given that the management
of patients with angioedema requires an interdisciplinary approach,
specialists from different fields were involved including allergology,
dermatology, emergency medicine, gastroenterology, hematology,
immunology, internal medicine, otolaryngology, and pediatrics.
The efforts of the expert panel were coordinated by the mem-
bers of the steering committee (MMau, MMag, SB and TC). All physi-
cian/clinician panel members needed to be actively treating patients
with angioedema and/or be involved in research directly related to
angioedema. All expert panel members provided financial disclosure.
This guideline is unique in that global involvement was ensured by
the participation of international experts from five continents and 28
different countries. All expert panel members obtained a mandate to
be the delegate of a national or international scientific society, which
confirmed in writing that it nominated the expert as its delegate, and
that it endorsed the guideline and will help with its dissemination.
Correspondence
Marcus Maurer and Markus Magerl,
Institute of Allergology, Charité–
Universitätsmedizin Berlin, Berlin,
Germany; and Fraunhofer Institute for
Translational Medicine and Pharmacology
ITMP, Immunology and Allergology, Berlin,
Germany.
Emails: marcus.maurer@charite.de
(Marcus Maurer); markus.magerl@charite.
de (Markus Magerl)
Funding information
Funding and support of the development
of this update and revision of the guideline
came from WAO and EA ACI. This revision
and update of the guideline benefitted
from the help and support of the GA2LEN/
HAEi net work of Angioedema Centers
of Reference and Excellence (ACARE,
https://acare - netwo rk.com)
Abstract
Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis
and effective therapy are critical. This revision and update of the global WAO/EAACI
guideline on the diagnosis and management of HAE provides up- to- date guidance for
the management of HAE. For this update and revision of the guideline, an international
panel of experts reviewed the existing evidence, developed 28 recommendations, and
established consensus by an online DELPHI process. The goal of these recommenda-
tions and guideline is to help physicians and their patients in making rational decisions
in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunc-
tional C1 inhibitor (type 2), by providing guidance on common and important clinical
issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients
receive prophylactic on top of on- demand treatment and what treatments should be
used? (3) What are the goals of treatment? (4) Should HAE management be different
for special HAE patient groups such as children or pregnant/breast- feeding women?
and (5) How should HAE patients monitor their disease activity, impact, and control?
It is also the intention of this guideline to help establish global standards for the man-
agement of HAE and to encourage and facilitate the use of recommended diagnostics
and therapies for all patients.
KEYWORDS
C1 inhibitor, DELPHI, disease control, guideline, hereditary angioedema, management
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M AURER Et Al .
Most of these experts were nominated by Allergy and Immunology
Associations of different countries affiliated to the WAO.
The goal of this guideline is to provide clinicians and their patients
with guidance that will assist them in making rational decisions in the
management of HAE, primarily HAE type 1 and type 2 (HAE- 1/2).
The reason to not focus upon HAE with normal C1 inhibitor is that,
for most patients, there is not a diagnostic test. In addition, genetic
testing can only identify a small subset of those suspected to have
the disease. Lastly, in some of the newly identified genetic abnormal-
ities, bradykinin's role as the main mediator of the edema is question-
able. This suggests re- evaluation of HAE with normal C1 inhibitor is
required. To this end, 28 recommendations (numbered and given in
framed boxes) were developed, of which seven are new, 13 are re-
vised, and eight are unchanged, compared with the previous version
of this guideline. Key questions covered by these recommendations
include (1) How shou ld HA E be de fine d and classi fied? (2) How sho uld
HA E b e dia gnos ed? (3) Ho w shou ld HA E pati ent s be trea t ed, an d wha t
treatment options should be used? (4) What are the goals of treating
HAE? (5) Should HAE management be different for special patient
groups such as children and pregnant/breast- feeding women? and (6)
How should HAE patients monitor their disease activity, impact, and
control? It is important to note that access to modern diag nostics and
therapies for HAE patients is limited in certain areas of the world.14
It is the intention of this revision and update of the guideline to help
change this and to encourage and facilitate the global use of recom-
mended diagnostics and therapies for all patients.
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recommendations
All authors were assigned to one of four taskforces, each dedicated
to a defined HAE subject area: (1) nomenclature and diagnosis, (2)
on- demand therapy, (3) prophylaxis, and (4) special populations and
management considerations. First, the taskforces were asked to re-
view the existing recommendations from the previous WAO/EAACI
guideline on HAE in their subject area and to assess these recom-
mendations for accuracy and relevance to current practice.4,5 The
taskforce members were then asked to critically review the wording
and to update it if is necessary. The taskforces were also asked to
consider if new recommendations were needed and to develop them
accordingly. The task forces searched and reviewed the literature re-
lated to each recommendation.
The recommendations provided by this guideline use standard-
ized wording, ie, “we recommend” or “we suggest”. “We recommend”
reflects a strong recommendation, implying: (1) that all or almost all
informed people would make that choice, (2) that less time is needed
for health care providers to make decisions and more time is avail-
able for overcoming barriers to their implementation and adherence,
and (3) that, in most clinical situations, the recommendation may be
adopted as policy. “We suggest” reflects a weak recommendation
implying: (1) that most informed people would make that choice, but
a substantial number would not, (2) that health care providers and
patients will need to devote more time on the process of decision
making as compared to strong recommendations, and (3) that policy
making may require the use of further resources. Importantly, this
guideline acknowledges and aims to mitigate the disparity in health
care resources for the management of HAE between countries. The
recommendations in this guideline are meant to inform an optimal ap-
proach to HAE, by developing global standards for the diagnosis and
treatment of HAE. This guideline will be in force for the next 4 years
after its publication, when it will be updated and revised. Novel in-
sights and impr ov ed tools, diagnostics and treatme nt s that mater ialize
before the next revision and update of this guideline should be used
to improve the management of HAE as soon as they become available.
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For the update and revision of recommendations from the previous
version of the guideline, a systematic search of the literature from
1 June 2016 was performed. For new and additional recommenda-
tions (recommendations 3, 11, 13, 16, 17, 19, and 25), as well as for
pre- existing recommendations with a revised wording (recommen-
dations 1, 2, 4, 5, 7, 9, 10, 12, 14, 18, 21, 22, and 28), a complete
search from 1 January 1985 was performed. Relevant information
was extracted from the publications identified, and their quality was
assessed with the help of a standardized worksheet as described be-
fore.4,5 Each manuscript/trial included in the guideline was evaluated
with regard to its methodological quality (Table 1), and the literature
search and evaluation process continued during the review process
and manuscript development and was continuously updated until
19 July 2021.
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Consensus was established as described in the previous revision of
the WAO/EAACI guideline for HAE, with the exception that an on-
line DELPHI process was used rather than a consensus conference,
due to the COVID- 19 pandemic. The DELPHI process was facilitated
TAB LE 1 Evidence grades
A. Randomized, double- blind clinical trial of high quality (eg, sample
size calculation, flow char t of patient inclusion, intention- to- treat
(ITT) analysis and sufficient sample size)
B. Randomized clinical trial of lesser quality (eg, only single- blind,
limited sample size: at least 15 patients per study arm)
C. Comparative trial with severe methodological limitations (eg,
not blinded, very small sample size and no randomization) or
large retrospective observational study, large open- label- study,
registry data
D. Adapted from existing consensus document or statement based
on exper t opinion voting during consensus conference, evidence
non A– C
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MAURER Et A l.
by KW, with the help of dedicated software (Welphi®; decisioneyes,
Lisbon, Portugal). The DELPHI process is a validated approach to
evaluate and to refine group opinion through iterative rounds of
questioning. The anonymity of this process is key and enables views
to be changed over the course of the process, while ensuring that
opinions are considered equally.15
The DELPHI panel comprised the voting members of the expert
panel including the members of the steering committee. The Delphi
process was performed in two rounds, the final round of which
achieved consensus on all 28 recommendations of the guideline.
In round 1 (22 days from 11 November to 3 December 2020) and
round 2 (15 days from 29 January to 11 February 2021), 53 and
52 participants took part, respectively. All participants voted on all
suggested recommendations provided by the taskforces; accord-
ingly, the absolute number of voters was 53 or 52 for all recom-
mendations. In round 1, recommendations developed by the four
task forces were evaluated by all participants with the two options
‘I agree to the text and the strength of the recommendation’ or ‘I
do not agree’. In case participants did not agree, they were asked
to make a specific suggestion for an alternative recommendation
wording together with a justification for the suggested change. All
participants had the opportunity to provide additional feedback
with free- text responses. Respondents were asked to consider their
clinical experience, the patient management approach followed in
their practice, and their broader knowledge on HAE. The steering
committee members revised the recommendations based on the
results and feedback obtained in round 1 and provided feedback to
all comments made.
In round 2, to gain consensus, respondents were asked if they
agree or disagree with each revised recommendation. Strong con-
sensus and consensus were defined, a priori, as agreement by at least
>90% and >75% of respondents, and percentage agreement was re-
corded for each recommendation.16 Again, the steering committee
members addressed the comments made by expert panel members
and provided to all of them. The input of expert panel members from
both DELPHI rounds was used to develop the final version of the
manuscript, which was consented for publication by all.
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Each recommendation is shown in a box, which contains (1) the rec-
ommendation, (2) the level of consensus reached, and (3) the level of
quality of the data that support the recommendation.
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CLASSIFICATION
Angioedema is characterized by a transient vascular reaction of deep
dermal/subcutaneous tissues or mucosal/submucosal tissues with
localized increased permeability of blood vessels resulting in tissue
swelling.17– 21 Angioedema can be mediated by bradykinin and/or
TAB LE 2 Classification of angioedema
Bradykinin- induced AE Mast cell mediator– induced AE Unknown mediator
C1- INH deficiency/defect C1- INH normal IgE- mediated non- IgE- mediated Idiopathic AE
Inherited Acquired Inherited Acquired
H A E - 1
H A E - 2
A A E - C 1 - I N H HAE- nC1- INH (HAE- FXII, HAE- PLG, HAE-
KNG1, HAE- HS3ST6, HAE- ANGPTI+,
HAE- MYOF+, HAE- UNK)
A C E I - A E
Other drug- induced AE*
Angioedema with anaphylaxis
Angioedema with or without wheals
(Urticaria)
Angioedema with or
without wheals
(Urticaria)
Note: HAE- 1: hereditary angioedema due to C1- inhibitor deficiency; HAE- 2: hereditary angioedema due to C1- inhibitor dysfunction; A AE- C1- INH: acquired angioedema due to C1- inhibitor deficiency;
HAE- nC1- INH: hereditary angioedema with normal C1- Inhibitor levels, either due to a mutation in F XII (Factor 12), ANGPT1 (angiopoietin- 1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin) and
HS3ST6 (heparan sulfate- glucosamine 3- O- sulfotransferase 6) or unknown (UNK). + HAE- ANGPT1 and HAE- MYOF are due to mutations involving the vascular endothelium and the role of bradykinin as
mediator of angioedema symptoms seems to be an indirect or conditional one. ACEI- AE angiotensin- conver ting enzyme inhibitor- induced angioedema, * other drugs like angiotensin II receptor blockers,
gliptins, neprilysin inhibitors or tissue plasminogen activators are thought to potentially induce bradykinin- mediated AE.
