# French protocol for the diagnosis and management of hereditary angioedema.

Isabelle Boccon-Gibod, O. Fain, D. Gobert, S. Debord, M. Aubineau, N.

Ozanne, F. Defendi, A. Gompel, G. Hardy, N. Javaud, et al.

► To cite this version:

Isabelle Boccon-Gibod, O. Fain, D. Gobert, S. Debord, M. Aubineau, et al. French protocol for the diagnosis and management of hereditary angioedema. La Revue de Médecine Interne, 2025, La Revue de Médecine Interne, 10.1016/j.revmed.2025.09.005. hal-05382855

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Review article

French protocol for the diagnosis and management of hereditary angioedema

Protocole national de diagnostic et de soins pour l'angiœdème héréditaire

Isabelle Boccon-Gibod<sup>a</sup>, Olivier Fain<sup>b</sup>, Delphine Gobert<sup>b</sup>, Sophie Debord<sup>c</sup>, Magali Aubineau<sup>d</sup>, Nicolas Ozanne<sup>e</sup>, Federica Defendi<sup>f</sup>, Anne Gompel<sup>g</sup>, Gaelle Hardy<sup>h</sup>, Nicolas Javaud<sup>i</sup>, Audrey Lehmann<sup>j</sup>, Anne Pagnier<sup>k</sup>, Fabien Pelletier<sup>l</sup>, Alexis Bocquet<sup>a,m</sup>, Aurelie Du Thanh<sup>n,p</sup>, David Launay<sup>o,q</sup>, Laurence Bouillet<sup>a,*,m</sup>, and CREAK collaborators<sup>l</sup>

INFO ARTICLE

Historique de l'article :

Disponible sur Internet le xxx

Keywords :

Angioedema
Hereditary angioedema
FXII
PLG
Bradykinin
C1inhibitor
Kallikrein

ABSTRACT

Recurrent isolated angioedema (AE) is a diagnostic and therapeutic challenge. Only a rigorous clinical approach can rule out the most obvious diagnoses. The recent international classification recognizes 7 subgroups: mast cells induced AE (spontaneous, allergic), Bradykinin mediated AE (Hereditary or acquired C1Inh; kallikrein-kinin mutations), HAE due to vascular endothelium dysfunction, drug induced AE and AE of unknow origin. Bradykinin-mediated hereditary angioedema (BK-HAE) are rare conditions. The currently accepted incidence of HAE-C1INH is approximately 1 in 50,000 inhabitants per year. Bradykinin is released following activation of the kallikrein/kinin pathway in the vascular lumen and is rapidly degraded by kininases, the main one being angiotensin-converting enzyme. The disease manifests as subcutaneous or submucosal edema. When an attack occurs in the pharynx/larynx area, there is a high risk of asphyxia (25% in the absence of specific treatment). This risk is unpredictable and exists throughout the patient's life. AE can be localized in the abdomen and resemble a surgical emergency. The disease is more symptomatic in women, as estrogen is an aggravating factor. In AE due to C1INH deficiency,

<footnote><sup>a</sup> National reference center for angioedema (CREAK), Internal medicine department, Grenoble University Hospital, Grenoble, France</footnote>

<footnote><sup>b</sup> Sorbonne Université, service de médecine interne, AP-HP, Hôpital Saint-Antoine, 75012 Paris, France</footnote>

<footnote><sup>c</sup> Department of Anesthesiology and Intensive Care Medicine, Édouard-Herriot Hospital, Hospices Civils de Lyon (HCL), Lyon, France</footnote>

<footnote><sup>d</sup> Internal Medicine Department, Édouard-Herriot Hospital, Hospices Civils de Lyon, Lyons, France</footnote>

<footnote><sup>e</sup> Department of Internal Medicine, CHU Rouen, Rouen, France</footnote>

<footnote><sup>f</sup> University Grenoble Alpes, CHU Grenoble Alpes, Laboratoire d'Immunologie, 38000 Grenoble, France</footnote>

<footnote><sup>g</sup> Université Paris Cité, Gynécologie médicale, Port Royal Cochin, Paris, France</footnote>

<footnote><sup>h</sup> Laboratory of Molecular Genetics, Centre Hospitalier Universitaire de Grenoble Alpes, Grenoble Alpes, France</footnote>

<footnote><sup>i</sup> Université Paris Cité, Urgences, AP-HP, Centre de référence des angiœdèmes à kinines (CREAK), hôpital Louis Mourier, 92700 Colombes, France</footnote>

<footnote><sup>j</sup> Department of Pharmacy, Université Grenoble Alpes, CHU Grenoble Alpes, Grenoble, France</footnote>

<footnote><sup>k</sup> National reference center for angioedema (CREAK), Pediatric department, Grenoble University Hospital, Grenoble, France</footnote>

<footnote><sup>l</sup> Service de Dermatologie-Allergologie, CHU Besançon, INSERM UMR 1098 RIGHT, Université Marie-et Louis-Pasteur, Besançon, France</footnote>

<footnote><sup>m</sup> University Grenoble Alpes, T-RAIG unit, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble, France</footnote>

<footnote><sup>n</sup> Department of Dermatology, University of Montpellier, Montpellier, France</footnote>

<footnote><sup>o</sup> University of Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, 59000 Lille, France</footnote>

<footnote><sup>p</sup> Inserm U1058 Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, Montpellier, France</footnote>

<footnote><sup>q</sup> Inserm, Department of Internal Medicine and Clinical Immunology, CHU Lille, National Reference Center for Angioedema (CREAK), Lille, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>Adresse e-mail : lbouillet@chu-grenoble.fr (L. Bouillet).</footnote>

