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International consensus on hereditary and acquired angioedema

International consensus on hereditary and acquired angioedema David M. Lang, MD Werner Aberer, MD y; Jonathan A. Bernstein, MD z; Hiok Hee Chng, MD x;Anete Sevciovic Grumach, MD, PhD jj; Michihiro Hide, MD, PhD {; Marcus Maurer, MD Richard Weber, MD and Bruce Zuraw, MD yy * Allergy/Immunology, Respiratory Institute, Cleveland Clinic, Cleveland, Ohioy Department of Dermatology, Medical University of Graz, Graz, Austriaz Department of Internal Medicine, Division of Immunology/Allergy, University of Cincinnati, Cincinnati, Ohiox Department of Rheumatology, Allergy, and Immunology Tan Tock Seng Hospital, Singaporejj Faculty of Medicine ABC, São Paulo, Brazil{ Department of Dermatology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan# Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité e Universitätsmedizin Berlin, Germany** Department of Medicine, Division of Allergy/Immunology, National Jewish Health, Denver, Coloradoyy Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of San Diego, San Diego, California Article history:Received for publication October 8, 2012.
Accepted for publication October 15, 2012.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 Definition and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .397 HAE-1/2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 HAE with normal C1INH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 ACID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 ACEI-associated angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .397 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 Treatment of attacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 Long-term prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 Short-term prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 Treatment in special groups: children, women, and pregnant women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 ACID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 Angioedema associated with ACEIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 Unmet Needs: Diagnosis and Management in Resource-Limited Environments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Reprints: David M. Lang, MD, Department of Allergy/Immunology, Cleveland Clinic, ViroPharma Inc. Dr. Maurer has served as a consultant and speaker for Shire 9500 Euclid Avenue, A90, Cleveland, OH 44022; E-mail: .
Pharmaceuticals, ViroPharma Inc, Pharming, Isis Pharmaceuticals Inc, and Bio- Disclosures: Dr. Lang has served as a speaker for Genentech/Novartis; and as cryst Pharmaceuticals. Dr. Weber has been on the speakers bureau for Genentech a speaker and consultant for GlasxoSmithKline and Merck. Dr. Lang has also and AstraZeneca. Dr. Weber has also received research grants from Genentech, received research support from Genentech/Novartis. Dr. Lang is on the AAAAI Merck, and GlaxoSmithKline. Dr. Weber is the ACAAI President-Elect. Dr. Zuraw Board of Directors. Dr. Aberer has served as a speaker for SOBI, Shire Pharma- has served as a consultant an speaker for Dyax, a consultant for CSL Behring ceuticals, and CSL Behring. Dr. Aberer has also received an unrestricted research and Shire Pharmaceuticals. Dr. Zuraw has also received research support from grant from Shire Pharmaceuticals. Dr. Berstein has served as a consultant and Shire Pharmaceuticals, National Institutes of Health, US Department of Veterans speaker for ViraPharma, Dyax, Shire Pharmaceuticals, and CSL Behring. Dr. Ber- Affairs, and US Department of Defense. Dr. Zuraw is the Chair of the US HAEA stein has also received research support from ViraPharma, CSL Behring, Dyax, Medical Advisory Board. Drs Chng and Grumach have no conflicts of interest to Shire Pharmaceuticals, and Pharming. Dr. Hide has served as an advisor for 1081-1206/12/$36.00 - see front matter Ó 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
D.M. Lang et al. / Ann Allergy Asthma Immunol 109 (2012) 395e402 the vascular to the interstitial compartment and edema forma-tion.Angioedema can involve virtually any site, including In light of the remarkable progress recently achieved in our extremities, genitourinary tract, bowel, face, oropharynx, or understanding of angioedema, the American Academy of Allergy, Bradykinin is the mediator responsible for angioedema in Asthma and Immunology, American College of Allergy, Asthma and patients with HAEHigh levels of bradykinin are present in plasma Immunology, European Association of Allergy and Clinical Immu- from patients with angioedema due to C1INH deficiencyBradyki- nology, and World Allergy Organization have joined together to nin is cleaved from high-molecular-weight kininogen by plasma promote communication about diagnosis and management of kallikrein, which is physiologically generated from its zymogen by angioedema on a global scale. Within the framework of this collab- activated factor XII (FXII) on contact system activationThe mech- oration, termed the International Collaboration in Asthma, Allergy, anism leading to contact system activation in vivo has not been and Immunology (iCAALL), a series of International Consensus determined. C1INH intervenes at several steps in controlling contact (ICON) documents are being developed to serve as a resource and to system activation, being an important inhibitor of FXII and plasma support physicians and other health care professionals in caring for kallikrein. Reduced levels or impaired function of C1INH can lead to patients with allergic and immunologic disorders.