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M AURER Et Al .
mast cell mediators including histamine (Table 2).22– 26 Bradykinin-
mediated angioedema is either hereditary or acquired. Hereditary
angioedema (HAE) can be due to a deficiency/defect of C1 inhibitor
(C1- INH) or other mechanisms (Table 2).27– 2 9 Different forms of he-
reditary angioedema (HAE) are currently recognized and genetically
identifiable: (1) HAE due to C1- INH deficiency (Type 1 HAE, HAE- 1),
characterized by low antigenic and functional C1- INH levels; (2) HAE
due to C1- INH dysfunction (Type 2 HAE, HAE- 2), characterized by
normal (or elevated) antigenic but low functional C1- INH levels,1,2
(3) HAE with mutation in the factor XII gene (HAE- FXII)30 ,31; (4)
HAE with mutation in the angiopoietin- 1 gene (HAE- ANGPT1)32; (5)
HAE with mutation in the plasminogen gene (HAE- PLG),33 (6) HAE
with mutation in the kininogen 1 gene (HAE- KNG1),34 (7) HAE with
mutation in the myoferlin gene (HAE- MYOF),35 and (8) HAE with
mutation in the heparan sulfate 3- O- sulfotransferase 6 gene (HAE-
HS 3 S T6). 36 In addition, some patients have HAE due to unknown
mutations (HAE- UNK). The different forms of HAE share some clini-
cal features and, possibly, therapeutic options.3 7,3 8
There are several types of bradykinin- mediated acquired
angioedema. Underlying causes include acquired C1- INH de-
ficiency with low C1 inhibitor (AAE- C1- INH), and angiotensin-
converting enzyme (ACE) inhibitors induced angioedema (ACEI- AE)
(Table 2).3 9 – 4 4 These types of angioedema share some clinical fea-
tures and treatment options with HAE.
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HAE- 1/2 is a rare autosomal dominant disease that is estimated
to affect, globally, 1 in 50,000 individuals.4 5 – 4 8 HAE- 1/2 is caused
by a mutation in the SERPING1 gene, which codes for C1- INH.49
Currently, more than 700 different SERPING1 variants are known
to be linked to HAE- 1/2.50 In approximately 20%– 25% of pa-
tients, a de novo mutation of SERPING1 is responsible for the
disease.5 1 – 5 3
C1- INH is a serine protease inhibitor (SERPIN) and the major
inhibitor of several complement proteases (C1r, C1s, and mannose-
binding lectin- associated serine protease [MASP] 1 and 2) and
contact- system proteases (plasma kallikrein and coagulation factor
XIIa) as well as a relatively minor inhibitor of the fibrinolytic prote-
ase plasmin.5 4 – 5 6
The primary mediator of swelling in HAE- 1/2 is bradykinin,3 a
low molecular weight nonapeptide that is generated when active
plasma kallikrein cleaves high molecular weight kininogen (HMWK).
Bradykinin is rapidly metabolized by endogenous metalloproteases
including angiotensin- converting enzyme (ACE). Plasma kallikrein
is activated from its inactive zymogen prekallikrein by the prote-
ase factor XII, which autoactivates upon contact with negatively
charged surfaces. Both, plasma kallikrein and factor XII are in-
hibited by C1- INH. Increased vascular permeability and swelling
induced by bradykinin are primarily mediated through the bradyki-
nin B2 receptor.5 6 – 6 1
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C1 inhibitor
HAE with normal C1- INH (HAE- nC1- INH) is a group of very rare
diseases. The clinical appearance of HAE- nC1- INH largely resem-
bles that of HAE- 1/2.38 Six types of HAE- nC1- INH are currently
recognized, based on underlying mutations of (1) factor XII (FXII),
(2) angiopoietin- 1 (ANGPT1), (3) plasminogen (PLG), (4) kininogen 1
(KNG1), (5) myoferlin (MYOF), and (6) heparan sulfate- glucosamine
3- O- sulfotransferase 6 (HS3ST6).30– 36 However, in many patients
with HAE- nC1- INH, no gene mutation can be found, and the
pathogenesis remains to be characterized in detail. There is clinical
evidence that bradykinin may play a major role in most types of HAE-
nC1- INH, primarily in patients with HAE- FXII and HAE- PLG.62,6 3
HAE- ANGPT1 and HAE- MYOF are due to mutations involving the
vascular endothelium.35 Although HAE- nC1- INH shares some clini-
cal features and, possibly, therapeutic options with HAE- 1/2, this
guideline focuses on HAE- 1/2.
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HAE- 1/2 should be suspected when a patient presents with a his-
tory of recurrent swelling of the skin (extremities, face and genitals),
gastrointestinal attacks (painful abdominal cramps and/or laryngeal
ed ema). Susp ici on of HAE- 1/2 is fu r the r sus pect ed wh en patie nts re -
port any or all of the following: (1) a positive family history (although
this may not be present in up to 25% of patients), (2) onset of symp-
toms in childhood/adolescence, (3) recurrent and painful abdominal
symptoms, (4) occurrence of upper airway edema, (5) failure to re-
spond to antihistamines, glucocorticoids, omalizumab or epineph-
rine, (6) presence of prodromal signs or symptoms before swellings
and (7) the absence of wheals. Suspicion of HAE- 1/2 should prompt
laboratory investigations to support the diagnosis of HAE- 1/2.10,64,65
Measurements of serum/plasma levels of C1- INH function, C1-
INH protein, and C4 are used to diagnose HAE- 1/2 (Recommendation
1, Figure 1). With th e com bined us e of th e se th ree tes ts, th e dia gnos-
tic accuracy for identifying HAE- 1/2 is very high, higher than with
the use of any of the three alone.6 6– 69 This guideline acknowledges
that the availability and quality of tests for C1- INH function, C1- INH
protein, and C4 vary throughout the world, necessitating physicians
in some countries to adapt their own diagnostic approach (eg, the
sensitivity of a C4 test can be increased by drawing blood during
an emerging attack, but without improving specificity). In countries
where recommended diagnostic tests are not available, these guide-
lines should be used to advocate to health authorities to fund the
appropriate diagnostic testing to decrease mortality and morbidity
associated with HAE.14
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MAURER Et A l.
In HAE- 1, which comprises about 85% of HAE- 1/2 patients, both
the concentration and function of C1- INH are low (<50% of nor-
mal) (Table 3). In HAE- 2, C1- INH concentrations are either normal
or elevated, whereas C1- INH function is reduced (<50% of normal).
C4 levels are usually low in HAE- 1/2 patients, but the sensitivity and
specificity of C4 as a marker for HAE are limited.66,67,69– 71 Because
of this, its use for screening patients and its use as only parameter to
diagnose HAE- 1/2 are not recommended. Complement C3 levels are
expected to be normal in HAE, and testing is not helpful. Sequencing
of the SERPING1 gene can be supportive in the diagnostic workup of
some HAE- 1/2 patients (including prenatal diagnosis); however, bio-
chemical C1- INH testing is effective and less expensive than genetic
testing.70 DNA sequencing may miss mutations such as those creating
cryptic splice sites. Genetic testing may be relevant in particular cases
such as mo saici sms in orde r to allow for correct gene tic couns eli ng.72,73
RECOMMENDATION 1
We recommend that all patients suspected to have HAE are
assessed for blood levels of C1- INH function, C1- INH protein,
and C4.
92% agreement, evidence level D
Test results that point to HAE- 1/2 should be confirmed,
ie, testing should be repeated, ideally in a certified laboratory
(Recommendation 2). The same is true for inconsistent results or
results in contradiction to the phenotype.68 HAE implicates nu-
merous and life- long consequences, for patients and their fam-
ilies; so, its diagnosis should be based on confirmed test results
(Figure 1). Tests for C1- INH, by many laboratories, are performed
infr eque ntl y, whic h run s the ri sk of fals e- po sit ive and fal se- nega tiv e
results, which is mitigated by repeat testing. More robust tests are
under development.71 The recommendation to repeat testing for
C1- INH function, C1- INH protein, and C4 refers only to the initial
diagnosis of HAE. There is no indication for repeated testing once
the diagnosis has been established. Of note, confirmation of HAE
by repeat testing, in patients who tested positive, must not delay
effective treatment.
RECOMMENDATION 2
We suggest that testing for C1- INH function, C1- INH protein, and
C4 is repeated in patients who test positive, to confirm the
diagnosis of HAE- 1/2.
87% agreement, evidence level D
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HAE
The differential diagnoses of HAE- 1/2 include HAE with normal C1
inhibitor, bradykinin- mediated types of acquired angioedema such
as AAE- C1- INH and ACEI- AE, and mast cell- mediated types of ac-
quired angioedema, such as angioedema in patients with chronic
spontaneous urticaria without wheals and allergic angioedema, as
well as idiopathic acquired angioedema (Table 2).22,52,74 Because the
pathophysiology and the management of these diseases are differ-
ent from those of HAE- 1/2, it is important to determine the correct
diagnosis.
Using laboratory tests, HAE with normal C1 inhibitor can cur-
rently only be diagnosed by genetic testing, which is becoming
increasingly available. In patients with normal C1- INH levels and
function suspected to have HAE, genetic testing should be per-
formed (Recommendation 3). Currently, this should include testing
for HAE with mutation in the factor XII gene (HAE- FXII), HAE with
mutation in the angiopoietin- 1 gene (HAE- ANGPT1), HAE with mu-
tation in the plasminogen gene (HAE- PLG), HAE with mutation in
the kininogen 1 gene (HAE- KNG1), HAE with mutation in the my-
oferlin gene (HAE- MYOF), and HAE with mutation in the heparan
sulfate 3- O- sulfotransferase 6 gene (HAE- HS3ST6).30– 36 Additional
mutations are likely to be identified in the future and should be in-
cluded in the genetic diagnostic workup for HAE.75 This guideline
works with the intention that recommended diagnostic procedures,
eg, genetic testing, should be used where available and that other
options should be considered where recommended procedures are
not available. Family history is an important tool for identif ying pa-
tients with HAE- nC1- INH.76
RECOMMENDATION 3
We recommend that patients who are suspected to have HAE and
have normal C1- INH levels and function are assessed for known
mutations underlying HAE- nC1- INH
91% agreement, evidence level D
AAE- C1- INH occurs less frequently than HAE- 1/2. AAE- C1- INH
symptoms are similar to those of HAE- 1/2, and the basic diagnos-
tic laboratory profile (C1- INH function, C1- INH protein and C4) is
indistinguishable from HAE- 1. Differences include onset at later
age, underlying diseases such as lymphoma or benign monoclonal
gammopathy (MGUS), occasional constitutional symptoms (B symp-
toms), and often decreased C1q levels.39,44,77,78 C1q level should be
measured to investigate patients for AAE- C1- INH, especially those
with new onset of angioedema after the age of 30 years and a neg-
ative family history. C1q is nearly always normal in HAE.44 C1q is
low in 75% of patients with AAE- C1- INH.79 C1q may be normal in
AAE- C1- INH, particularly in patients taking anabolic androgens.