<footnote n="1">¹ Marie Antignac, Pharmacy Saint Antoine Hospital, AP-HP, Paris; Alexandre Belot, Pediatrics, HCL; Claire Blanchard Delaunay, Internal Medicine, Niort; Chantal Dumestre Perard, Immunology Laboratory, Chuga, Grenoble; Claire De Moreuil, Department of Internal Medicine, Brest CHRU; Alban Deroux, Internal Medicine, Clinical Immunology, CHUGA, Grenoble; Marie Dubrel, Pediatrics, Bayonne Hospital; Stéphane Gayet, Internal Medicine, La Timone Hospital, AP-HM, Marseille; Constance Guillaud Danis, Internal Medicine, Henri Mondor Hospital, Créteil; Florence Hacard, Allergology and Clinical Immunology, South Lyon Hospital, Lyon; Diane Hengy, General Medicine, Bron; Mélanie Javaud, Therapeutic Education Nurse, Internal Medicine, Saint Antoine Hospital, AP-HP, Paris; Pierre-Yves Jeandel, Internal Medicine, Archet 1 Hospital, Nice CHU; Charlotte Kevorkian, Pediatrics, CHUGA, Grenoble; Nicolas Marmion, Allergology, Saint Pierre, Réunion CHU; Michel Raguet, Chair of the AMSAO; Anne Sarrat, Biology, Bordeaux; Nicolas Simon, Internal Medicine, Clinical Immunology, CHUGA, Grenoble; Angèle Soria, Dermatology-Allergology, Tenon Hospital, AP-HP, Paris.</footnote>
the diagnosis is based on the search for a weight and/or functional deficiency in C1 inhibitor. In the forms with normal C1 inhibitor, the diagnosis is solely genetic, such as F12, PLG, or KNG1 mutations. The prognosis for these rare diseases has changed considerably in recent years with the arrival of new, highly effective specific drugs. Patient education is an important part of management. We present here the French protocol for the diagnosis and management of bradykinin-mediated hereditary AE.

© 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Société Nationale Française de Médecine Interne (SNFMI). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

Mots clés :

Angioédème

Angioédème héréditaire

FXII

PLG

Bradykinine

C1Inhibiteur

Kallicréine

L'angio-œdème isolé récurrent (AE) représente un défi diagnostique et thérapeutique. Seule une approche clinique rigoureuse permet d'écarter les diagnostics les plus évidents. La classification internationale récente reconnaît 7 sous-groupes: l'AE secondaire à l'activation des mastocytes (spontané, ou allergique), l'AE médié par la bradykinine (C1Inh héréditaire ou acquis ; mutations dans la voie kallikréine-kinine), l'AE héréditaire dû à un dysfonctionnement de l'endothélium vasculaire, l'AE induit par des médicaments et l'AE d'origine inconnue. L'angio-œdème héréditaire induit par la bradykinine (AEH-BK) est une affection rare. L'incidence actuellement admise de l'AEH-C1Inh est d'environ 1 cas pour 50 000 habitants par an. La bradykinine est libérée suite de l'activation de la voie kallikréine/kinine dans la lumière vasculaire et est rapidement dégradée par les kininases, dont la principale est l'enzyme de conversion de l'angiotensine. La maladie se manifeste par un œdème sous-cutané ou sous-muqueux. Lorsqu'une crise survient au niveau du pharynx/larynx, le risque d'asphyxie est élevé (25 % en l'absence de traitement spécifique). Ce risque est imprévisible et existe tout au long de la vie du patient. L'AE peut être localisé dans l'abdomen et ressembler à une urgence chirurgicale. La maladie est plus symptomatique chez les femmes, car l'œstrogène est un facteur aggravant. Dans l'AE due à un déficit en C1INH, le diagnostic repose sur la recherche d'un déficit pondéral et/ou fonctionnel en inhibiteur C1. Dans les formes avec inhibiteur C1 normal, le diagnostic est uniquement génétique (recherche de variant pathogènes dans F12, PLG ou KNG1). Le pronostic de ces maladies rares a considérablement évolué ces dernières années avec l'arrivée de nouveaux médicaments spécifiques très efficaces. L'éducation des patients est un élément important de la prise en charge. Nous présentons ici le protocole français pour le diagnostic et la prise en charge de l'AE héréditaire médiée par la bradykinine.

© 2025 Les Auteurs. Publié par Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

# 1. Abbreviations

AAE Acquired angioedema

ACE Angiotensin-converting enzyme

AE-QoL Angioedema quality of life

AAS-28 Angioedema activity score

AMSAO Association of patients with angioedema

APP Aminopeptidase P

BK Bradykinin

C1-INH C1 inhibitor

CBC Complete blood count

CREAK Reference center for angioedema

CRMR Reference Center for Rare Diseases

DPPIV Dipeptidyl peptidase IV

F12 Factor XII

HAE Hereditary angioedema

HAE-C1INH Hereditary angioedema due to C1-inhibitor deficiency

IUD Intra-uterine device

KNG1 Kininogen 1

LTC Long-term condition

MA Marketing Authorization

MARIH Rare Immunohematologic Diseases network

MLPA Multiplex ligation-dependent probe amplification

NABM Nomenclature of medical biology procedures]

NEP Neprilysin

PLG Plasminogen

RHA Regional Health Agency

RIHN List of non-coded innovative procedures]

SIV Slow intravenous

TAU Temporary authorization for use

TPE Therapeutic patient education

# 2. Introduction (Classification and epidemiology)

According to the most recent international classification (AAAI, ACAAI, ACARE, and APAACI DANCE Consensus), there are three main types of hereditary angioedema (HAE) (Fig. 1) [1]:

## Bradykinin-mediated HAE (BK-HAE) covered by this French protocol:

* HAE with C1Inh deficiency (HAE-C1INH) linked to variants in the SERPING1 gene, causing either a defect in C1Inh production (type I, the most common form, 85%) or the production of a non-functional protein (type II, 15%)

* HAE with normal C1inh (HAE-nC1INH) associated with variants of genes involved in the kallikrein-kinin pathway: F12, PLG, KNG1.

## HAE due to vascular endothelium dysfunction, not covered by this protocol:
associated with variants of genes involved in intrinsic vascular endothelium dysfunction whose mediators are not currently known (ANGPT1, HS3ST6, MYOF and DAB2IP).