excessive bradykinin release and angioedem This document was developed by an international workgroup, Bradykinin-mediated angioedema can be either hereditary or formed to develop an ICON document in which the pathogenesis, acquired Two forms of HAE have been defi(1) HAE prevalence, clinical manifestations, diagnosis, and management of due to C1INH deficiency and (2) HAE with normal or near-normal angioedema are described. Angioedema may occur with or without antigenic and functional levels of C1INH. HAE due to C1INH defi- concomitant hives. The consensus of the leadership of the 4 soci- ciency can be further divided based on the C1INH antigenic level: eties and the author group was that based on improvements in our type I HAE (HAE-1) is characterized by low antigenic and functional understanding of hereditary angioedema (HAE) in recent years and C1INH levels, whereas type II HAE (HAE-2) is due to C1INH the recent introduction of 5 HAE-specific drugs, the goals of iCAALL dysfunction and is characterized by normal (or elevated) antigenic would best be served by focusing this ICON on angioedema but low functional C1INH levels. There are also 2 subtypes of HAE occurring without concomitant hives and more specifically by with normal C1INH, either associated with a mutation in the FXII concentrating primarily on C1 inhibitor (C1INH) deficiency gene or of unknown cause. Mutations of the FXII gene have been syndromes. The author group was subdivided based on topic identified in some families, but the pathophysiology is still unde- preference to generate specific sections of the ICON. Content was fined. Acquired C1INH deficiency (ACID) is frequently associated derived from literature searches, published guidelines, and clinical with lymphoproliferative diseases and/or autoantibodies against expertise. Drafts of the ICON were peer reviewed within the author C1INH that may be responsible for C1INH consumption. Autoim- group and subsequently by a steering group of the 4 societies.
mune disorders (eg, systemic lupus erythematosus) have also been Where evidence gaps were encountered, content was determined described in association with ACID. Angioedema may also be caused by an angiotensin-converting enzyme inhibitor (ACEI),which interferes with bradykinin degr Angioedema is a vascular reaction of the deeper layers of the skin and mucous membranes, with localized blood vessel dilatation and HAE-1/2 is a rare autosomal dominant disorder that affects increased permeability that result in tissue swelling.The swelling is approximately 1:50,000 individuals, with reported ranges from asymmetric, nondependent, and nonpitting and resolves without 10,000 to 1:150,000Many different mutations of the SERPING1, scarring or discoloration. The angioedema is caused by a temporary which codes for C1INH, are known to cause HAE-1/2. Approxi- increase in vascular permeability mediated by release of one or more mately 85% of the mutations result in HAE-1, and 15% of them result mediators. The specific cellular mechanisms that increase endo- in HAE-2; de novo mutations of SERPING1 account for approxi- thelial permeability during angioedema have not been determined.
mately 20% to 25% of HAE with normal C1INH is less However, histamine and bradykinin, the mediators responsible for most angioedema, act through G proteinecoupled receptorsexpressed on cell membranes. Bradykinin enhances vascular permeability via phosphorylation of vascular endothelial cell cad-herin and activation of phospholipase, leading to intracellular There is no sex predominance in HAE-1/2.Most cases of HAE calcium mobilization and eventually allowing flow of plasma from with normal C1INH are female. Data from recent studies in Japan Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ACID, acquired angioedema due to C1 inhibitor deficiency; AE, angioedema; C1INH, C1 inhibitor; HAE-1,hereditary angioedema type 1 (due to C1 inhibitor deficiency); HAE-2, hereditary angioedema type 2 (due to C1 inhibitor defect).
aMast cellemediated angioedema may occur with concomitant hives. Nonclassified implies that no cause has been identified. High-quality evidence indicates bradykinin is themediator responsible for angioedema in HAE-1/2 and in association with ACEI; for HAE with normal C1INH levels, the role of bradykinin is assumed, and additional evidence isrequired to support this.