Many patients with AAE- C1- INH have autoantibodies that inacti-
vate C1- INH.7 7,8 0
Patients who are diagnosed with ACEI- AE should be tested for
HAE- 1/2, as the occurrence of angioedema attacks after the initia-
tion of treatment with an ACE inhibitor may point to previously as-
ymptomatic HAE.81 Angioedema attacks in patients with ACEI- AE
inhibitors are thought to be bradykinin- mediated.38,82– 85
Recurrent mast cell- mediated angioedema is frequently associ-
ated with intensely pruritic wheals (hives) in patients with chronic
spontaneous urticaria (CSU). Some CSU patients do not develop
wheals and exclusively have angioedema.24, 86 Importantly, CSU is
a common disease, which can also affect HAE patients.8 7,8 8 The oc-
currence of wheals, therefore, does not necessarily exclude HAE,
and the absence of wheals does not exclude mast cell- mediated
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M AURER Et Al .
angioedema.89 Nonsedating antihistamines, at standard or higher
than standard doses, alone or in combination with omalizumab or
immune modulators such as cyclosporine can prevent wheals and
angioedema in CSU patients.86,9 0 Because mast cell- mediated an-
gioedema is far more common than HAE- 1/2, on- demand ther-
apy with antihistamines and, if necessary, with epinephrine and
corticosteroids, is indicated when the diagnosis is not yet deter-
mined and the history seems to be inconsistent with HAE.9 1– 93
|
ATTAC K S
HAE attacks of the upper airways can result in asphyxiation.9 4 – 9 7
Abdominal attacks are painful and debilitating.9 8 – 1 0 0 Peripheral
attacks such as those of hands or feet result in impaired func-
tion.101 All of these consequences of HAE attacks can be mini-
mized by on- demand treatment,102,103 and on- demand treatment
should, therefore, be considered to be used to treat all attacks
(Recommendation 4).
RECOMMENDATION 4
We recommend that all attacks are considered for on- demand
treatment.
98% agreement, evidence level D
On- demand treatment of attacks that affect or that may affect
the upper airway is mandator y (Recommendation 5).104– 106
FIGURE 1 Diagnostic workup in patients suspected to have HAE. HAE- 1: hereditary angioedema due to C1- inhibitor deficiency; HAE- 2:
hereditary angioedema due to C1- inhibitor dysfunction; AAE- C1- INH: acquired angioedema due to C1- inhibitor deficiency; HAE- nC1- INH:
hereditary angioedema with normal C1- inhibitor levels, either due to a mutation in ANGPT1 (angiopoietin- 1), PLG (plasminogen), KNG1
(kininogen), MYOF (myoferlin) and HS3ST6 (heparan sulfate- glucosamine 3- O- sulfotransferase 6) or unknown (UNK). ACEi- AE angiotensin-
converting enzyme inhibitor- induced angioedema, * other drugs like angiotensin II receptor blockers, gliptins, neprilysin inhibitors or tissue
plasminogen activators might induce bradykinin- mediated
TAB LE 3 Typical diagnostic laboratory profile of HAE- 1 and
HAE- 2 patients
C1- INH
function
C1- INH
protein level
C4 protein
level
H A E - 1 ↓ ↓ ↓
H A E - 2 ↓N/↑↓
Note: The most straightforward parameter is the assessment of C1- INH
function, which is low in HAE- 1 and 2. For daily routine diagnostic
purposes, three commercial test kits are available. The read outs are
either by chromogenic substrates or the formation of C1- INH- C1s
complexes. For apparent C1- INH function, the read out matters. Only
skilled laboratories can provide correct interpretation of results. In
HAE- 1, the concentration of the inhibitor y protein is low (<50% of the
normal mean), while in HAE- 2 the concentration is normal or elevated.
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MAURER Et A l.
RECOMMENDATION 5
We recommend that any attack affecting or potentially affecting
the upper airway is treated.
100% agreement, evidence level C
Early on- demand treatment of HAE attacks with intravenous- C1-
INH, ecallantide or icatibant provides a better treatment response
than late treatment, and HAE attacks should, therefore, be treated
as early as possibl e (Recommen dation 6).107– 110 E arl y treatme nt is as-
sociated with a shor ter time to resolution of symptoms and shorter
total attack duration regardless of attack severity.110,111 As early
treatment is facilitated by self- administration, all patients with HAE-
1/2 should be considered for home therapy and self- administration
training. In many patients, a significant number of attacks are pre-
ceded by prodromal symptoms, and in some, this may be an oppor-
tunity to treat before an attack occurs. The specificity of prodromes
is still not known, and this may lead to over usage of on- demand
therapy.11 2– 11 5 All C1- INH concentrates and icatibant are licensed
for self- administration, although approved product indications vary
around the world.116– 120
RECOMMENDATION 6
We recommend that attacks are treated as early as possible.
100% agreement, evidence level B
For HAE- 1/2, icatibant, ecallantide and intravenous C1-
INH are the recommended on- demand treatments of choice
(Recommendation 7).121– 126 Where these first- line therapies are not
available, attacks should be treated with solvent detergent- treated
plasma (SDP). If SDP is not available, attacks should be treated with
fresh frozen plasma (FFP), where safe supply is available.127– 129 We
advise against the use of antifibrinolyt ic s (eg, tranexamic acid) or an-
drogen s (eg, danazo l) for on- dema nd tr eatme nt of HAE atta cks ,13 0 as
these drugs show no or only minimal benefit.
|
Treatment with plasma- derived or recombinant C1- INH replaces
the deficient/dysfunctional protein in HAE- 1/2 patients. Exogenous
C1- INH acts on the same targets as endogenous C1- INH. Treatment
results in an increase of the plasma levels of C1- INH and helps to
regulate all cascade systems involved in the production of brady-
kinin during attacks.105,122,131– 133 One unit of C1- INH concentrate
corresponds to the mean quantity of C1- INH present in 1 ml of fresh
normal plasma. For on- demand treatment, only the intravenous ap-
plication of C1- INH is effective.134 – 136
Plasma- derived C1- INH (pdC1- INH) is obtained by separat-
ing C1- INH from cryodepleted human plasma by adsorption and
precipitation, purification, pasteurization and virus filtration. Two
pdC1- INH concentrates are available for on- demand treatment of
HAE- 1/2, Berinert (CSL Behring) and Cinryze (Takeda). Approved
product indications vary around the world. The mean plasma half- life
of pdC1- INH is longer than 30 h.134– 138 The safety and tolerability of
all available pdC1- INH are good, and few adverse events have been
reported. The risk of allergic reactions is negligible. Modern pdC1-
INH use has neither been associated with transmission of hepatitis B
or C nor human immunodeficiency viruses.1 3 9 – 1 4 2
Ruconest (Pharming) is the only available recombinant human
C1- INH (rhC1- INH). Its mode of action is identical to that of pdC1-
INH. RhC1- INH is indicated for on- demand treatment of all types
of HAE attacks in adults and children (2 years or older).125, 143 It is
derived from the milk of transgenic rabbits using a 3- step purifica-
tion procedure including cation- exchange chromatography, anion-
exchange chromatography and affinity chromatography. It appears
that differential glycosylation of Ruconest relative to the human
protein decreases the plasma half- life to approximately 3 h.144– 146
Safety data from controlled and uncontrolled studies with rhC1- INH
support a favorable safety profile. Transmission of human viruses is
not a concern.147– 149
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inhibitor ecallantide
The kallikrein inhibitor ecallantide (Kalbitor; Takeda) is licensed only
in the United States and a few Latin American countries for the on-
demand treatment of all types of HAE attacks in HAE- 1/2 patients
aged 12 years and older.118,150 Inhibition of kallikrein activity inhibits
the cleavage of high- molecular weight kininogen to bradykinin as well
as the further activation of FXIIa, halting the positive feedback mech-
anism leading to additional kallikrein production. Ecallantide is a 60-
amino acid recombinant protein produced by expression in the yeast
Pichia pastoris and has a plasma half- life of 2 h. The main safety con-
cern is potentially serious hypersensitivity reactions, including ana-
phylaxis, which was reported in 3%– 4% of treated patients. The drug,
therefore, should only be administered by a health care professional
with appropriate medical support to manage anaphylaxis.118,123 ,151,152
|
receptor antagonist icatibant
Bradykinin binds to and stimulates the bradykinin B2 recep-
tor, thereby mediating vasodilatation and increased capillary
permeability.153– 155 Icatibant (Firazyr; Takeda), a 10- amino acid syn-
thetic peptide, is a specific and selective competitive antagonist of
the bradykinin B2 receptor and prevents binding of bradykinin to
its receptor. Icatibant is indicated for self- administered on- demand
treatment of all types of HAE attacks in adults and children.120 It
has a plasma half- life of 1– 2 h. By far the most attacks resolve with
one injection of icatibant.156 The safety and tolerability of icatibant
are good, although transient local injection site reactions (erythema,
wheal, pruritus and burning sensation) may occur. Allergic reactions
have not been reported.121,157– 159
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M AURER Et Al .
RECOMMENDATION 7
We recommend that attacks are treated with either intravenous C1
inhibitor, ecallantide or icatibant
96% agreement, evidence level A
The clinical course of HAE attacks is unpredictable. Mortality
due to laryngeal angioedema occurs, and extreme caution is essen-
tial.97,104– 106 Laryngeal HAE attacks should be considered as medical
emergencies. Rapid treatment with an effective HAE on- demand
medication is essential in addition to preparing for emergency air-
way management procedures if respiratory compromise develops.
Intubation or surgical intervention, after the injection of on- demand
medication, should be considered early in all progressive HAE at-
tacks affecting the upper airway (Recommendation 8).160,161
RECOMMENDATION 8
We recommend that intubation or surgical airway intervention is
considered early in progressive upper airway edema
100% agreement, evidence level D
|
demand medication
HAE is unpredictable, and any attack may be followed by another
one in short succession. It is essential that patients have on- demand
medication to treat all attacks. We, therefore, recommend that all
patients have and carry on- demand medication for the treatment
of at least two attacks (Recommendation 9).162 In patients with fre-
quent attacks, the time it takes to obtain more on- demand medica-
tion should be taken into consideration in the provision of treatment,
so that they never run out of on- demand medication.
RECOMMENDATION 9
We recommend that all patients have sufficient medication for on-
demand treatment of at least two attacks and carry on- demand
medication at all times
100% agreement, evidence level D
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TREATMENT OF HAE
The treatment of HAE patients with the intent of minimizing the
consequent risk of angioedema during exposure situations where
there is an increased risk of an attack is referred to as short- term
prophylaxis, sometimes also called situational prophylaxis.