The currently accepted incidence of HAE-C1INH is approximately 1 in 50,000 inhabitants per year. According to the Epi-AOH study conducted in Paris and extrapolated to the whole of France, the total number of patients is estimated at 1500. HAE-nC1INH are rarer: the French registry has recorded 111 HAE-FXII and 19 HAE-PLG symptomatic patients spread across 154 HAE-FXII and 26 HAE-PLG families [2].

This French protocol for the diagnosis and management (FPDM) does not apply to angioedema caused by acquired C1 inhibitor
I. Boccon-Gibod, O. Fain, D. Gobert et al.

La Revue de médecine interne xxx (xxxx) xxx-xxx

<figure><img src="image_2.png" /><figcaption>**Fig. 1.** DANCE Classification. AE: angioedema; AE-MC: Mast cells mediated angioedema; BK: bradykinin-mediated angioedema; C1INH: C1 Inhibitor; UNK: unknown; DI: Drug induced.</figcaption></figure>

deficiency or drug-induced angioedema (angiotensin-converting enzyme inhibitors, ACEi).

# 3. Objectives of the French protocol for the diagnosis and management and methods

## 3.1. Objectives

The FPDM aims to harmonize the care and monitoring of the disease in order to improve the quality of life of patients and their families. However, this protocol cannot cover all specific cases, comorbidities or complications, therapeutic particularities, or protocols. This FPDM describes the standard care for patients with BK-HAE. It will be updated based on new validated data.

## 3.2. Methods

The first FPDM for BK-HAE was developed in 2021 by the accredited reference centre for angioedema (CREAK). This is the first revision according to the National Authority for Health (HAS) methodological guide of 2012.

# 4. Definition and pathophysiology [3], (Fig. 2)

BK-HAE is caused by excessive production of bradykinin (BK), a peptide with powerful vasodilatory properties. BK is produced by activation of the kallikrein-kinin pathway, a proteolytic cascade involving several proteins and proteases: Activation of Factor XII induces the conversion of prekallikrein to kallikrein, which in turn cleaves high molecular weight kininogen to generate BK. Plasmin plays an amplifying role, promoting the activation of FXII. BK binds to B2 receptors constitutively expressed on the surface of endothelial cells and activates them. This leads to the release of mediators such as nitric oxide and prostacyclin, which cause smooth muscle cell relaxation, vasodilation, and increased vascular permeability.

These changes cause plasma to extravasate into the extracellular space, resulting in edema formation. C1-INH is the main negative regulator of the BK production pathway.

Once produced, BK is mainly broken down (75%) by the angiotensin-converting enzyme (ACE); other enzymes are involved in its catabolism: aminopeptidase P (APP), carboxypeptidase N, dipeptidyl peptidase IV (DPPIV) and neprilysin (NEP).

C1-INH is also a major player in the regulation of the classical pathway of the complement system. C1-INH deficiency leads to spontaneous activation of the classical pathway, resulting in the consumption of C4 and C2. This explains the decrease in C4 levels found in more than 80% of patients.

# 5. Diagnostic approach and differential diagnoses (Fig. 3)

## 5.1. Main objectives

* Diagnosis.

* Rule out differential diagnoses.

* Confirm the diagnosis at CREAK referral sites.

* Conduct a family investigation.

## 5.2. Professionals involved

The initial diagnosis may be made by various professionals: general practitioners, dermatologists, allergists, anesthesiologists, biologists, dentists, gastroenterologists, gynecologists, obstetricians, internists, otolaryngologists, pediatricians, pharmacists, and emergency physicians.

## 5.3. Clinical diagnosis

BK-HAE should be considered in cases of recurrent, isolated angioedema (without wheals) that does not respond to increased doses of antihistamine treatment: up to 4 times the approved dose, taken continuously for several weeks (± additional omalizumab), occurring in a family context (which may however be absent in ¼ of patients due to possible *de novo* mutation). The edema is skin-colored, localized, transient, and disappears within 2 to 5 days without sequelae, in the absence of treatment. There is no pruritus or fever. Angioedema attacks are unpredictable and can affect any part of the body, but are more likely to occur in the face and upper airways (including the tongue), extremities, digestive tract, and genitals [4].

Attacks are sometimes preceded by a very specific non-itchy reticular rash, which should not be confused with urticaria during questioning, and may be followed by significant asthenia.

Upper airway involvement, including laryngeal and tongue edema, can be life-threatening due to asphyxia in the absence of specific treatment [5].

Digestive involvement may lead to recurrent sub occlusive episodes without fever or biological inflammatory syndrome, which resolve spontaneously within 48 to 72 h. These are accompanied by severe pain, sometimes hypotensive symptoms, nausea, vomiting, acute intestinal intussusception in children (especially over the age of 3), and severe diarrhea at the end of the attack. Hemoconcentration is possible, resulting in hyperleukocytosis and increased hematocrit. Abdominal imaging is abnormal: ascites is visible on ultrasound or CT scan in 90% of cases. Edema of the digestive wall is visible on CT scan in 50% of cases [6].

The location, intensity, and frequency of attacks vary throughout a patient's life, from one patient to another, and within the same family.

Attacks are often spontaneous but can be triggered by physical trauma, including even minor medical procedures. Other
<figure><img src="image_3.png" /></figure>

ACE: Angiotensin I-converting enzyme, APP: Aminopeptidase P, CPN: Carboxypeptidase N, DPP4: Dipeptidyl peptidase IV, NEP: Neprilysin