D.M. Lang et al. / Ann Allergy Asthma Immunol 109 (2012) 395e402 (132 patients), China (133 patients), and Brazil (210 patients) preceding attacks, and an older age of symptom onset.As noted suggest a lower HAE prevalence in these countries than in Europe in evidence indicates the angioedema in HAE1/2 and and North The reasons are unknown but may include angioedema associated with ACEIs are mediated by bradykinin; for underdiagnosis or a lower prevalence in Asian populations. HAE HAE with normal C1-INH, the role of bradykinin is assumed. States severity varies considerably, even in family members with the same of increased estrogen exposure due to either pregnancy or exoge- gene mutation. The mean age at onset of symptoms is 8 to 12 years; nous estrogen administration frequently exacerbate HAE with 75% experience their first attack by the age of 15 y normal C1INH. Disease severity is typically more pronounced inwomen compared with men. Inheritance suggests an autosomal dominant pattern; however, penetrance appears to be lower thanwith HAE-1/2.
Compared with urticarial swelling, the swelling of angioedema is deeper and longer lasting, is nonpruritic, and may be painful.
Although the appearance of the angioedema itself cannot establishthe cause or specific diagnosis, details of the swelling may aid the ACID is analogous in its presentation to HAE-1/2, except that clinician in distinguishing the different causes of angioedema.
a family history is lacking and angioedema generally develops after and list pertinent characteristics of angioedema as Angioedema related to ACEIs has a strong predilection to involve Angioedema attacks typically involve the extremities, genito- the face, lips, and tongue.Angioedema affecting the bowels or urinary tract, bowel, face, oropharynx, or larynx. Attacks may last extremities is less common. Risk of angioedema from ACEIs is for 72 to 96 hours, are often severe and disabling, and may be higher in smokers, African Americans, and women; diabetes has associated with significant morbidity and risk for mortality.
been associated with lower riskAngioedema most commonly Extremity and abdominal attacks each account for almost 50% occurs in the first month of treatment; however, more than 25% of of all attacks, and more than 50% of patients experience at least patients experience their first attack of angioedema 6 months or one upper airway attack with risk for asphyxiation during their longer after beginning ACEI therapy; some patients have received lifetime.The frequency of attacks is highly variable. Most often, ACEIs for years before their first episode. Nearly 50% have angioe- patients present with symptoms during childhood,with dema recurrences, which may continue for months after ACEI a worsening of symptoms around pubertyProdromal symp- toms, such as fatigue, irritability, weakness, nausea, and erythemamarginatum, precede an angioedema attack by several hours or up to a day in up to 50% of HAE patients.Symptoms may be Elucidating the cause of angioedema involves a detailed history, worsened by stress, trauma, exogenous estrogens, ACEIs, menses, careful physical examination, and appropriate laboratory testing.
As indicated in the differential diagnosis of HAE or ACID includes chronic spontaneous angioedema, IgE-mediated angioe- The clinical presentation of HAE with normal C1INH resembles dema, and ACEI-associated angioedema. These conditions can be that of HAE-1/2, with the following key differences: fewer attacks suspected based on exposure history. IgE-mediated angioedema with more attack-free intervals, higher percentage of cutaneous can be confirmed by cutaneous or in vitro testing for immediate and facial attacks, lower percentage of abdominal attacks, lower hypersensitivity, but routine testing without a suspected allergen is percentage of multisite attacks, no erythema marginatum not indicated. Clinical clues for angioedema diagnosis are describedin .