It is well recognized that surgical trauma, dental surgery and
other interventions associated with mechanical impact to the upper
aerodigestive tract (eg, endotracheal intubation, bronchoscopy or
esophagogastroduodenoscopy) may precipitate angioedema near
the site of intervention. Angioedema associated with these proce-
dures usually occurs within 48 h. Following tooth extraction, more
than one third of patients without preprocedural prophylaxis may
develop local angioedema, and 50% of the swellings occur within
10 h, and 75% start within 24 h.163– 168 Preprocedural prophylaxis
reduces the risk of angioedema associated with these interven-
tions. We, therefore, recommend short- term prophylactic treatment
before medical, surgical or dental procedures as well as exposure
to other angioedema attack- inducing events (Recommendation
10).165,16 8– 171 Expert clinical judgment is needed, and individualized
risk assessment should be used in the identification of angioedema-
inducing events that warrant short- term prophylaxis.
RECOMMENDATION 10
We recommend considering shor t- term prophylaxis before medical,
surgical or dental procedures as well as exposure to other
angioedema attack- inducing events
94% agreement, evidence level C
We recommend the use of intravenous pdC1- INH as first- line
short- term prophylaxis (Recommendation 11),165,166 ,168,170 ,172 although
evidence for its efficacy is scarce. Case repor ts and series suggest that
angioedema may occur even after relatively minor procedures de-
spite prophylaxis.163,166 However, several reports document a reduc-
tion in the incidence of angioedema for both adults and children with
pdC1- INH used intravenously as preprocedural prophylaxis, and the
response appears to be dose- related.165,166,169,170 Preprocedural pro-
phylaxis with intravenous pdC1- INH concentrate is therefore recom-
mende d for all med ical , su rgi cal, and dent al pr oce dures asso cia ted wit h
any mechanical impact to the upper aerodigestive tract. Intravenous
pdC1- INH concentrate should be used for preprocedural prophylaxis,
as close as possible to the start of the procedure. Dosage has yet to
be fully established. Product- approved indication may vary by coun-
tr y.116 ,117 Most experts use either 1000 units or a dose of 20 units/kg
of pdC1- INH. Some recent evidence suggests benefit with rhC1- INH
shor t- ter m pr op hy laxis as it redu ce d th e rate of postproced ure HAE at-
tacks compared with control procedures without prophylaxis.171 This
could be considered if intravenous pdC1- INH is not available.
Fresh frozen plasma (FFP) may be used for short- term prophy-
laxis, but it is not as safe as intravenous pdC1- INH concentrate and
is a second- line agent because of the greater risk of blood- borne
disease transmission and allosensitization.7,11,169,173– 176
Attenuated androgens (eg, danazol) have been recommended
in the past for preprocedural prophylaxis as an alternative to intra-
venous pdC1- INH concentrates,170 but intravenous pdC1- INH con-
centrate is considered the prophylactic agent of choice.166 Frequent
short courses of attenuated androgens may lead to side effects
associated with long- term use. For scheduled preprocedural pro-
phylaxis, androgens are used for 5 days before and 2– 3 days poste-
vent. Tranexamic acid has been used for preprocedural prophylaxis
in the past; however, it is not recommended by most guideline
experts7,11,169,173– 175
With all preprocedural prophylactic treatments, breakthrough
attacks can occur, so patients and treating physicians should be
aware of this increased risk and understand the treatment plan, and
on- demand treatment needs to be available.11,165,16 6,173,176
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MAURER Et A l.
It is possibl e that shor t- t erm pr oph yla xis sh oul d be hand led di f-
ferently in patients with complete response to effective long- term
prophylaxis, for example, subcutaneous C1- INH, lanadelumab or
berotralstat. No recommendation on this can be given at this tim e,
as data ar e lacking. We encoura ge studies an d repor ts on the need
for short- term prophylaxis in patients on long- term prophylaxis.
RECOMMENDATION 11
We recommend the use of intravenous plasma- derived C1 inhibitor
as first- line short- term prophylaxis
91% agreement, evidence level C
In addition to specific medical procedures, there can be patient-
specific angioedema- inducing situations such as emotional stress-
ors that can precipitate attacks. Currently, there are no controlled
clinical trials in this area, and data come from personal experience,
retrospective reviews, and surveys. Nevertheless, a similar approach
to short- term prophylaxis should be considered when patients are
exposed to specific situations known to increase the risk of attacks
for a given patient (Recommendation 12).4,176 ,177
RECOMMENDATION 12
We suggest considering prophylaxis prior to exposure to patient-
specific angioedema- inducing situations
90% agreement, evidence level D
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TREATMENT OF HAE
The goals of treatment, in HAE, are to achieve complete control
of the disease and to normalize patients' lives (Recommendation
13).178 This can currently only be achieved by long- term prophylac-
tic treatment, also referred to as long- term prophylaxis (LTP), ie, the
regular use of medication that reduces the burden of the disease by
preventing attacks.
RECOMMENDATION 13
We recommend that the goals of treatment are to achieve total
control of the disease and to normalize patients' lives
100% agreement, evidence level D
Complete control of their disease, for HAE patients, translates
to no longer having attacks. Over the past years, several new long-
term prophylactic treatments have become available. These treat-
ments significantly reduce attack rates, and many patients achieve
complete response. In addition to achieving complete disease con-
trol, treatment of HAE should aim at normalizing the patient's life.
The impact of HAE on health- related QoL is well documented, as
is the reduction of QoL impairment by modern treatment op-
tions.1 2 6 , 1 7 9 – 1 8 3 The availability of modern prophylactic treatments,
personalized disease management and instruments for measuring its
outcome means that complete control of HAE is now a realistic pos-
sibility for many patients.1 8 4 – 1 9 3
Long- term prophylaxis should be individualized and considered
in all HAE- 1/2 patients taking into consideration the disease ac-
tivity, patient's quality of life, availability of health care resources,
and failure to achieve adequate control by appropriate on- demand
therapy. We, therefore, recommend evaluating patients with HAE
for LTP at every visit, taking disease activity, burden, and control
as well as patient preference into consideration (Recommendation
14).1 8 2 ,1 9 4 – 2 0 1 As all of these factors can vary over time, all patients
should be evaluated for LTP at least once a year. The goal of LTP is to
achieve full control of disease burden while attempting to minimize
treatment burden and side effects. Successful LTP requires a high
degree of compliance; therefore, the patient's preferences should be
taken into consideration. This requires appropriate and comprehen-
sive physician patient communication and allocating time for this.
Patients who use LTP should be assessed regularly for efficacy
and safety of the therapy, and dosage and/or treatment interval
should be adapted according to the clinical response. Upper air way
edema and other attacks may occur despite the use of long- term
prophylaxis.195,197,202– 207 Therefore, all patients using long- term
prophylaxis should also have on- demand medication (intravenous-
C1- IN H , ec allant i d e or ic atiba nt ) as pe r recomme n d a t i o n 7.6 – 8 , 2 0 8 – 2 1 2
RECOMMENDATION 14
We recommend that patients are evaluated for long- term
prophylaxis at every visit, taking disease activity, burden, and
control as well as patient preference into consideration
96% agreement, evidence level D
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C1- INH
Plasma- derived C1- INH is currently a preferred LTP agent for the
prevention of HAE attacks, and we recommend its use as first-
line long- term prophylaxis (Recommendation 15).126,197,205,213– 216
Approved product indications vary around the world. Dosing should
be twice a week based upon the half- life of pdC1- INH. Dose and/
or frequency may need adjustment for optimum efficacy.126,217– 220
Recent studies show that subcutaneous twice- weekly admin-
istration of pdC1- INH at a dose of 60 U per kilogram bodyweight
provided very good and dose- dependent preventive effects on the
occurrence of HAE attacks.205 The subcutaneous route may pro-
vide more convenient administration as well as maintain improved
steady- state plasma concentrations of C1- INH compared to LTP with
intravenous C1- INH, allowing for better symptom control..221– 224
RECOMMENDATION 15
We recommend the use of plasma- derived C1 inhibitor as first- line
long- term prophylaxis
87% agreement, evidence level A
Appropriate vaccination for hepatitis A and B should be generally
considered for patients in regular/repeated administration of human
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M AURER Et Al .
plasma- derived products including C1 inhibitor.140,141 Routine pro-
phylaxis with pdC1- INH has been shown to be safe and effective,
and it improves quality of life in patients with relatively frequent
HAE attacks compared with acute treatment of individual HAE
attacks.210,222,223,225– 227
Thromboembolic events due to C1- INH concentrate use in HAE
are rare, and patients who experience such events often have un-
derlying thromboembolic risk factors (eg, implanted central venous
catheters).2 28– 233 There are no known interactions with other me-
dicinal products. Tachyphylaxis seems rare with only one report of
increasing doses required to prevent attacks when C1- INH concen-
trate is used regularly for prophylaxis.234
|
Lanadelumab is a subcutaneously injectable, fully human, antiactive
plasma kallikrein monoclonal antibody (IgG1/κ- light chai n). It is a pr e-
ferred LTP agent for the prevention of HAE attacks due to its efficacy
and the fact it is administered subcutaneously. We, therefore, rec-
ommend the use of lanadelumab as first- line LTP (Recommendation
16).195,235– 237 It is typically administered as 300 mg ever y 2 weeks;
however, a dosing interval of 300 mg every 4 weeks may be consid-
ered if a patient is well controlled (eg, attack free).196, 238 It appears
safe with the rate of adverse events not appreciably higher among
patients who received lanadelumab than among those who received
placebo.195, 204
RECOMMENDATION 16
We recommend the use of lanadelumab as first- line long- term
prophylaxis
89% agreement (strong recommendation), evidence level A
|
Berotralstat is a plasma kallikrein inhibitor that binds to plasma
kallikrein and inhibits its proteolytic activity. It is a preferred LTP
agent for the prevention of HAE attacks due to its efficacy and
the fact it is an oral medication (Recommendation 17).206,239,240 It
is typically administered as 150 mg orally with food with dose re-
ductions to 110 mg in some regions where it is licensed based on
if there is hepatic impairment, use of P- glycoprotein or BCRP in-
hibitors (drug interactions) or patients experience gastrointestinal
symptoms on the 150- mg dose.241 Berotralstat appears safe, with
the most common side effects being gastrointestinal reactions,
including abdominal pain, vomiting, and diarrhea, which occurred
more frequently in patients receiving 150 versus 110 mg or pla-
cebo.24 0 These reactions generally occurred early after initiation of
treatment with Berotralstat, became less frequent with time and
typically self- resolved.242,243
RECOMMENDATION 17
We recommend the use of berotralstat as first- line long- term
prophylaxis
81% agreement, evidence level A
Taken together, this guideline recommends any of the three
medications for the first- line long- term prophylactic treatment of
patients with HAE- 1/2, ie, plasma- derived C1- INH, lanadelumab and
berotralstat, based on the results of randomized controlled clini-
cal trials.126,205,235,240 Where all three first- line LTP medications are
available, the choice of which one to use should be made by shared
decision making.24 4 This guideline encourages studies that compare
the efficacy and safety of first- line LTP medications and the identi-
fication of predictors of treatment responses. Currently, there is not
enough evidence to recommend any of these three treatment options
over each other. Where none of the three recommended first- line LTP
treatments are available, efforts should aim to change this. Alternative
options for LTP, in the absence of all three first- line LTP treatments,
include the off- label use of intravenous recombinant C1- INH.245
Importantly, first- line LTP treatments should be initiated as ap-
proved. For lanadelumab, and to some extent for C1- INH, adapting
the dose and/or treatment interval, after achieving complete re-
sponse, can decrease treatment burden.196, 219,2 20 Changes in the
dose or the treatment intervals should be based on data obtained
using patient- reported outcome measures. Poor control should
prompt treatment optimization including consideration of switching
LTP medication to improve efficacy.198,201,246,247
|
Attenuated androgens have traditionally been used for long- term
prophylaxis of HAE- 1/2.24 8 – 2 5 2 Androgen derivatives have been dem-
ons trated to be effecti ve in HAE- 1/2, and the oral administration facil-
itates their use.248,253 H owever, an drogen s must be regard ed cri ti cally,
especially in light of their adverse androgenic and anabolic effects,
drug interactions, and contraindications. Side effects are numerous
and involve most patients; in other words, the absence of side effects is
exceptional.250,254 Side effects appear to be dose- related. Virilization
is the most feared complication in women; menstrual disorders and
even amenorrhea as well as diminished libido and hirsutism are also
common,255– 257 as are weight gain, headache, myalgia, depression,
and acne. Androgens may lead to virilization of the female fetus and
are, therefore, absolutely contraindicated during pregnancy.258,259 In
children and adolescents, therapy with androgens may interfere with
the natur al growth and maturation process. In addition, androgens are
subject to numerous contraindications and show interactions with
many other drugs (eg, statins and antidepressants).211, 260,261 Careful
surveillance is imperative in long- term prophylaxis with androgens.