<figure><img src="image_4.png" /><figcaption>**Fig. 3.** Diagnosis approach. ACEi: angiotensin-converting enzyme inhibitor; AE: angioedema; anti H1: antihistamine; BK-HAE: bradykinin-mediated hereditary angioedema; HAE: hereditary angioedema; HAE-C1INH: hereditary angioedema with C1INH deficiency; HAE-nC1INH: hereditary angioedema with normal C1INH; LTP: long-term prophylaxis; MC-AE: mast cell mediated angioedema; MGUS: monoclonal gammopathy of undetermined significance; Sd: syndrome.</figcaption></figure>
<table><caption>**Table 1**
Classification of bradykinin-mediated angioedema.</caption><thead><tr><th></th><th>C1INH</th><th>C1INH functional assay</th><th>C1q</th><th>Antibodies</th><th>Causal variant</th></tr></thead><tbody><tr><td></td><td></td><td></td><td></td><td>Anti-C1INH</td><td></td></tr><tr><td>Type 1 HAE-C1INH</td><td>Low</td><td>Low</td><td>Normal</td><td>Absent</td><td><strong>SERPING1</strong><br>Not found:<br>5 to 10%</td></tr><tr><td>Type 2 HAE-C1INH</td><td>Normal</td><td>Low</td><td>Normal</td><td>Absent</td><td><strong>SERPING1</strong></td></tr><tr><td>HAE-nc1inh</td><td>Normal</td><td>Normal</td><td>Normal</td><td>Absent</td><td>Factor XII (F12)<br>Plasminogen (PLG)</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>Kininogen (KNG1)</td></tr><tr><td>Drug-induced acquired AE</td><td>Normal</td><td>Normal</td><td>Normal</td><td>Absent</td><td>Not found<br>Absent</td></tr></tbody></table>

C1INH: C1 Inhibiteur; HAE: hereditary angioedema.

triggers are possible: positive or negative emotions, physical or psychological trauma, infections, medications, mainly estrogen, and angiotensin-converting enzyme inhibitors.

## 5.4. Biological diagnosis (Table 1), [7]

Once BK-HAE is suspected, biological tests to confirm the diagnosis should include concentration and functional measurements of C1INH protein. These tests do not need to be performed during an attack. They should be performed at a distance from certain treatments: 2 weeks after administration of C1-INH concentrates (Berinert®, Cinryze®), one month after stopping Danazol®. Tranexamic acid and icatibant do not interfere with C1 inhibitor testing.

During estrogen treatment and pregnancy, C1-INH levels may be physiologically reduced and should be rechecked after a period of time (> 3 months).

The nature and quality of the sample are important for obtaining reliable results: it is recommended to check with each laboratory in advance to find out the conditions for collection and transport. Always check at least twice and take a second sample before confirming the diagnosis.

### 5.4.1. C1 inhibitor explorations

The concentration of C1-INH is assessed using immunochemical methods (nephelometry, turbidimetry). The functional activity of C1-INH is measured using a spectrophotometric-enzymatic method. Reference values depend on the measurement technique and vary from one laboratory to another. HAE with C1-INH deficiency is suspected when functional activity is less than 50% of the reference values in two tests performed at least one month apart, at least one of which must be performed in a reference laboratory. A normal C1-INH concentration in plasma does not rule out the diagnosis of HAE: functional testing is essential and must be requested systematically. There is no correlation between C1-INH levels and clinical phenotype. When the functional activity of C1-INH is between 50% and 60% of the reference values, the result must be checked on a second sample, in consultation with the biologist, and must be interpreted according to the clinical picture, away from pregnancy and any estrogen treatment.

### 5.4.2. Biological tests in children

Like most complement proteins, C1-INH levels vary with age and reach adult levels between 6 and 36 months. In children with a family history of HAE, early diagnosis is important as attacks can occur in the first few months of life. Two methods may be proposed: (1) measurement of C1-INH levels and function at 6 months of age, to be checked again after 1 year of age, even if the first result is

normal; (2) in the case of a known pathogenic variant in the affected parent, a presymptomatic genetic diagnosis may be offered in conjunction with a clinical genetics consultation, based on a blood sample or buccal swab taken at birth [8].

C1-INH measurement in cord blood is not interpretable. There is no indication for prenatal screening in France.

### 5.4.3. C1q measurement

This is generally normal in cases of HAE; it should only be measured if angioedema due to acquired C1-INH deficiency is suspected. The same applies to testing for anti-C1-INH antibodies.

## 5.5. Genetic diagnosis

### 5.5.1. HAE-C1INH [9]

HAE-C1INH is an autosomal dominant disorder with incomplete penetrance. It is caused by pathogenic variants in the gene encoding C1INH, known as SERPING1 (NM_000062.3, OMIM#606860). The pathogenic variant is inherited from a parent or appears de novo in the patient, which means that the absence of a family history should not rule out a hereditary C1-INH deficiency. Molecular testing includes sequencing of the 8 exons of the gene and testing for rearrangements by Multiplex Ligation-dependent Probe Amplification (MLPA) if sequencing does not identify a pathogenic variant. In approximately 5 to 10% of AOH cases with C1-INH deficiency, no pathogenic variant is found on the SERPING1 gene.

The search for a causal variant must be performed in all index patients from a new family. This is only carried out in two laboratories in France (Grenoble, CRM Reference Medical Biology Laboratory, Grenoble Alpes University Hospital https://biologie.chu-grenoble.fr/catalogue-des-examens and Paris (AP-HP) Biological Immunology Laboratory https://hupo.manuelprelevement.fr/).

### 5.5.2. HAE-nC1INH [10]

Three susceptibility genes have been identified recurrently to date: the gene encoding factor XII (F12), the gene encoding plasminogen (PLG), and the gene encoding kininogen (KNG1). Analysis of the F12 gene should be performed in all patients suspected of having HAE-nC1INH, particularly when estrogen is identified as a trigger for attacks, or when the patient is of North African origin. The main pathogenic missense variant is c.983C > A (p.Thr328Lys). This is an ancestral pathogenic variant responsible for a founder effect.

Analysis of the PLG gene should also be performed systematically in patients who are not carriers of a pathogenic variant of the F12 gene. Again, a pathogenic missense variant with a founder effect has been described in patients with HAE-nC1INH: c.988A > G
(p.Lys330Glu). Patients identified to date have a family history and recurrent tongue edema and angioedema attacks triggered by ACE inhibitors.

Two families have so far been identified as carriers of a pathogonic variant of the *KNG1* gene: c.1136T > A (p.Met379Lys). Molecular testing of the *KNG1* gene is only performed as a second-line investigation in informative families (several affected individuals).