C1INH deficiency merits investigation in patients with recurrent angioedema without concomitant hives, including patients with ACEI-associated A diagnosis of C1INH defi- ciency requires laboratory confirmation with measurement of theC4 level, C1INH antigenic level, and C1INH functional level. May be IgE mediated, noneIgE mediated, or gives the complement profiles in various forms of recurrent angioedema. C4 is an excellent screening test for C1INH deficiency; Mast cellemediated angioedema typically lasts <48 most patients with C1INH deficiency have a reduced C4 level. This hours; bradykinin-mediated angioedema often reduced C4 level is found in nearly 100% of cases during attacks A normal C4 level during an attack of angioedema strongly Very frequent in HAE-1/2 or ACID; less common but may occur in HAE with normal C1-INH level;uncommon but may occur with ACEI-associated If C1INH deficiency cannot be confirmed by laboratory testing, a strong family history of angioedema without concomitant hives, not responsive to high-dose antihistamines, supports a diagnosis of Suggestive of ACEI-induced angioedema or HAE with HAE with normal C1INH. Search for the FXII mutation can be per- formed in these patients and if detected can con Characteristic of HAE, especially erythema marginatum; occurs in up to 50% of HAE patients HAE with normal C1INH; however, lack of FXII mutation does not Present in 75% of patients with HAE due to C1INH deficiency; a required element for diagnosis of HAE In ACID, the C1q level, which is normal in HAE patients with rare exceptions, is low in most Presence of an underlying Abbreviations: ACID, acquired angioedema due to C1INH deficiency; ACEI, malignant tumor or detection of C1INH autoantibodies strongly angiotensin-converting enzyme inhibitor; C1INH; C1 inhibitor; FXII, factor XII; HAE- supports a diagnosis of ACID. The diagnosis of idiopathic angioe- 1, hereditary angioedema type 1 (due to C1 inhibitor deficiency); HAE-2, hereditaryangioedema type 2 (due to C1 inhibitor defect).
dema is based on the exclusion of known causes of angioedema, aNonclassified implies that no cause has been identified.
D.M. Lang et al. / Ann Allergy Asthma Immunol 109 (2012) 395e402 Table 3Complement levels in the diagnosis of HAE Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ACID, acquired angioedema due to C1INH deficiency; HAE-1, hereditary angioedema type 1 (due to C1INHdeficiency); HAE-2, hereditary angioedema type 2 (due to C1INH defect); C1INH, C1 inhibitor.
aNonclassified implies that no cause has been identified.
attacks, but long-term use may be associated with more potentialfor harm. Both the efficacy and adverse effects of 17a-alkylated Treatment of HAE can be categorized as treatment of attacks androgens are dose related; for this reason, these agents are rec- (on-demand treatment) and prophylactic treatment (short term ommended at the lowest dose that achieves control of attacks.
and long term). All patients with C1INH deficiency should have an Although generally less efficacious than attenuated androgens, established plan on how to respond and effective drugs immedi- some patients benefit with the antifibrinolytic drug ε-aminocaproic acid (Amicar; Xanodyne Pharmaceuticals, Newport, Kentucky) forlong-term prophylaxis of HAE.Another antifibrinolytic drug, tranexamic acid (Cyklokapron, Transamin; Pfizer Inc, New York, Standard angioedema treatment modalities, such as epineph- New York), has also been widely used in Europe for long-term rine, corticosteroids, or antihistamines, do not have a salutary effect prophylaxis of and has recently become available in oral and are not recommended. Currently approved treatments for form in the United States (Lysteda 650; Ferring Pharmaceuticals, attacks are listed in These agents are efficacious and safefor on-demand treatment and are most effective whenadministered early in an attack.
Fresh frozen plasma (FFP) should be used to treat attacks of HAE Short-term prophylaxis can be achieved with administration of when no other treatment proven to be effective is available. FFP is 1,000-2,000 U of plasma-derived C1INH or, if plasma-derived generally effective in treating acute attacks of ; C1-INH is not available, infusion of 2 U (10 mL/kg for children) of however, sometimes it lacks efficacy or can cause sudden wors- solvent or detergent-treated plasma or FFP several (up to 6) hours ening of symptoms. FFP also carries a risk of viral transmission.