In addition to clinical tests and examinations and questioning of the
patient, semiannual blood and urine tests (standard urine test strip)
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MAURER Et A l.
are needed, and at least once a year, an ultrasound of the liver should
be performed.211, 260,26 2,263 Because of this, androgens should not be
used as first- line LTP, and we recommend using them only as second-
line long- term prophylactic treatment (Recommendation 18).2 52,26 4
RECOMMENDATION 18
We recommend the use of androgens only as second- line long- term
prophylaxis
89% agreement, evidence level C
The dose of androgens needed to control HAE attacks can vary
between the equivalent of 100 mg every other day and 20 0 mg of da-
na zol th r e e times a day. The min ima l effective do s e should be us ed.7, 174
Dosages above 200 mg of danazol daily for extended periods of time
are not recommended, be cause of side effects .265,266 The response to
androgens varies considerably, and the dose required for long- term
prophylaxis is variable. For this reason, the dosage should be adjusted
according to clinical response and not C4 or C1- INH levels.6, 7, 26 7 It is
unclear if stopping long- term prophylaxis with attenuated androgens
should be done by tapering off gradually over time.262, 268,269 This
guideline encourages studies that will help to guide physicians and
patients on how to best discontinue androgen treatment.
|
Antifibrinol ytics such as tr an examic acid are not recommended for long-
term prophylaxis. Data for their efficacy are largely lacking, but some
patients may find them helpful.270– 274 They are primarily used where
first- line prophylactic treatment options are not available and androgens
are contraindicated. The safety profile of antifibrinolytics is good. The
most common side effect is gastrointestinal upset. Contraindications/
precautions include the presence of thrombophilia or increased throm-
botic risk or acute thrombosis, eg, deep venous thrombosis and pulmo-
nary embolism. The doses of tranexamic acid used range from 30 to
50 mg/kg body weight daily divided into two or three doses to a maxi-
mum of 6 g per day. Dose- ranging studies and comparisons with other
prophylactic medications have not been performed.6,7,272,275, 276
|
Patients with HAE should monitor their disease activity, impact, and
control, and this is especially important in patients who use long-
term prophylactic treatment (Recommendation 19).184,246,277– 279
Validated patient- reported outcome measures such as the angi-
oedema activity score (AAS),192,2 80 the hereditary angioedema
activity score (HAE- AS),186 the angioedema quality of life question-
naire (AE- QoL),191,193,2 81 the hereditary angioedema quality of life
questionnaire (HAE- QoL),187,188 and the angioedema control test
(AECT)18 9,19 0 are available in a wide range of languages and should
be use d fo r this pu rpose .277,282 The aim s of effe ctive HAE trea tment ,
ie, the absence of attacks, normalization of QoL, and complete con-
trol, are best achieved when assessed by appropriate tools.
Monitoring of HAE disease activity is based on the regular as-
sessment and documentation of attacks by the patient. As HAE ac-
tivity can change frequently, it is best measured by advising patients
to document their attacks continuously, for example, with the help
of the AA S.26,19 2 The AAS has be en tr ansla ted into mo re th an 80 lan-
guages for use in more than 50 countries and is a valid and reliable
instrument, with high convergent and known- group validities, excel-
lent internal consistency, and good test- retest reliability280 The A AS
and other disease activity scores are widely used in clinical studies
and routine clinical practice.283, 284
High HAE disease activit y often comes with low QoL. However,
some patients with low attack rates also have markedly impaired
QoL, possibly linked to the unpredictability of HAE and continuous
fear of attacks, the need to avoid triggers of attacks, psychological
distress due to chronic disease burden, and the presence of comor-
bid diseases, such as depression and anxiety, which are common in
HAE patients.247 It is, therefore, important for patients and their
physicians to assess the impact of HAE on QoL, in addition to disease
activity. Validated PROMs for the evaluation of HAE- driven QoL im-
pairment include the HAE- QoL and AE- QoL.187,188,191,193 ,281 Both
are used in clinical practice and trials of HAE therapies.195,240,285– 287
The assessment of HAE disease control is done with the AECT.
The four questions of the AECT address the frequency of symptoms,
QoL impairment, the unpredictability of episodes, and the level of
control achieved by current therapy. Responses use a 5- point Likert
scale and are scored from 0 to 4 points, with a minimum and maxi-
mum total score of 0 (no control) and 16 (complete control), respec-
tively. The higher the AECT score the better the control of HAE. The
AECT comes with high levels of internal consistency and test- retest
reliability and a cut- off value of 10 points to distinguish patients
with poorly controlled and well- controlled HAE.189,1 90 The AECT is
available in two versions, one with a recall period of 4 weeks and
the other with a recall period of 3 months. Both yield largely similar
results, are easy to administer, complete, and score, and can help to
guide treatment decisions in HAE.
RECOMMENDATION 19
We suggest all patient s who are using long- term prophylaxis be
routinely monitored for disease activity, impact, and control to
inform optimization of treatment dosages and outcomes
98% agreement, evidence level A
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CHILDREN
|
HAE
The gene defect (SERPING1 mutation) of HAE- 1/2 is already pre-
sent at birth, but symptoms are uncommon in neonates and infants.
Attacks can first occur at any age but usually start in childhood or
adolescence. Half of all female HAE patients develop first attacks
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M AURER Et Al .
before the age of 12, and 90% by the time they are 23 years old. Of
male patients with HAE, 50% and 90% have first attacks before the
age of 13 and 25, respectively.28 8 Most attacks and most first at-
tacks, in children, manifest with angioedema of the skin. Abdominal
attacks may often go unrecognized in children, as abdominal pain
is common in childhood. With angioedema of the upper airway,
asphyxia can ensue rapidly in children, probably because of the
small airway diameter.289 The earliest occurrence was described
in a 4- week- old boy.161 The frequency and the severity of attacks
may increase during puberty and adolescence. The earlier the onset
of symptoms, the more severe the subsequent course of HAE-
1/2.290,291 Erythema marginatum as a prodromal sign is more fre-
quent in the pediatric population and occurs in 42%– 58% of cases.
It is often misdiagnosed as urticaria, which can lead to incorrect or
insufficient treatment.87,275,276,292– 298
|
With autosomal dominant inheritance, the offspring of a patient with
HAE- 1/2 stands a 50% chance of inheriting the disease. Newborns
with a positive family history are considered potentially affected
until HAE- C1- INH is excluded and must be well observed and tested
as early as possible, ideally before the onset of clinical manifesta-
tions, to ensure optimal management of the disease.299 Therefore,
we recommend testing children of parents with HAE- 1/2 as early
as possible (Recommendation 20).70,297,300– 302 Until a full investi-
gation for HAE- 1/2 is complete, all offspring of parents with HAE-
1/2 should be considered to also have the disease.
RECOMMENDATION 20
We recommend testing children from HAE- affected families be
carried out as soon as possible and all offspring of an affected
parent be tested
98% agreement, evidence level D
Complement levels measured in the umbilical cord blood of full-
term neonates are lower than maternal levels. Antigenic and func-
tional C1- INH levels correspond to 70% and 62% of adult values,
respectively.297,301,303 Therefore, using umbilical cord blood for com-
plement measurements may produce false- positive (low) results. The
assessment of complement in peripheral venous blood (serum/plasma)
in children lacks reference values. However, C1- INH antigenic levels
and/or functional activity in children with HAE- 1/2, who are <1 year
old, are low, with exceptions.70,3 00 In contrast, the measurement of
C4 was found not to be useful for diagnosing HAE- 1/2 in children
below the age of 12 months, as C4 levels are frequently low in healthy
infants.70, 300 Genetic testing increases the diagnostic reliability in
children and may be helpful where biochemical measurements are in-
conclusive,, and the genetic mutation of the parent is known.7 0 ,2 97, 3 0 0
All early complement testing performed in offspring of HAE- 1/2 pa-
tients should be repeated after the age of 1 year.70,275,297,30 0,304
Prenatal diagnosis of HAE- 1/2 is not common in clinical prac-
tice.299 Reasons inclu de th at (1) mut ation s in affe cte d parent C1- INH
gene are not detected in up to 10% of cases, (2) identical mutations
may be associated with substantially different phenotypes, and (3)
advances in therapy have significantly improved the QoL and dis-
ease control of patients with HAE- 1/2.49,72,275,305,306
Measurements of C1- INH antigen (protein) level, C1- INH func-
tional (activity) level, and C4 level are advisable in children with an-
gioedema without wheals.
|
Like adults, all pediatric HAE- 1/2 patients need to have a treatment
action plan (see below) and on- demand therapy (Recommendation
21).143, 214,307– 3 09 C1- INH and icatibant are the only approved on-
demand treatments for children with HAE- 1/2.116,117,119,120 Both are
effective, well tolerated and show a good safety profile. For abdominal
attacks, parenteral fluid replacement may be required as children are
more susceptible to hypovolemia and dehydration, and extravasation
into the peritoneal cavity and the intestinal lumen can be substantial.
When C1- INH and icatibant are not available, SDP is preferred over
FFP, but both are considered second- line treatment. Ecallantide is li-
censed for the use in adolescents in the United States.118
RECOMMENDATION 21
We recommend C1 inhibitor or icatibant be used for the treatment
of attacks in children under the age of 12
94% agreement, evidence level A
As in ad u lt s, prep roc e dural pr oph ylaxis is recom men ded fo r med-
ical, surgical, and dental procedures associated with any mechanical
impact to the upper aerodigestive tract.165,16 6 Plasma- derived C1-
INH is the first- line preprocedural prophylactic option, and short
courses of attenuated androgens should only be used second line,
when C1- INH concentrate is not available. With either option, on-
demand therapy should be available because shor t- term prophylaxis
is not 100% effective.168
The indications for long- term prophylaxis in adolescents are
the same as in adults (see above). The preferred therapy in children
younger than 12 years of age for long- term prophylaxis is pdC1- INH.
