Articles
Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema

https://doi.org/10.1016/S1081-1206(10)60584-4Get rights and content

Background

We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) in 2004.

Objective

To ensure that this consensus remains current.

Methods

In collaboration with the Canadian Network of Rare Blood Disorder Organizations, we held the second Canadian Consensus discussion with our international colleagues in Toronto, Ontario, on February 3, 2006, and reviewed its content at the Fifth C1 Inhibitor Deficiency Workshop in Budapest on June 2, 2007. Papers were presented by international investigators, and this consensus algorithm approach resulted.

Results

This consensus algorithm outlines the approach recommended for the diagnosis, therapy, and management of HAE, which was agreed on by the authors of this report. This document is only a consensus algorithm approach and continues to require validation. As such, participants agreed to make this a living 2007 algorithm, a work in progress, and to review its content at future international HAE meetings.

Conclusions

There is a paucity of double-blind, placebo-controlled trials on the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Controlled trials currently under way will provide further insight into the management of HAE. As with our Canadian 2003 Consensus, this 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE was formed through the meeting and agreement of patient care professionals along with patient group representatives and individual patients.

Section snippets

INTRODUCTION

C1 inhibitor (C1-INH) deficiency (congenital or hereditary angioedema [HAE]) was first described by Quincke in 18821; its inheritance nature was evidenced by Osler in 18882 and further defined as autosomal dominant by Crowder and Crowder in 1917. The protein defect was described by Donaldson in 1963.3 An acquired form (acquired angioedema [AAE]) was described in 1972.4 The approach to patients who present with angioedema without urticaria was recently presented by Zingale et al.5 The incidence

PATIENT GROUP PERSPECTIVE

The HAE patient societies, including the CHAES/SAHC, have proposed establishment of comprehensive care clinics for the diagnosis, therapy, and management of HAE, including the development of home infusion and home care programs.16, 21 Similar to the presentation by Hungarian-sponsored HAE workshops in their publication,8 we think it appropriate to share the patient perspective of HAE management to help administrators reflect on the development of comprehensive care clinics for HAE. The

CLINICAL CHARACTERISTICS

HAE may present as recurrent angioedema (swelling) without urticaria (without hiving) and usually nonpruritic (without itch).23 Sometimes there is a nonpruritic serpentine erythematous rash.24 Distinguishing features of HAE are reviewed by Zingale et al5 and Bork et al.24 Swelling may affect any part of the body, including the extremities, face, trunk, gastrointestinal tract, genitourinary regions, or upper airways. Abdominal symptoms may mimic infantile colic, acute appendicitis, or other

DIAGNOSIS

Indications for testing include clinical suspicion at any age or, if the family history is positive, test at any age. Tests may not be reliable in patients younger than 1 year (false-negative and false-positive testings may occur unless using genetic typing). Testing performed in patients before the age of 1 year should be confirmed after the age of 1 year.31 A serpiginous rash is sometimes seen with the prodrome of HAE, but clinical urticaria (hives) usually make the diagnosis of HAE unlikely.

DIAGNOSTIC TESTING

If C1-INH deficiency is clinically suspected, we recommend screening with serum C4 and C1-INH proteins. C4 is normal between swelling events in only 2% of cases, so a normal C4 level should make one question the diagnosis of HAE. If there is a low index of suspicion, it may be more cost effective to screen with C4 alone (it is not necessary to screen with CH50 or C3).32 If serum C4 and C1-INH antigenic protein levels are both low and AAE not suspected, then the diagnosis is compatible with type

BASELINE LABORATORY TESTING AT DIAGNOSIS AT ANY AGE

Baseline bloodborne pathogen surveillance (hemovigilance) samples should be collected and stored at baseline and annually through national programs similar to the Canadian hemophilia hemovigilance program (Dr Bruce Ritchie: [email protected]; http://www.ahcdc.ca/BBPSP; baseline sample storing for testing for human immunodeficiency virus; human T-cell lymphoma; hepatitis B, C, and G; and future testing for possible emerging pathogens).16, 17, 22, 33 C1-INH hormone replacement (C1INHRP)

VACCINATION RECOMMENDATIONS

It is recommended that patients who may need to receive blood products receive vaccination to hepatitis B (may be in combination with a hepatitis A vaccine such as Twinrix).