However, the absence of pathogenic variants in the *F12*, *PLG* or *KNG1* genes does not rule out a diagnosis of HAE-nC1INH. Other genes are likely to be identified in the coming years.

Genetic counseling should be provided during a consultation with a referring physician or clinical geneticist.

## 5.6. Differential diagnosis [4]

The problem of differential diagnosis of HAE revolves around three questions: Is it angioedema? If so, is it BK-induced? If so, is it hereditary or acquired? In fact, 95% of AE cases are spontaneous (non-allergic) mast cell mediated reactions and correspond to spontaneous urticaria, 4% are allergic mast cell mediated reactions, and less than 1% are BK-mediated.

Angioedema (AE) is a clinical syndrome. It does not form blisters and is not inflammatory. It's localized, transient and disappears spontaneously within a maximum of 5 days without sequelae. AE may be sensitive or even painful. It's never accompanied by fever and biological inflammatory syndrome unless triggered by an infectious agent. If all of these criteria are not met, the condition is not angioedema and a differential diagnosis should be considered (Table 2).

### 5.6.1. Differential diagnoses of AE-BK (Table 3)

Once a positive diagnosis of AE has been made, BK-induced causes must be distinguished from other causes. The most feared but nevertheless rare differential diagnosis is allergic or anaphylactic mast cell AE, which manifests as a submucosal edema that is often painful, non-pruritic, extensive, and occurs within minutes of exposure to an allergen. It is usually associated with other signs of mast cell degranulation or anaphylaxis (malaise, hypotension, superficial urticaria, palmoplantar pruritus, diffuse erythema, bronchospasm, diarrhea). The chronology helps identify the triggering factor and should lead to allergy testing to confirm the allergy to the substance in question (medication, food, Hymenoptera venom, etc.) and to investigate possible cross-allergies.

However, the most common cause in both adults and children is non-allergic mast cell AE, which is never life-threatening (except in cases of mastocytosis).

### 5.6.2. Differential diagnosis of BK-HAE

Among AE caused by BK, several entities can be distinguished: HAE with or without C1-INH deficiency and acquired AE with or without C1-INH deficiency, whether drug-induced or not (see Table 2).

Acquired drug-induced AE-BK is mainly secondary to ACE inhibitor use; it can occur years after the start of treatment and is not related to an immuno-allergic mechanism. The risk of occurrence is increased with concomitant treatment with gliptins, mTOR inhibitors, racecadotril, or thrombolytics [11].

In these situations of drug-induced AE, C1-INH testing is recommended: if normal, this rules out HAE with underlying C1-INH deficiency or AE to underlying- unrecognized C1-INH deficiency revealed by the use of the drug. The absence of recurrence after discontinuation of treatment confirms the acquired drug-induced nature. Conversely, recurrence should suggest either a mast cell cause or HAE with normal C1-INH.

AE due to acquired C1-INH deficiency occurs in individuals over the age of 40 with no family history; the clinical manifestations

cannot be distinguished from HAE. The decrease in functional C1-INH is constant; C1q is reduced in 70 to 90% of cases. Anti-C1-INH antibodies are present in 50% of cases. They may be isolated or associated with a lymphoproliferative syndrome (most often marginal zone lymphoma) or monoclonal gammopathy [12].

## 6. Therapeutic care

### 6.1.1. Main objectives

HAE is a chronic disease with unpredictable and dangerous attacks. Treatment has two objectives:

* treat attacks;

* prevent their occurrence in the short and long term;

* improve the quality of life of patients.

Attack treatment should be administered as soon as possible for maximum effectiveness and patient safety. Self-administration or administration by a caregiver should be encouraged to promote patient independence and save time in administering treatment.

In some patients, long-term treatment should be implemented to limit the occurrence of attacks and ultimately improve patient safety and quality of life.

Short-term prophylactic treatments are recommended and should be administered systematically in the event of exposure to situations or factors that trigger attacks (surgery, dental treatment, etc.).

### 6.2. Impact

The occurrence of attacks, which can be serious at any time in the patient's life, significantly impairs their quality of life. These patients experience high levels of anxiety due to the risk of asphyxia caused by swelling of the upper airways. Abdominal attacks, which are often extremely painful, are also very distressing for patients. Some of them have developed an addiction to morphine due to the high frequency of their attacks. Peripheral attacks (swelling of the hands and feet) last at least two days and can cause severe and recurrent disability in patients, who are unable to carry out their daily and/or professional tasks. School or work absenteeism is often significant, with signs of depression observed in 42% of patients. Psychological follow-up is often helpful [13].

### 6.3. Patient education and lifestyle changes [14]

According to the WHO definition (1996), Patient education (PE) should enable patients to "acquire and/or maintain the skills necessary" to manage their chronic disease as effectively as possible.

Given the unpredictability and potential severity of BK-HAE, patients must acquire theoretical and practical knowledge to take charge of their own care and know how to respond to therapeutic emergencies. Patient education for patients and their families is essential: it is an integral and permanent part of their care. It begins at the first consultation with the CREAK referral physician. This is a long, specialized consultation, the primary purpose of which is to provide accurate and clear information tailored to the needs of the patient and their family and friends.

The national patient education program for BK-HAE, "Educréak," is designed to enable patients and their families to acquire the skills they need to become more independent and better manage their condition on a daily basis. The priority objectives are:

* to provide a duly completed care and emergency card after confirmation of the diagnosis;
<table><caption>**Table 2**
Differential diagnosis of angioedema.</caption><thead><tr><th></th><th>Common or serious diagnoses</th><th>Other etiologies</th></tr></thead><tbody><tr><td>Edema localized to the face<br>Infectious causes</td><td>Erysipelas<br>Facial cellulitis<br>Odontogenic abscesses</td><td>Herpes or shingles<br>Parvovirus B19<br>Mononucleosis<br>Infectious Trichinosis<br>American Trypanosomiasis</td></tr><tr><td>Vascular causes</td><td>Superior vena cava syndrome (may initially be transient)<br>Thrombosis of the cavernous sinuses</td><td>Cystic lymphatic malformations</td></tr><tr><td>Granulomatous causes</td><td>Sarcoidosis</td><td>Orofacial granulomatosis: Melkersson-Rosenthal syndrome;</td></tr><tr><td>Dermatological causes</td><td>Dermatomyositis<br>Lupus erythematosus</td><td>Miescher's granulomatous cheilitis<br>Morbihan syndrome</td></tr><tr><td>Various causes</td><td>DRESS-syndrome<br>Nephrotic syndrome<br>Parotiditis<br>Sinusitis<br>Subcutaneous emphysema</td><td>Scleredema of Buschke<br>Contact eczema<br>Dacryocystitis<br>Graves' eye disease<br>Floppy Eyelid<br>SAS with CPAP<br>Münchhausen syndrome<br>(Kelly Jenner challenge)</td></tr><tr><td>Edema of the uvula: isolated, they are not suggestive of bradykinin-mediated angioedema</td><td>Gastroesophageal reflux Sleep apnea syndrome</td><td>Intake of toxic drugs: cannabis, cocaine, alcohol<br>Chronic inducible urticaria (vibratory angioedema)</td></tr><tr><td>Laryngeal edema</td><td>Post-intubation infectious laryngitis</td><td>Paradoxical vocal cord movement<br>Vascular corditis</td></tr><tr><td>Edema of the limbs<br>Vascular causes</td><td>Lymphedema<br>Venous thrombosis</td><td>Cystic lymphoid malformation</td></tr><tr><td>Infectious causes</td><td>Dermohypodermitis</td><td>Filariasis<br>Envenomations</td></tr></tbody></table>

<table><caption>**Table 3**
Differential diagnosis of AE-BK.</caption><thead><tr><th></th><th>Mast cell-mediated angioedema</th><th>Bradykinin-mediated angioedema</th></tr></thead><tbody><tr><td>Frequency</td><td>&gt; 90%</td><td>&lt; 1%</td></tr><tr><td>Atopic background and superficial urticaria (including dermographism)</td><td>Present but not constant</td><td>Absent</td></tr><tr><td>Signs of anaphylaxis (bronchospasm, malaise, hypotension)</td><td>Possible</td><td>No</td></tr><tr><td>Face involvement</td><td>Yes</td><td>Yes</td></tr><tr><td>Intense abdominal pain for 48 to 72 hrs. or partial occlusion of the intestine</td><td>No</td><td>Yes</td></tr><tr><td>Duration of angioedema</td><td>From a few hours to 72 h</td><td>2–5 days (never less than 24 h)</td></tr><tr><td>Efficacy of long-term antihistamines at the optimal dose</td><td>Yes</td><td>No</td></tr></tbody></table>

AE-BK: bradykinin-mediated angioedema.

* explaining the disease and its symptoms to the patient and their family and friends;

* knowing how to recognize severe attacks, identify triggering factors, recognize risky situations and use preventive measures;

* learning how to manage attacks: knowing how to use specific treatments, treating severe attacks early, and never being alone after self-administration;

* offer training in self-administration and/or home administration (subcutaneous or intravenous) with one or more sessions (at least five sessions for slow IV) in the presence of the person likely to administer the injection (spouse, parent, etc.);

* encourage comprehensive family screening;

* know how to adapt to everyday issues and questions;

Patients must have at least one specialized consultation per year to ensure they have sufficient and up-to-date knowledge about their disease and treatments.

In terms of self-care and skills, to be independent and safe, they must be able to recognize severe attacks and be able to use specific treatments in an emergency (learning self-administration and/or home administration by a third party).

## 6.4. Treatment of attacks (Fig. 4)

Treatment will vary depending on the severity of the attack and its functional impact. Non-severe attacks do not always require specific treatment [15].

Corticosteroids, adrenaline, and antihistamines are not effective in treating these attacks. Tranexamic acid and danazol are not a treatment for attacks.

The medications available for treating AE-BK are: icatibant (B2 receptor antagonist; 30 mg sub cutaneous injection) and plasma derived C1inh concentrate (20 UI/kg; Berinert and Cinryze).

All patients with HA-BK (even asymptomatic ones) should have access to the equivalent of treatment for two attacks (icatibant or C1-INH) and be trained in self-administration so that they can administer the treatment as soon as possible wherever they are. The earlier the treatment is administered, the more effective it is [16].

### 6.4.1. Treatment of severe attacks

There are two types of severe attacks:
<figure><img src="image_5.png" /><figcaption>**Fig. 4.** Management of bradykinin-mediated angioedema attacks. C1INH: C1 Inhibitor; SC: subcutaneous; IV: intravenous.</figcaption></figure>

* life-threatening crises: affecting the face, tongue, and upper airway: upper airway crises are fatal in 25% of cases without specific treatment;

* attacks causing major functional impairment: abdominal attacks, peripheral involvement leading to functional incapacity, pain, or absence from school or work.

The patient must not be left alone, especially if the upper airways are affected.

First-line treatment: icatibant, one subcutaneous injection of 30 mg in adults. Self-administration or administration by a family member is possible.

The effectiveness of the treatment should be assessed within one hour of administration based on the cessation of edema progression or reduction in abdominal pain. In cases of laryngeal involvement, effectiveness should be assessed 30 to 40 mins after treatment of the attack.

A second injection is possible if the initial treatment is effective but the symptoms return (rebound effect), provided that a 6 h interval is observed, with a maximum of three injections per 24 h and eight injections per month.

If icatibant is not available, a C1-INH concentrate (Berinert®, Cinryze®) at 20 IU/kg IVL is recommended. Slow IV administration takes 10-15 mins for the total dose without waiting between vials; any vial that has been opened must be administered in its entirety.

In a hospital setting, the patient may return home within two hours of symptom improvement, provided that they have their emergency treatment with them and have been informed of the risk of recurrence/rebound.