The dosing interval and dose may need to be adjusted according
to the individual response. When C1- INH concentrate is not avail-
able for long- term prophylaxis, antifibrinolytics (ie, tranexamic acid
20– 50 mg/kg) are preferred to androgens because of their better
safety profile; however, efficacy is questioned by many, and data
in support of its use are not available. Epsilon aminocaproic acid is
less well tolerated than tranexamic acid. Androgens are not recom-
mended for long- term prophylaxis in children and adolescents prior
to Tanner Stage V. The administration of androgens requires careful
safety monitoring. The continued need for regular prophylaxis with
androgens and the dosing should be reviewed on a regular basis.
Initial danazol dose for children is 2.5 mg/kg per day with subse-
quent adjustment, until symptom suppression or the maximum tol-
erated, or maximum recommended dose is reached, with a maximum
single dose of 200 mg per day. Androgens result in masculinization
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MAURER Et A l.
and hypogonadism in boys and menstruation irregularities in girls.
Unfavorable effects on behavior are possible. Reduction in ultimate
body height may occur owing to the premature closure of epiphyseal
growth plates.6,7,297– 29 9, 310,311
|
considerations in children with HAE
As in adults, most attacks in children with HAE- 1/2 occur without an
obvious trigger.312 Infections seem to be more common triggers of at-
tacks in childhood. Compulsory and recommended vaccinations for
children are safe, and the prevention of infections (eg, throat infec-
tions) may reduce the frequency of attacks. Medicinal products that
can cause edema as an adverse effect are less frequently used in chil-
dren. Treatment with an ACE inhibitor is less often necessary during
childhood. However, early initiation of oral estrogen- containing con-
traceptives is increasingly common, may trigger attacks and should be
avoided. Hormonal contraception with progesterone- only pills may
benefit many young women with HAE- 1/2275, 313,314 or at least should
not increase attack frequency. Other triggers like strenuous physical
activities involving mechanical trauma and emotional challenges (stress)
are essential elements of childhood and adolescence.315 Restrictions of
suspected triggers should be individualized and sensibly applied, along
with the use of prophylaxis where necessary, with the aim of avoiding
any limitations in activities and lifestyle. The aim of HAE- 1/2 manage-
ment at all ages is to normalize the lives of patients.297,316
Providing pediatric patients and their families with appropri-
ate information is indispensable to support them to adopt a suit-
able lifestyle and to avoid complications. Educators, teachers, and
health care personnel responsible for the child at day care or school
should receive written information on the disease, with advice on
the management of HAE attacks, including the urgency of treatment
for airway attacks. C1- INH or icatibant for emergency use should be
available at home, school, and travel including school field trips. An
action plan is necessar y, and the family and local hospital should have
therapies available for emergency treatment, and this should be in-
cluded in the treatment plan. All HAE patients have a potential for
receiving human blood products. Vaccinations for hepatitis A and B
are re com men ded by ma ny exper t s.295,297 All pat ien ts sh oul d be co n-
sidered to receive influenza vaccine and other routine vaccinations.
|
PREGNANT AND BREASTFEEDING
PATIENTS
|
breastfeeding patients with HAE
The anatomical, physiological, and hormonal changes during preg-
nancy may influence the manifestations and affect the course and
treatment of HAE- 1/2. Pregnancy can mitigate or aggravate HAE
disease activity or have no effect. Infrequently, the manifestations
of HAE- 1/2 first occur during pregnancy. Attack frequency observed
during previous pregnancies is only in part predictive of that in sub-
sequent ones.31 7– 3 21 Pregnant HAE- 1/2 patients require vigilant
care and meticulous monitoring by an HAE expert. Patients should
be managed in close cooperation by professionals from relevant
medical specialties. Labor and delivery only rarely induce an attack,
which may occur either during labor or within 48 h of deliver y. Close
follow- up is recommended for at least 72 h postpartum after un-
complicated vaginal delivery. Breastfeeding may be associated with
an increased number of maternal attacks, with abdominal symptoms
and facial edema, but is recommended based on benefits provided
to the infant.275,317,318,322 Care for C- section, especially if intubation
is necessary, should proceed as in any other surgical procedure per-
formed on a patient with HAE- 1/2 as covered below.
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breastfeeding patients with HAE
In healthy women, the plasma levels of C1- INH decrease during
pregnancy and return to normal after delivery.323,324 Therefore,
measurements of levels of C1- INH function, C1- INH protein and C4
for the purpose of diagnosing HAE- 1/2 during pregnancy should be
interpreted with caution. It is recommended to repeat the measure-
ments after childbirth to confirm the diagnosis of HAE.275, 322
|
breastfeeding patients with HAE
C1- INH is recommended as first- line therapy for pregnant or breast-
feeding HAE- 1/2 patients as it is safe and effective (Recommendation
22).222, 325– 329 The use of ecallantide, lanadelumab and berotralstat
in pregnancy is off label and not recommended as no published ex-
perience is available as of now. Although contraindicated by label,
there are isolated case reports about the administration of icati-
bant during pregnancy with no maternal or fetal adverse effects
reported.330– 332 SDP may be used when C1- INH is not available and
fresh frozen plasma when SDP is not available.275,317– 319,333– 337
RECOMMENDATION 22
We recommend plasma- derived C1 inhibitor as the preferred
therapy during pregnancy and lactation
100% agreement, evidence level D
Preprocedural prophylaxis in pregnancy is recommended, pref-
erably with C1- INH, for inter ventions that come with a risk of at-
tacks such as chorionic villus sampling, amniocentesis, and induced
surgical abortion. Alternatively, C1- INH should be available and ad-
ministered immediately at the onset of an attack. It is recommended
to manage childbirth in the hospital setting unless robust measures
for the prompt and effective treatment of HAE attacks are avail-
able. Although mechanical trauma and stress are known to trigger
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M AURER Et Al .
attacks, few women develop angioedema during labor and deliv-
er y.275, 319 Therefore, routine administration of preprocedural pro-
phylaxis before uncomplicated natural delivery is not mandator y, but
C1- INH concentrate should be available for immediate on- demand
use. Administering C1- INH concentrate as preprocedural prophylaxis
is recommended before labor and delivery when symptoms have
been recurring frequ ently during the third trimes te r, and the patient's
history includes genital edema caused by mechanical trauma, during
forceps delivery or vacuum extraction. Vaginal delivery is preferred
because surgery or general anasthesia may involve endotracheal in-
tubation. Preprocedural prophylaxis with C1- INH and epidural anas-
thesia is recommended before a cesarean section, and intubation
should be avoided if possible. If intubation is planned, preprocedural
prophylaxis is mandatory (see recommendation 10 and 11).
LTP may become indicated during pregnancy, especially in
women experiencing an increase of attack frequency. In these
women, C1- INH is considered a safe and effective prophylactic
treatment option.318 Antifibrinolytics may be considered if C1- INH
concentrate is unavailable, but efficacy is not proven.275,322,337,338
Androgens are contraindicated, as these drugs cross the placenta.
The most common adverse effects is masculinization of the female
fetus.258,259 Breastfeeding should be discontinued before andro-
gens are introduced. Terminating lactation itself may reduce attack
frequency.318
Plasma- derived C1- INH is considered the best therapy for on-
demand treatment, short- term prophylaxis and long- term prophy-
laxis when indicated during lactation. Androgens and antifibrinolytics
are secreted in breast milk. In contrast to androgens, tranexamic acid
was found to be safe during breastfeeding.339
|
AND SELF- ADMINISTRATION, AND OTHER
MANAGEMENT CONSIDERATIONS
|
Patient organizations and support groups provide help and support
for HAE patients, caregivers and family members. They endorse that
all patients worldwide should have sufficient resources to control
th eir HA E sympt oms an d fulf i ll th e ir po tent ial at schoo l, at work an d i n
their relationships. HAEi, the international umbrella organization for
the world's HAE patient groups, and national HAE associations have
active informative web sites for patients and health care providers.
HAEi has launched a “call to action” aimed at increasing the aware-
ness and knowledge on HAE with governments, health authorities,
and health care professionals and to achieve recognition of HAE as a
serious, disabling, potentially life- threatening, and chronic condition
that must receive timely accurate diagnosis and effective treatment.
Patient organizations also work toward identifying and address-
ing unmet needs in HAE management, which include the develop-
ment of safe and well- tolerated new prophylactic and on- demand
therapies, the optimization of existing long- term prophylactic and
on- demand therapies (eg, by dose- ranging studies and pediatric
studies), increasing the availability of modern treatment options
worldwide, especially in low- income countries, emphasizing the
need for self- care, individual action plans, early therapy, and re-
search. Information obtained from the internet is not always accu-
rate and reliable; however, HAEi provides reviewed, updated, and
scientifically sound information and is a quality source for patient
education.
|
for patients with HAE
Because HAE- 1/2 is an unpredictable, painful, and life- threatening
condition that can incur a huge stressful burden on patients and
their families, an individualized treatment plan should be care-
fully developed by shared decision making (Recommendation
23).4,176,226 ,279,340– 3 46 Individualized treatment plans should address
preventive measures as well as home care and self- administration. It
should include an effective emergency (on- demand) treatment plan,
with clear instructions on how to best use medications to treat HAE
attacks. Patients should carry on- demand medication and an HAE
identification card with instructions on how to manage an HAE at-
tack. Patients on long- term prophylaxis also require an action plan
and available therapy for on- demand use.3 4 7 – 3 5 0
Patients should be appropriately prepared for surgery, dental
work and procedures, and also surgeons, dentists, and procedural-
ists should be informed about the need of a short- term prophylaxis if
the procedure is in proximation of the airway. Co- management with
an HAE expert is recommended.344
RECOMMENDATION 23
We recommend that all patients have an action plan
98% agreement, evidence level D
HAE is a rare, complex, unpredictable life- long, and devastating
disease, with impact on life. Effective HAE management requires
comprehensive and integrated care, which should be available for
all patients (Recommendation 24).176, 297,34 6,351– 354 Integrated HAE
management aims to achieve improved patient care through opti-
mized coordination of ser vices provided. It helps improve patient
outcomes and allows for a proactive approach to the identification,
prevention, and management of potential complications.
RECOMMENDATION 24
We recommend that HAE- specific comprehensive, integrated care
is available for all patients
100% agreement, evidence level D
|
HAE- 1/2 patients are encouraged to find a health care provider
with HAE- specific knowledge, interest, expertise, and experience.
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MAURER Et A l.