MEDICATIONS TO AVOID IN PATIENTS WITH HAE

Some medications may trigger or worsen angioedema events in patients with HAE and should be avoided, including ACE-Is5, 16 and estrogen contraceptives.8, 16, 28, 29 Plasminogen activators are a theoretical risk, but the benefit may outweigh the risk.37, 38, 39

SHORT-TERM PROPHYLAXIS: MINOR MANIPULATIONS

If only mild manipulation, such as mild dental work, is required or if C1INHRP therapy is immediately available, then no prophylaxis is required. If C1INHRP therapy is not available, then danazol prophylaxis is required. Injection of local anesthetic may precipitate an attack. Figure 2 shows the HAE prophylaxis algorithm.

If considering more than mild manipulation such as dental work, danazol is recommended (even in children and in women in the last trimester of pregnancy; avoid in the first 2

SHORT-TERM PROPHYLAXIS: INTUBATION OR MAJOR PROCEDURES

C1INHRP therapy 1 hour before surgery (to be used if intubation is used; not available in all countries and currently not available in the United States). The recommended dosage is 500 U up to a weight of 50 kg (110 lb), 1,000 U for weight greater than 50 kg (110 lb) and less than 100 kg (220 lb), and 1,500 U if weight is greater than 100 kg (>220 lb). A second dose of an equal amount should be immediately available at time of surgery.8, 16, 17, 40 Repeat daily or as needed until there is no

LONG-TERM PROPHYLAXIS

If a patient experiences more than 1 severe event per month or is disabled more than 5 days per month or if the patient has a history of previous airway compromise, then consider prophylaxis with tranexamic acid, androgens, or C1INHRP therapy on demand. The number of events per year does not predict severity of the next event or whether the first or next event will be an airway event.

Attenuated androgens danazol and stanozolol (stanozolol is available in the United States through pharmacies

TREATMENT OF ACUTE HAE ATTACKS

The first-line therapy for treatment of any significant angioedema event is C1INHRP (C1INHRP administered at 500 U up to a weight of 50 kg, 1,000 U for a weight of more than 50 kg to less than 100 kg (220 lb), and 1,500 U if weight is more than 100 kg).8, 16, 17, 22, 27, 66

If C1INHRP is not available, other therapies may include increasing (usually doubling) the androgen (danazol or stanozolol) dose, tranexamic acid (Table 1), early use of adrenaline (if other therapy is not available but

BLOOD PRODUCT RISKS

Blood product infusion risks are reviewed annually by the Canadian Pediatric Society, Infectious Diseases and Immunization Committee,68 and the safety profile for pasteurized C1INHRP has been previously presented.34 We recommend patients receiving blood products should undergo annual hemosurveillance similar to the Canadian Hemophilia Program (Dr Bruce Ritchie, [email protected]).33 To date, bloodborne pathogen transmission with pasteurized C1INHRP has not been reported.16, 22, 34

COMPREHENSIVE CARE CLINICS

We recommend that a comprehensive care clinic programs be established for the diagnosis, therapy, and management of HAE similar to the model for comprehensive care of hemophilia in Canada.8, 16, 17, 19, 22, 21, 27, 64 A suggested CHAES/SAHC clinic model for HAE is included in http://www.hemophilia.ca/nrbdo/en/home.php, conference proceedings and conference recommendations,16, 18, 19, 21 and is outlined in Table 2.

DATABASE REGISTRY FOR HAE

We recommend comprehensive care clinics be encouraged to register HAE patients in national and international database registries to facilitate progress in management of this disorder. The European HAE network PREHAEAT chaired by Marco Cicardi established a European HAE Register (www.haeregister.org) and invited international collaboration in this and the International Hereditary Angioedema group (http://www.haei.org/) to facilitate advancement in HAE management. Countries are encouraged to fund

EMERGING THERAPIES

Double-blind, placebo-controlled clinical trials are under way, including human blood product C1-INH products, kallikrein inhibitor, bradykinin β2-receptor inhibitor, and recombinant C1-INH. Results of these trials should be available in the near future and should provide expanded options for therapy (http://www.hemophilia.ca/nrbdo/en/home.php, conference presentations; Fifth C1 Inhibitor Deficiency Workshop).16

ACKNOWLEDGMENTS

We thank the partners, sponsors, and the NRBDO (Canada) Meeting Organizing committee for participating in and contributing financial support to the meeting held in Toronto, Ontario, Canada, February 3, 2006, and the Fifth C1 Inhibitor Deficiency Workshop at which the consensus described herein was agreed to (listed on the Canadian Hemophilia Society Web site: http://www.hemophilia.ca/nrbdo/en/home.php, NRBDO, final program, and on the program for the Fifth C1 Inhibitor Deficiency Workshop found

REFERENCES (68)

  • H Farkas et al.