**In case of upper airway involvement** [17], it is dangerous and thus prohibited to perform endoscopic or invasive ENT examinations (risk of worsening the attack). In the event of signs of respiratory distress, airway control must be ensured by a senior physician (ideally an anesthesiologist and surgeon); intubation is still an option in the early stages, with concomitant preparation of cricothyroidotomy equipment. The absence of desaturation may be falsely reassuring. In the event of stage 3 respiratory distress (loss of consciousness, cardiorespiratory arrest): cricothyroidotomy or

tracheotomy should be considered immediately and performed by a senior resuscitation physician or ENT surgeon. Attempting orotracheal or nasotracheal intubation is pointless in this situation due to the severe edema of the laryngeal airway.

### 6.4.2. *Treatment of non-severe attacks*

Non-severe attacks do not always require treatment but must be monitored as they can develop into severe attacks.

### 6.5. *Long term prophylaxis (LTP) [15]*

The goal of long-term treatment is to prevent attacks and improve the patient's quality of life.

Long-term treatment should be offered to any patient who has:

* at least one attack per month;

* or 5 severe attacks per year;

* or attacks that have a significant impact on their quality of life.

First-line maintenance treatments will be personalized and tailored to the patient's profile, based on their age, gender, comorbidities, severity of the disease, and the extent to which their quality of life is impaired. The various basic treatments may have a delayed effect: they must be evaluated 3 months and then 6 months after initiation.

New, highly effective treatments with very few side effects are now available. For this reason, older treatments should no longer be prescribed because:

* Danazol has numerous metabolic side effects. Long-term prescription increases the risk of cardiovascular disease and cancer;

* Tranexamic acid is ineffective in HAE-C1INH. It can improve HAE-PLG;

* Macro progestogens are no longer recommended as a long-term treatment for HAE due to the risk of meningioma.

There are currently two LTP treatments targeting kallikrein:
* Lanadelumab is a fully humanized IgG1 monoclonal antibody. It inhibits the proteolytic activity of active plasma kallikrein. It has been approved since 2018. The recommended starting dose is 300 mg every two weeks by subcutaneous injection. After 3 to 6 months and in the absence of attacks, the injection schedule may be extended to once every 3 to 4 weeks [18]. Reported side effects are reactions at the injection site;

* Berotralstat, which has been approved since April 2021, is an oral kallikrein inhibitor [19]. The recommended dose is 150 mg in capsule form, taken once a day during or at the end of a meal. The reported side effects are mainly digestive disorders, which are often temporary. It is contraindicated in cases of severe renal impairment and moderate to severe hepatic impairment.

## 6.6. Short-term prophylaxis

It is recommended before:

* Dental procedures involving traumatic treatment (tooth extraction, root canal treatment, etc.) [20];

* Surgery under general anesthesia;

* Endoscopic procedures.

Practical guidelines for short-term prophylaxis:

* Infusion of C1-INH concentrate (Berinert®, Cinryze®): 20 IU/kg to be injected no more than 6 h before the procedure (ideally within the hour before). As indicated above, even though the market authorization for Cinryze is 1000 IU, the FPDM also recommends 20 IU/kg for this molecule;

* Icatibant cannot be used for prophylaxis;

* it is essential to have treatment available in the recovery room in case of an attack: icatibant (30 mg) or C1-inh concentrate (Berinert®, Cinryze®, 20 IU/kg). The anesthesiologist in charge of the patient must be informed of the specific procedures for managing patients with HAE;

* in the case of non-traumatic dental care (scaling), if the patient has specific treatment for the attacks available within 24 h of the procedure, prophylaxis is not mandatory and should be discussed on a case-by-case basis with the referring physician.

## 6.7. Contraindicated medications

All treatments containing an angiotensin-converting enzyme (ACE) inhibitor are contraindicated.

In cases where blocking the renin-angiotensin axis is important, it is entirely possible to introduce a sartan: however, it is recommended to check that there is no worsening of attacks after starting sartan treatment (currently controversial data regarding sartans). This should be done in consultation with the physician who wishes to initiate treatment with sartans.

Given the estrogen sensitivity of the disease, estrogen, which may aggravate the condition, is also contraindicated.

# 7. Women and angioedema [21]

Given the estrogen sensitivity of the disease, women are generally more symptomatic than men.

## 7.1. Contraception

Progestin only pill ("microprogestatifs"), are indicated as first-line treatment. Drospirenone alone should not be used as first-line treatment due to its more pronounced anti-androgenic effect. Estrogen-progestogen contraception is strongly discouraged in

patients with BK-HAE as it may increase the risk of attacks. There are no contraindications to inserting a copper or levonorgestrel IUD. It is recommended that treatment for severe attacks be available at the time of insertion.

## 7.2. Pregnancy, childbirth, breastfeeding

A pre-conception consultation and consultation at the beginning of pregnancy with a CREAK consultant and their obstetrician is recommended. Pregnancy may be associated with worsening attacks. The impact of pregnancy on the disease varies from one pregnancy to another, even in the same woman.

Indications for treatment of attacks and long-term prophylaxis should be broad due to the risk of fetal death in utero if attacks are not treated. Possible treatments include tranexamic acid and C1-INH concentrates. Icatibant, lanadelumab, and berotralstat are not approved for use during pregnancy.

Vaginal delivery is recommended. Short-term prophylaxis is not systematic for delivery in patients who are asymptomatic during pregnancy, provided that C1-INH concentrates are available in the delivery room. Epidural anesthesia is recommended.

In the event of a cesarean section, regional anesthesia is preferable to general anesthesia requiring access to the upper airways, and prophylaxis with C1-INH concentrates will be systematic; delivery should take place in a maternity ward with an anesthesiologist on site and C1-INH concentrates available; Medical supervision is required for the first 24 h after delivery.

Breastfeeding is not contraindicated. Treatments that can be used during an attack in breastfeeding women are C1-INH concentrates.

There is no indication for prenatal screening.

## 7.3. Assisted reproductive technology

Ovulation stimulation protocols using the lowest levels of estradiol should be preferred to avoid attacks. Oestroprogestative contraceptives (sometimes used in the cycle(s) preceding the stimulation phase) are not recommended. The indications for prophylaxis with C1-INH concentrates should be broad throughout the process, in consultation with the CREAK referring physician.