All patients with HAE should be treated by a specialist with specific
expertise in HAE (Recommendation 25).4,176,244,297,346,347,355
There are several barriers for HAE patients to obtain optimal
care. They include long delays in obtaining the correct diagnosis,
physicians with little HAE knowledge and experience, not enough
time allocated for their visits and communication with their physi-
cian, disconnects between patients’ beliefs, expectations, and prior-
ities and those of their physicians, administrative and payer- related
requirements for obtaining appropriate treatment, and the lack of
therapies in their country. Cost and access may also be an issue for
patients. HAE expert physicians can help to overcome these barri-
ers. When and where possible, care should be provided by compre-
hensive angioedema centers with expertise in HAE. This guideline
acknowledges the fact that there are not enough HAE expert phy-
sicians and angioedema centers, globally, and supports all efforts to
change this, for example, through the GA2LEN/HAEi network of an-
gioedema centers of reference and excellence (ACARE).356
It is recommended that HAE patients have a medical evalua-
tion at least annually. Newly diagnosed patients and those on long-
term prophylaxis should be seen in shorter inter vals, until control is
achieved. Patients on androgens should continue to be seen twice
a ye a r.262 Evaluation at follow- up visits should include a review of
patient- documented disease activity, impact and control and of the
frequency of use and effectiveness of on- demand treatment for
swelling attacks. A physical examination and appropriate laboratory
evaluation should be conducted.177,343
Emergency departments and other medical treatment facilities
that provide acute care are strongly advised to develop and im-
plement angioedema management algorithms and train their staff
to effectively recognize and treat laryngeal and abdominal HAE
attacks.3 5 7 – 3 6 0
RECOMMENDATION 25
We recommend that patients are treated by a specialist with
specific expertise in managing HAE
100% agreement, evidence level D
|
Self- administration is crucial for an effective on- demand therapy
as early treatment of an attack. This effect is independent of the
on- demand medication used and facilitated by the skill of the self-
administrator or home therapy partner.9,110,340,352,361– 363 Similarly,
self- administration facilitates long- term prophylaxis. Every pa-
tient with HAE should be considered for home therapy and self-
administration. All patients who are provided with on- demand
treatment licensed for self- administration should be taught to self-
administer (Recommendation 26).111,36 3,3 64
Having to attend a medical facility to receive on- demand medi-
cation may result in delayed treatment, prolonged observation and
inappropriate therapy. Self- administration training should ideally
include a home therapy partner, ie, a family member or friend who
can provide support, advice and administration of therapy when
the patient is compromised or unable or uncomfortable with self-
treatment. Home therapy decreases the severity and duration of
HAE at tacks , red uce s mor bidit y and disab ility, an d can improve qua l-
ity of life and productivity. In addition, the cost of care is reduced
considerably using home and self- therapy.9,210,350, 365– 373
RECOMMENDATION 26
We recommend that all patients who are provided with on- demand
treatment licensed for self- administration should be taught to
self- administer
98% agreement, evidence level C
Home therapy is also suitable for children with HAE, where a
responsible adult is available and willing to undertake training.
Experience with hemophilia suggests that it is beneficial for children
to be encouraged to take an active part early in their treatment, and
subcutaneous and intravenous self- administration has been demon-
strated to be possible and safe in patients as young as 8 years.365,374
Advanced age is not a contraindication for home therapy if patients
and/or home therapy partners can safely and effectively administer
the treatment. The subcutaneous route may provide more conve-
nient administration in all age groups.
Early treatment is crucial in cases of upper airway involvement
(eg, tongue, posterior pharyngeal, uvula, larynx and vocal cords).
Patients should self- administer treatment while awaiting transfer to
the hospital. It is extremely important to encourage all patients to
seek further care immediately after the administration of therapy.
Upper airway swelling may progress or rebound and repeat dosing
may be necessary. Seeking emergency care after therapy is essential
to reduce the risk of asphy xia.
|
A variety of conditions and events are known to trigger HAE at-
tacks. Trauma, whether accidental or associated with dental, medical
and surgical procedures may result in a swelling attack. The use of
es tro gen - conta ining or al contr ace ptiv e agen t s and est rogen ho r m one
replacement therapy may trigger attacks and should be avoided.
Hormonal contraception with progesterone- only pills may be benefi-
ci al fo r many wo m e n wi t h HAE- 1/2 .275,313, 314 Antihypertensive agents
containing ACE inhibitors may increase the frequency or precipitate
HAE attacks and should therefore be strictly avoided. Other reported
triggers include psychological stress, fatigue, febrile illness and the
mens trual cycle . All pat ients with HAE sh oul d be educate d abo ut tr ig-
gers that may induce attacks (Recommendation 27).4,176,342,349,375– 377
RECOMMENDATION 27
We recommend that all patients should be educated about triggers
that may induce attacks
100% agreement, evidence level D
Patients should be made aware of potentially relevant triggers
of symptoms to reduce precipitation of attacks. However, most
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M AURER Et Al .
attacks are unpredictable and not prompted by triggers. Therefore,
physicians should not support excessive avoidance of suspected
triggers, in order not to limit the patient's normal life. Influenza
vaccine may reduce upper airway infections and possibly reduce
upper airway swelling. Good dental care can reduce extractions,
need for aggressive dental procedures and prevent acute or
chronic intraoral inflammation, which may reduce the threshold for
attacks.164,167,312,315,378,379
The severe acute respiratory syndrome coronavirus type 2
(SARS- CoV- 2) disease COVID- 19 pandemic has raised many ques-
tions and created uncertainty among patients with HAE and their
health care providers. Questions are primarily related to the risk of
infection, the risk of increased severity of COVID- 19 disease, the risk
of an increase in activity of HAE disease due to SARS- CoV- 2 infec-
tion, modification of COVID- 19 by therapies approved for HAE and
effects of COVID- 19 vaccines on patients with HAE. To date, there
are minimal data available to answer these questions and address
these concerns. Initial data from Brazil, France and Turkey showed
no significant increase in HAE- 1/2 activity during or after COVID- 19,
although some patients who were only using on- demand therapy
did report increased HAE activity.380– 383 A manuscript, in press,
using the database of the HAE- A demonstrated no evidence that
HAE patients were at greater risk for infection or for serious infec-
tion, nor adverse effects to the vaccine. In a recent survey from the
Netherlands, following 111 COVID- 19 vaccine doses administered,
11 attacks were reported, six arose more than 48 h after vaccina-
tion. Seven attacks were reported to be mild, four were assessed as
moderate, and most were treated with on- demand medication. The
majority of the attacks occurred in patients whose disease was not
well controlled (AECT < 10).384 These initial data underscore the im-
portance of optimal control of HAE- 1/2 disease, particularly during
the pandemic, first to minimize the attack rate and second to reduce
the need to visit emergency treatment facilities due to the poten-
tially increased risk of COVID- 19 infection.
|
HAE- 1/2 is a genetic disorder with autosomal dominant trans-
mission. Family members including grandparents, parents, sib-
lings, children and grandchildren of HAE- 1/2 patients should be
screened for C1- INH function, C1- INH protein and C4 plasma levels
(Recommendation 28).4,176,297,355 ,385– 387 Delayed diagnosis leads to
morbidity and decreased quality of life due to delayed introduction
of appropriate therapy. There is a risk that the first HAE attack may
affect the airway or the abdomen and could cause asphyxia or un-
necessary surgery.97 Once HAE is diagnosed, on- demand therapy
should be prescribed to be available for the first and subsequent at-
tacks, even if attacks have not yet occurred.
RECOMMENDATION 28
We recommend screening family members of patients for HAE
100% agreement, evidence level D
ACKNOWLEDGEMENTS
The authors would like to thank to Sofia Dorsano and Beate Schinzel
for their fantastic support during the process of the guideline devel-
opment. They would also like to thank the national societies for the
support of their delegates. Open access funding enabled and organ-
ized by ProjektDEAL.
CONFLICT OF INTEREST
Dr. Maurer reports personal fees from Alnylam, grants and personal
fees from BioCr yst, grant s from Centogene, grants and personal fees
from CSL Behring, grants from Dyax, grants and personal fees from
Kalvista, grants from Pharming, personal fees from Pharvaris, and
grants and personal fees from Shire/Takeda, outside the submitted
work . Dr. Ma gerl re por ts persona l fee s and non fin ancia l suppor t fro m
Shire/Takeda, personal fees and nonfinancial suppor t from CSL
Behr ing, pe rso nal fees fr om Phar ming, personal fees and nonf inancia l
support from Biocryst, during the conduct of the study, per sonal fees
and nonfinancial support from Shire/Takeda, personal fees and non-
financial support from CSL Behring, personal fees from Pharming,
personal fees and nonfinancial support from Biocryst, personal fees
from Kalvista, personal fees from Octapharma, personal fees from
Novartis, outside the submitted work. Dr Betschel has received fees
for advisory boards, presentations and research from CSL and
Takeda. Advisor fees from Biocryst and Kalvista, Octapharma,
Pharming, outside the submitted work. Dr. Aberer has nothing to dis-
close. Dr. Ansotegui has nothing to disclose. Dr. Aygören- Pürsün re-
ports personal fees from Biocryst, personal fees from Biomarin,
personal fees from Centogene, grants and personal fees from CSL
Behring, personal fees from Kalvista, personal fees from Pharming,
personal fees from Pharvaris, grants and personal fees from Shire/
Takeda, outside the submitted work. Dr. Banerji reports grants from
Takeda, Biocryst, other from Takeda, Biocryst, Pharming, CSL,
Kalvista, Pharvaris, outside the submitted work. Dr. Bara repor ts per-
sonal fees from commercial sponsor, outside the submitted work. Dr.
Boccon- gibod reports grants, personal fees and nonfinancial support
from Takeda, grants, personal fees and nonfinancial support from
Biocryst Pharmaceutical, nonfinancial support from Pharming, out-
side the submitted work. Dr. Bork reports grants and personal fees
from CSL Behring, personal fees from Shire/Takeda, personal fees
from Pharvaris, outside the submitted work. Dr. Bouillet reports
grants and personal fees from Takeda, Biocryst, Novartis, and GSK.
H. B. Boyse n has nothing to disclose. Dr. Brodski has nothing rel evant
to disclose. Dr. Busse reports grants and personal fees from CSL
Behring, BioCryst, Takeda; personal fees from Medscape, CVS
Health, Novartis, Regeneron. Dr. Bygum reports grants and personal
fees from CSL Behring, grants from BioCryst, personal fees from
Takeda/Shire outside the submitted work. Dr. Caballero reports
grants, personal fees and other from CSL BEHRING, grants, personal
fees and other from TAKEDA, personal fees and other from
PHARMING NV, personal fees from OCTAPHARMA, personal fees
and other from BIOCRYST, personal fees and other from NOVARTIS,
outside the submitted work. Dr. Cancian reports and has received
grant research support and/or speaker/consultancy fees from
|
MAURER Et A l.
BioCryst, CSL Behring, Kalvista, Pharming, Shire (a Takeda company)
and SOBI; has received funding to attend conferences/educational
events from CSL Behring, Menarini, MSD, Novartis, Pharming and
Shire; is/has been a clinical trial/registry investigator for BioCryst,
CSL Behring, Kalvista, Novartis, Pharming, Shire and UCB. Dr.