before a scheduled procedure.High-dose 17a-alkylatedandrogens (6-10 mg/kg/day in divided doses to a maximum of 200 mg 3 times daily of danazol per day or equivalent) taken for 5 Patients not treated successfully with on-demand therapy to 7 days before and 2 days after the procedure is an alternative should be considered for long-term prophylaxis. Attack frequency strategy for short-term prophyBecause there are no and severity, location of and access to acute care, other comorbid studies assessing the comparative efficacy of these drugs for short- conditions, individual circumstances, and patient values and pref- term prophylaxis, our recommendations are based on expert erences may all influence the decision to undergo treatment opinion and small, uncontrolled, observational studies. For emer- with long-term prophylaxis. In addition to being efficacious for gency procedures and in pregnant patients, administration of on-demand treatment of attacks, plasma-derived C1INH has also plasma-derived C1INH is preferred. A dose of on-demand short- been reported to be effective for long-term prophyThe term treatment drug (C1INH, ecallantide, or icatibant) should be additional agents that can be used for long-term prophylaxis are readily available, particularly for dental procedures or surgical listed in . Treatment with oral 17a-alkylated androg procedures that require intubation. In selected situations (eg, when has been reported to decrease the frequency and severity of HAE trauma is expected to be minimal and on-demand therapy is also short-term prophylaxisand on-demand in Europe Abbreviations: EMA, European Medicines Agency; FDA, US Food and Drug Administration.
aRegistration and availability of these drugs differ from country to country.
D.M. Lang et al. / Ann Allergy Asthma Immunol 109 (2012) 395e402 Table 5Drugs commonly used for long-term HAE prophylaxis 17a-Alkylated androgensDanazol (Danocrine; Sanofi- hypertension, alterations in lipid profile Unusual: Decreased growth rate in children, masculinization of the female fetus,cholestatic jaundice, peliosis hepatis andhepatocellular adenoma Antifibrinolyticsε-Aminocaproic acid (Amicar; Abbreviations: FDA, US Food and Drug Administration; HAE, hereditary angioedema.
aRegistration and availability of these drugs differ from country to country.
readily available), omission of preprocedural treatment with on- demand treatment contingent on any signs of an attack is an Angioedema, with a predilection for the face and tongue, has been observed in 0.1% to 0.7% of patients treated with A Treatment in special groups: children, women, and Because ACEIs are commonly prescribed, angioedema from ACEIs is encountered more frequently than angioedema from C1INHdeficiency. Bradykinin levels are elevated during episodes of Changes in estrogen in association with puberty, menopause, or hormone replacement therapy, oral contraceptive use, or preg- ACE is a dipeptidylcarboxypeptidase that converts angiotensin I nancy can provoke or exacerbate a tendency for more frequent and/ to angiotensin II. ACE is also a kininase II, an enzyme that catabo- or severe attacks in some women with C1INH deficiencyFor lizes bradykinin into inactive peptides. When ACE is inhibited, pregnant patients with more serious flares of HAE, long-term bradykinin degradation can be prolonged.The presence prophylaxis is an appropriate intervention because the potential of concomitant genetic variants affecting function of other for benefit exceeds the potential for harm and burden associated bradykinin-degrading enzymes may be necessary for development with this treatment.The decision to prescribe long-term of ACEI-induced angioedema.Consistent with this hypothesis, prophylaxis during pregnancy should be considered carefully on reduction in activity of another kininase, dipeptidyl peptidase IV, in an individualized basis and involve the patient in the decision- the context of immunosuppressive therapy for organ trans- making process. Because treatment with androgens is contra- plantation has been associated with an increase in angioedema in indicated during pregnancy,plasma-derived C1INH is preferred and may also be considered for women desiring to become preg- Angioedema has also been reported in association with Angioedema attacks during labor and delivery are relatively angiotensin receptor blockers (ARBs) and with aliskiren, a renin raThis can be managed expectantly by having an on-demand inhibitor.The rate of angioedema in patients receiving an ARB HAE-specific agent available should an episode of angioedema is substantially lower compared with patients treated with an occur. Clinical trials investigating the efficacy and safety of these AA 0.4% rate of angioedema (relative risk, 0.31; 95% confi- novel agents for children are lacking. However, clinical experience dence interval, 0.07-1.47, for 150 mg; relative risk, 0.57; 95% with C1INH replacement therapy in children implies these agents confidence interval, 0.17-1.89, for 300 mg) has been observed with are favorable from the standpoint of balancing the potential for benefit with the potential for harm or