## 7.4. Menopause

The progression of attacks after menopause is unpredictable. For climacteric syndrome, progesterone may be offered as a first-line treatment. Vaginal estrogen is permitted.

# 8. Follow-up of a patient with hereditary angioedema

## 8.1. Objectives

Once the initial assessment has been carried out at the CREAK and the patient has been involved in the patient education process, the objectives of the follow-up are:

* regular assessment of disease activity;

* adjustment of treatment;

* verifying the patient's knowledge and the appropriate course of action in various situations;

* frequency and content of consultations.

Patients must have at least one consultation per year with a specialist doctor at one of the CREAK sites, even if they are asymptomatic, particularly adolescents who received little treatment during childhood. The frequency of these consultations and para-
clinical examinations must be tailored to each patient and their specific situation, depending on:

* the patient's clinical condition;

* the severity of the condition and its progression under treatment;

* the intensity and recurrence of attacks (severe or not);

* the treatments used (monitoring, tolerance, adverse effects); for patients receiving long-term prophylaxis, six-monthly follow-up is preferable.

## 8.2. The first consultation

This is a specialized consultation to announce the diagnosis and provide information and education to the patient and their family. This consultation must be carried out by a physician from a CREAK reference or competence center.

The main objectives are:

* confirm the diagnosis;

* explain the disease, its symptoms, and the available treatments;

* teach the patient to recognize severe attacks and how to treat them;

* identify triggering factors;

* learn to recognize high-risk situations requiring short-term prophylaxis;

* teach self-administration of injectable treatments;

* conduct a family history survey that is as comprehensive as possible;

* explain how the disease is transmitted within the family, draw up a family tree, discuss how to inform other relatives (by the patient themselves or by the doctor) or refer them for genetic counseling if available;

* provide the "care and emergency card" duly completed with the contact details of the referring doctors and the national CREAK on-call number;

* write or provide information on the care protocol for ALD applications;

* provide the attack and treatment diary;

* offer participation in a therapeutic education program;

* discuss contraception or hormone replacement therapy for women (estrogen withdrawal).

## 8.3. Follow-up consultations

Follow-up consultations should be used to determine the severity of the condition, evaluate the effectiveness of treatments, and adjust the therapeutic strategy, considering the patient's quality of life.

To do this, the following information must be collected:

* clinical examination data;

* disease activity using the patient's attack diary, a standard Angioedema Activity Score (AAS-28) questionnaire, the number of severe attacks, treated or untreated, since the previous consultation, and any use of emergency services, resuscitation or hospitalization;

* an assessment of quality of life using the AE-QoL questionnaires;

* an assessment of background treatment using the AECT (Angioedema Control Test) score over the last 4 weeks or 3 months (Appendix 9 bis) on disease control;

* the number of days of school absenteeism or work stoppage related to AE;

* the psychological impact of the disease; if necessary, specialized care may be required;

* side effects of treatments, paraclinical monitoring data for background treatments;

* if short-term prophylaxis is indicated, the patient's referring physician should be contacted to specify the nature and method of use of the prophylactic treatment.

During follow-up consultations, care should be taken to ensure that each patient has at least two treatments for a severe attack and that they and their family are trained in how to administer them. These consultations should also be an opportunity to ensure that the patient and their family have sufficient knowledge of the disease, particularly with regard to emergency situations. If necessary, clear and appropriate additional information should be provided. Participation in a patient education program should be offered.

## Human and animal rights

The authors declare that the work described has not involved experimentation on humans or animals.

## Informed consent and patient details

The authors declare that the work described does not involve patients or volunteers.

## Funding

This study was not supported by research funding but FAI2R is funded by "le Ministère des Solidarités et de la Santé" (French Ministry of Solidarity and Health).

Filière de santé maladies rares immuno-hématologiques (MARIH).

## Authors' contributions

All authors wrote the first draft and participated in drafting the manuscript. All authors participated in editing the manuscript, as well as reading and approving the final version of the manuscript.

All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship.

## Disclosure of interest

Alexis Bocquet has consulted/served as speaker for, engaged in research and educational projects with or accepted travel grants from the following companies: BioCryst, and Takeda.

Laurence Bouillet has consulted/served as speaker for, engaged in research and educational projects with or accepted travel grants from the following companies: BioCryst, CSL Behring, Takeda and kalvista.

Gaelle Hardy has consulted/served as speaker for Biocryst and Takeda.

Isabelle Boccon-Gibod receipt of grants/research supports from Takeda, Biocryst, Pharming, CSL Behring, Pharvaris, Kalvista, Novartis. Receipt of honoraria or consultation fees from Takeda, Biocryst, Pharming, CSL Behring, Pharvaris, Kalvista, Novartis.

Fabien Pelletier: receipt of honoraria or consultation fees from Takeda, CSL Behring; accepted travel grants from Biocryst.

Aurélie Du Thanh: speaker and/or principal investigator or sub-investigator and/or expert for Biocryst and Takeda.

Nicolas Ozanne accepted travel grants from Biocryst.

David Launay has consulted/served as speaker for, engaged in research and educational projects with or accepted travel grants from the following companies Takeda, CSL Behring, Biocryst.
Olivier Fain has consulted/served as speaker for, engaged in research and educational projects with or accepted travel grants from the following companies: BioCryst, CSL Behring, Kalvista and Takeda.

Delphine Gobert has consulted/served as speaker for, engaged in research and educational projects with or accepted travel grants from the following companies: BioCryst, CSL Behring, Kalvista and Takeda.

Audrey Lhemann, magali Aubineau, Anne Gompel, Nicolas Javaud, Anne Pagnier declare that they have no competing interests.

All participants in the development of the FPDM completed a declaration of interest. The declarations of interest are online and available on the FAI²R website.

## Acknowledgements

We would like to thank the Rare Autoimmune and Autoinflam-
matory Diseases Network (FAI²R) for its technical assistance and
help with editing (Hélène MAILLARD).

The French version is available free of charge on the HAS website.

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