Castald o ha s nothing to disclo se. Dr. Cohn rep orts per sonal fees from
CSL Behring, personal fees from Shire/Takeda, personal fees from
Ion is Pharmaceuticals, Inc, personal fee s from Kal Vista, personal fees
from BioCryst, personal fees from Pharming, personal fees from
Pharvaris, personal fees from Sanofi/Genzyme Europe, outside the
submitted work. Dr. Csuka has nothing to disclose. Dr. Farkas report s
grants and personal fees from CSL Behring, grants and personal fees
from Shire/Takeda, grants and personal fees from Pharming Group
NV, personal fees from Biocryst Pharmaceuticals, personal fees from
Kalvista, personal fees from ONO Pharmaceuticals, outside the sub-
mitted work . Dr. Go mpe ls repo r ts fe e for CSL and conferenc e at tend-
ance support, member of the immunology clinical reference group,
clinical trial work for Novartis, BioCryst. Dr. Gower reports industry
funded research/investigator: BioCryst, Kalvista, Pharming,
Pharvaris, Takeda/Shire/Dyax Consultant: BioCryst, CSL Behring,
Fresenius Kabi, Pharming, Takeda/Shire/Dyax Speakers Bureau,
Faculty, Peer Reviewer: BioCryst, Pharming, Takeda/Shire/Dyax
Advisory Committee/Board: BioCryst, CSL Behring, Fresenius Kabi,
Pharming, Takeda/Shire/Dyax. Dr Grumach reports grants from
Shire/Takeda and personal fees from CSL Behring, Takeda, and
Catalyst for educative programs and consulting. Dr. Guidos-
Fogelbach has nothing to disclose. Dr. Hide reports personal fees
from BioCryst, CSL Behring, Takeda, and Torii. Dr. Kang has nothing
to disclose. Dr. Kaplan has nothing to disclose. Dr. Katelaris repor ts
grants from CSL Behring, personal fees from CSL Behring, personal
fees from Takeda, during the conduct of the study. Dr. Kiani- Alikhan
repo rts pe rsona l fees fr om BioC r yst , per sonal fees fro m CSL Behrin g,
personal fees from Takeda, outside the submitted work. Dr. Lei has
nothing to disclose. Dr. Lockey has nothing to disclose. Dr. Longhurst
has consulted for, acted as speaker for or collaborated in research
with the following: Adverum, BioCryst, CSL Behring, GSK, Intellia,
Ionis, Kalivista, Pharming, Pharvaris, and Takeda. Dr. Lumry has con-
sulted for, acted as speaker for or collaborated in research with the
following: Adverum, Astra Zeneca, BioCryst, Biomarin, CSL Behring,
Fresenius Kabi, GSK, Intellia, Ionis, Kalivista, Pharming, Pharvaris,
Sanofi Regeneron, Takeda, and Teva. Dr. MacGinnitie reports per-
so nal fees fr om Bi ocrys t, durin g the condu c t of th e stud y. Dr. Malb ran
has nothing to disclose. Inmaculada Martinez Saguer has received
research grant support and/or speaker/consultancy fees from
BioC r yst, CSL Be hri ng, KalVi sta, Pha rmi ng, and Takeda. Dr. Mat ta has
nothing to disclose. Dr. Nast has no conflict of interest in relation to
this manuscript. Dr. Nguyen has nothing to disclose. Dr. Nieto-
Martinez has nothing to disclose. Dr. Pawankar declares no conflicts
of interest in relation to this manuscript. Dr. Peter has nothing to dis-
close. Dr. Por ebski is or re ce nt ly was a spe aker and/or adv is or for CSL
Behring, Takeda, Pharming and has served as an investigator for clini-
cal trials sponsored by BioCryst Pharmaceuticals. Dr. Prior reports
receipt of research grant support and/or speaker/consultancy fees
from CSL Behring, Pharming, and Shire (currently Takeda). Dr. Reshef
Received research grants, speakers, and consulting honoraria from
CSL Behri ng, Stal l erge ns, Tev a, Pha rmin g , Bio Crys t , Phar var is, Takeda
(Shire)— not related to the article. Dr. Marc Riedl has received re-
search grants from BioCryst, CSL Behring, Ionis, Kalvista, Pharvaris,
and Takeda outside the submitted work; consultancy fees from
Astria, BioCryst, Biomarin, CSL Behring, Cycle Pharma, Fresenius
Kabi, Ipsen, Kalvista, Ono Pharma, Pfizer, Pharming, Pharvaris,
RegenexBio, and Takeda outside the submitted work. Dr. Bruce
Ritchie has received Research grants from CSL Behring and has par-
ticipated in clinical trials with Biocrist, CSL Behring, Ionis, Kalvista,
Pharvaris, and Takeda. The University of Alberta has received dona-
tions in lieu of consultancy fees to Dr. Ritchie from CSL Behring,
Takeda. Dr. Sheikh reports other from Takeda, grants from CSL
Behring, outside the submitted work. Dr. Smith reports other from
Bi oCryst, du ring the con duct of the stu dy, pe r sona l f e es fro m Take da/
Shire, personal fees from CSL Behring, outside the submitted work.
Dr. Späth reports other from CSL Ltd, outside the submitted work,
and Expert in an ongoing litigation. Dr. Stobiecki reports other from
Takeda, Biocryst, Pharming, Kalvista, fees from CSL Behring, Takeda,
Biocryst, outside the submitted work. Dr. Toubi has no conflict of in-
terest in relation to this manuscript. Dr. Varga has no conflict of inter-
est in relation to this manuscript. Dr. Weller reports personal fees
from Biocryst, CSL Behring, MOXIE and Pharvaris as well as grants
and personal fees from Shire/Takeda, all outside the submitted work.
Dr. Zanichelli has no conflict of interest in relation to this manuscript.
Dr. Zhi has nothing to disclose. Dr. Zuraw has been a paid consultant
for Biomarin, CSL Behring, Cycle Pharma, Fresenius Kabi, and Takeda.
He serves on adjudication boards for Novartis and Genentech. Dr.
Craig doe s re s e arch for CS L Be h r ing, Ion is , Tak e d a, Kal v i s t a, Phar varis ,
BioMarin, and Biocryst. He speaks for CSL Behring, Takeda, and
Gr ifols . He has a grant to supp ort educ atio n from Takeda. He consu lts
with Spark, CSL Behring, Takeda, BioMarin, Pharming, and Biocryst.
NOTES ON USE/DISCL AIMER
This is an updated version of the international HAE guideline. It is
based on the update and revision of this guideline published in 2018:
Maurer, M., Magerl, M., Ansotegui, I., Aygören- Pürsün, E., Betschel,
S., Bork, K., Bowen, T., Balle Boysen, H., Farkas, H., Grumach, A.,
Hide, M., Katelaris, C., Lockey, R., Longhurst, H., Lumry, W., Martinez
Saguer, I., Moldovan, D., Nast, A., Pawankar, R., Potter, P., Riedl, M.,
Ritchie, B., Rosenwasser, L., Sánchez- Borges, M., Zhi, X., Zuraw, B.,
and Craig, T.: The international WAO/EAACI guideline for the man-
agement of hereditary angioedema— the 2017 revision and update.
WAO Journal 2018: 11; 5 and Allergy 2018: 73; 1575– 1596. This
article is co- published with permission in Allergy and the World
Allergy Organization Journal.
ENDORSING SOCIETIES
FOUNDER SOCIETIES
WAO (World Allergy Organization), EAACI (European Academy of
Allergy and Clinical Immunology).
|
M AURER Et Al .
ORGANIZ ATIONS REPRESENTED BY DELEGATES TO
THE EXPERT PANEL AND AUTHOR GROUP
Angioedema Centers of Reference and Excellence (ACARE).
Association of Allergy, Asthma and Immunology Buenos Aires
(AAIBA) Argentina.
Chinese College of Allergy and Asthma (CCA A).
Danish Dermatological Society (DDS).
Dutch Society for Internal Medicine (NIV).
German Society for Angioedema Research (DGA/GSAR).
German Society for Internal Medicine (DGIM).
Global Allergy and Asthma European Network (GA²LEN).
HAE International (HAEi).
HAE UK.
Hungarian Society of Immunology (IUIS).
Japanese Dermatological Association.
Latin American Association of HAE (ALaeh).
Swedish Physicians Association for Immunodeficiency (SLIPI).
urticaria network e.V. (unev).
WAO MEMBER SOCIETIES REPRESENTED BY DELE
GATES TO THE EXPERT PANEL AND AUTHORS GROUP
Allergy Society of South Africa (ALLSA).
American College of Allergy Asthma and Immunology (ACAAI).
Australasian Society of Clinical Immunology and Allergy (ASCIA).
Austrian Society of Allergology and Immunology (OEGAI).
Brazilian Association of Allergy and Immunology (ASBAI).
Canadian Society of Allergy and Clinical Immunology (CSACI).
Chinese Society of Allergy (CSA).
European Academy of Allergy and Clinical Immunology (EA ACI).
French Society of Allergology (SFA).
Global Allergy and Asthma European Network (GA2LEN).
Hungarian Society of Allergology and Clinical Immunology
(MAKIT).
Korean Academy of Asthma, Allergy, and Clinical Immunology
(KAAACI).
Japanese Society of Allergology (JSA).
Mexican College of Clinical Immunology and Allergy (CMICA).
Polish Society of Allergology (PSA).
Romanian Society of Allergy and Clinical Immunology (SRAIC).
Saudi Allergy, Asthma, and Immunology Society (SAAIS).
Spanish Society of Allergy & Clinical Immunology (SEAIC).
ORCID
Marcus Maurer https://orcid.org/0000-0002-4121-481X
Markus Magerl https://orcid.org/0000-0001-9218-5468
Konrad Bork https://orcid.org/0000-0002-6084-4577
Laurence Bouillet https://orcid.org/0000-0001-8245-4767
Teresa Caballero https://orcid.org/0000-0003-3005-9858
Dorottya Csuka https://orcid.org/0000-0003-3610-9852
Henriette Farkas https://orcid.org/0000-0003-2929-1721
Hye- Ryun Kang https://orcid.org/0000-0002-2317-4201
Allen Phillip Kaplan https://orcid.org/0000-0002-6566-4743
Wei- Te Lei https://orcid.org/0000-0003-1677-8901
Andrew MacGinnitie https://orcid.org/0000-0002-9451-3733
Alexander Nast https://orcid.org/0000-0003-3504-2203
Ruby Pawankar https://orcid.org/0000-0002-3091-7237
Jonathan Peter https://orcid.org/0000-0002-2658-0723
Grzegorz Porebski https://orcid.org/0000-0002-6146-0188
Avner Reshef https://orcid.org/0000-0002-3324-7072
Lilian Agnes Varga https://orcid.org/0000-0002-5484-364X
Karsten Weller https://orcid.org/0000-0003-4437-0313
Yuxiang Zhi https://orcid.org/0000-0001-7539-6650
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How to cite this article: Maurer M, Magerl M, Betschel S, et al.
The international WAO/EAACI guideline for the management
of hereditary angioedema— The 2021 revision and update.
Allergy. 2022;77:1961– 1990. doi:10.1111/all.15214
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