burden in properly selected Management of angioedema associated with ACEIs entails ACEI suspension.Because angioedema related to ACEI is a class effect,all ACEIs should henceforth be avoided. As with management of acute angioedema in patients with C1INH deficiency, adminis- Because the pathogenesis of ACID entails low levels of C1INH tration of antihistamines, corticosteroids, or epinephrine is not due to increased catabolism, either related to a malignant tumor associated with benefit and is not recommended. For severe (eg, lymphoma) or an autoimmune disorder (eg, systemic lupus angioedema episodes, hospitalization may be required; life- erythematosus), treatment of such an underlying condition can threatening airway obstruction may develop that mandates result in improvement in ACID.Compared with HAE, anecdotal intensive care management. Deaths from ACEI-induced laryngeal evidence implies these patients may be less responsive to attenu- edema have been reportedIcatibant and FFPhave been ated androgens but exhibit greater response to treatment with associated with salutary effects for treatment of ACEI-associated antifibrinolytic agents.7 Response to plasma-derived CINH may be angioedema; however, no data beyond these observational less reliable based on the presence of C1INH Icatibant reports have been published. No evidence exists at this time to and ecallantide have been reported to be efficacious for treatment guide management of acute angioedema associated with either an D.M. Lang et al. / Ann Allergy Asthma Immunol 109 (2012) 395e402 Patients with a history of angioedema during treatment with an not available in Taiwan. South American countries have access to ACEI may be at elevated risk if switched to aliskiren as an alter- quantitative C1INH evaluation, but access is limited in Central native antihypertensive agent, and aliskiren should be avoided if American countries. In countries in South and Central America, feasible in these patients. A modest risk for angioedema to recur C1INH functional level determination is available in only a few exists in patients who are switched to an ; however, most can locations. The cost of C1q and C1INH assays are deemed to be not receive ARB treatment without angioedema recurrence. One affordable to the average patient even in developed countries such found no statistically significant difference in recurrence as Singapore and Hong Kong. Interestingly, these 4 laboratory tests rates of angioedema comparing subsequent treatment with an ARB are available in Pakistan to patients seen at specialty centers.
and a calcium channel antagonist. A meta-analysisestimated Health care professionals practicing in locations where one or a 2% to 17% risk of recurrence of angioedema in patients who more tests are not available or affordable may use a thorough had ACEI-induced angioedema and were switched to an ARB, history to aid in reaching a diagnosis. Measurement of C4 levels is whereas a pooled analysis of 2 randomized controlled trials and a cost-effective screening test to rule out HAE, although the C4 level a meta-analysisgenerated an estimate of angioedema recurrence of 10% or less and reported that recurrent episodes of angioedema It is understandable that costs of drug registration and cost tended to be less severe and developed earlier in therapy. A recovery from sales in any country are important to a pharmaceu- persistent tendency to experience angioedema, irrespective of tical company. In the case of rare conditions, such as HAE and ACID, subsequent drug exposures, may exist in some patients despite low use may discourage new drug applications. Health care ACEI Additional studies with sufficiently large professionals who support coverage of medical expenses play an sample size will be required to more accurately define the potential important At the time of this writing, C1INH replacement for ongoing angioedema in patients with ACEI-associated angioe- therapy, ecallantide, and icatibant were not available in many dema and to guide proper pharmacologic management of these countries in the Asia-Pacific region, including India, Indonesia, patients. The decision to switch to an ARB (or to aliskiren) when Philippines, Pakistan, Thailand, Sri Lanka, Singapore, and Taiwan, suspending ACEI use due to angioedema should be considered in whereas ecallantide and icatibant were not available in Hong Kong, the context of a careful assessment of potential harm (recurrent Japan, and Korea. In the Latin American countries, Argentina has angioedema, which may be serious or even life-threatening) C1INH replacement therapy, and icatibant is available in Brazil and compared with benefit (therapeutic need for angiotensin/renin Mexico. Even the United States has had access to new therapies for inhibition, which in some patients may be associated with increased survival).This decision should be made in the context Attenuated androgens, danazol and stanozolol, and tranexamic of patient circumstances and include patient values and prefer- acid are more widely available and generally affordable. In several ences in the decision-making process.