    The Hungarian HAE experience

    Transfus Apheresis Sci

    (2003)
  • K Bork et al.

    Hereditary angioedema: new findings concerning symptoms, affected organs, and course

    Am J Med

    (2006)
  • K Bork et al.

    Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy

    Am J Med

    (2003)
  • BL Zuraw et al.

    The value of rocket immunoelectrophoresis for C4 activation in the evaluation of patients with angioedema or C1-inhibitor deficiency

    J Allergy Clin Immunol

    (1986)
  • B Ritchie

    Tissue archives to track blood borne pathogens in people receiving blood products

    Transfus Apheresis Sci

    (2003)
  • J DeSerres et al.

    Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinert P) in hereditary angioedema: a review

    Transfus Apheresis Sci

    (2003)
  • B Ritchie

    Protease inhibitors in the treatment of hereditary angioedema

    Transfus Apheresis Sci

    (2003)
  • A Agostoni et al.

    Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema

    J Allergy Clin Immunol

    (1980)
  • P Hellstern et al.

    Practical guidelines for the clinical use of plasma

    Thromb Res

    (2002)
  • M Cicardi et al.

    Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients

    J Allergy Clin Immunol

    (1997)
  • FL Johnson et al.

    Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma

    Lancet

    (1972)
  • H Falk et al.

    Hepatic angiosarcoma associated with androgenic-anabolic steroids

    Lancet

    (1979)
  • GL Andriole et al.

    Danazol-induced cystitis: an undescribed source of hematuria in patients with hereditary angioneurotic edema

    J Urol

    (1986)
  • D Crampon et al.

    Danazol therapy: an unusual aetiology of hepatocellular carcinoma [letter]

    J Hepatol

    (1998)
  • K Bork et al.

    Hepatocellular adenomas in patients taking danazol for hereditary angiooedema

    Lancet

    (1999)
  • K Bork et al.

    Danazol-induced hepatocellular adenoma in patients with hereditary angio-oedema

    J Hepatol

    (2002)
  • M Cicardi et al.

    How do we treat patients with hereditary angioedema

    Transfus Apheresis Sci

    (2003)
  • D Davies et al.

    Tranexamic acid and arterial thrombosis [letter]

    Lancet

    (1977)
  • E Rydin et al.

    Tranexamic acid and intracranial thrombosis [letter]

    Lancet

    (1976)
  • M Levi et al.

    Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency

    J Allergy Clin Immunol

    (2006)
  • BL Zuraw

    Diagnosis and management of hereditary angioedema: an American approach

    Transfus Apheresis Sci

    (2003)
  • H Quincke

    Concerning the acute localized oedema of the skin

    Monatsh Prakt Derm

    (1882)
  • W Osler

    Hereditary angio-neurotic oedema

    Am J Med Sci

    (1888)
  • LC Zingale et al.

    Angioedema without urticaria: a large clinical survey

    CMAJ

    (2006)
  • Cited by (196)

    • The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update

      2022, World Allergy Organization Journal
      Citation Excerpt :

      For scheduled pre-procedural prophylaxis, androgens are used for 5 days before and 2–3 days post event. Tranexamic acid has been used for pre-procedural prophylaxis in the past, however it is not recommended by most guideline experts7,11,169,173–175 With all pre-procedural prophylactic treatments, break-through 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.11,165,166,173,176

    • Angioedema with severe acute abdominal pain: Think of hereditary angioedema

      2021, Clinics and Research in Hepatology and Gastroenterology
    • Quality of life in patients with hereditary angioedema in Canada

      2021, Annals of Allergy, Asthma and Immunology
      Citation Excerpt :

      It manifests as recurrent attacks of nonpruritic and nonpitting subcutaneous or submucosal swelling. Typical areas affected are the upper airways, face, extremities, genitals, and gastrointestinal system.4 Angioedema of the throat or larynx can be life-threatening because of asphyxiation, whereas nausea, vomiting, and severe abdominal pain may result in unnecessary surgical procedures.5

    View all citing articles on Scopus

    Disclosures: Dr Bowen either has consultancy with or has been involved in educational programs and their organization that have required fundraising from Pharming, Jerini, Dyax-Genzyme, CSL Behring, and KOS. Dr Cicardi has consultancies with Jerini, Dyax, Lev Pharma, CSL Behring, and Pharming. Dr Zingale has consultancies with Pharming and Jerini.

    View full text