Latin American countries, however, attenuated androgens are notavailable and/or are costly (these drugs are supported by thegovernment in Brazil). In many areas of the world, treatment of HAE and ACID focuses on routine long-term prophylaxis because effec- tive short-term treatment is not available; for example, more than The unpredictable nature and severity of HAE may be associated half of Brazilian HAE patients are treated with FFP is still with physical, emotional, and economic burdens for patients and used in some countries, such as China, for prophylaxis before their families.To obtain a clearer understanding of the burden of surgical or dental procedures and for acute attacks.Even in HAE and unmet needs for its diagnosis and management in countries where on-demand treatment for attacks is available, resource-limited areas, a survey of health care professionals in the FFP has been used due to restricted access related to cost Asia-Pacific region was performed (Hiok Hee Chng, MD, unpub- Where HAE-specific drugs for acute attacks are not available, Although recent advances in our understanding of C1INH defi- emphasis must be placed on patient education for avoidance of ciency syndromes and the introduction of the 5 novel medications triggers, such as minor trauma (including dental procedures), listed in carry the promise of improved health care vigorous exercise, emotional stress, the use of estrogen-containing outcomes for patients with HAE, these advances have not trans- medications (eg, hormone replacement therapy and contracep- lated into improved outcomes for many patients with HAE and tives), alcohol, infection, and ACEIs in patients with HAE and ACID.
ACID in resource-limited environments. There are several factors For patients with ACID, treatment of the primary disease (if that appear to be contributing to this.
identified) may be effective in preventing recurrence of angioe- First, there is a lack of awareness by patients of the nature of dema.This finding should be emphasized, especially where their condition. Consequently, patients may fail to seek medical effective new therapies for acute attacks are lacking or not attention based on symptoms that are infrequent, mild, or both.
Moreover, based on misconceptions regarding their symptoms, A patient’s acceptance of the disease and adherence to treat- they may assume their angioedema is caused by allergy. Second ment and medical follow-up is an even more important component misdiagnosis by health care professionals can lead to mislabeling of of treatment success in developing countries. A World Health patients with HAE or ACID as having angioedema caused by allergy.
Reportaffirmed that “medication non-adherence is so great and The most serious consequence of this mislabeling is that patients the consequences are of such concern that more people worldwide with laryngeal attacks who are at risk of death might receive would benefit from efforts to improve medication adherence than treatment with epinephrine, antihistamines, and corticosteroids.
from development of new medical treatments.” In developed Third, diagnostic tests are either not available or beyond the countries, patients with chronic conditions have adherence rates of reach of the average patient. Although a C4 level is often readily 50% to 60%, despite evidence that medication improves quality of available and affordable in many countries, the same may not be life and prevents death.In economically challenged countries, true for C1q and C1INH antigenic and functional levels. Laboratories with poor access to health care, a lack of diagnostic assays, and provide services based on demand and cost recovery. In the limited availability of medications taken into account, poor Asia-Pacific region, C1q, C1INH antigenic, and C1INH functional adherence threatens all efforts to treat chronic conditions, such as levels are not available in India, Indonesia, Thailand, Philippines, diabetes, depression, and HIV/AIDS.Refusal to receive continuous and Vietnam, and both C1INH antigenic and functional levels are therapy can lead to higher morbidity and mortality in D.M. Lang et al. / Ann Allergy Asthma Immunol 109 (2012) 395e402 Because even a history of asphyxia in one’s family may not lead [21] Zingale LC, Castelli R, Zanichelli A, Cicardi M. Acquired deficiency of the some patients to seek medical care, it is likely that adherence in inhibitor of the first complement component: presentation, diagnosis, course,and conventional management. Immunol Allergy Clin North Am. 2006;26: HAE, although not formally evaluated, is a major challenge.
The authors of this ICON recommend a public health initiative, [22] Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor- particularly in resource-limited areas, for HAE, to include the associated angioedema. Immunol Allergy Clin North Am. 2006;26:725e737.
[23] Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associatedangioedema. Clin Pharmacol Ther. 1996;60:8e13.
 Educational programs for the public and health care [24] Gibbs C, Lip G, Beevers D. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Pharmacol. 1999;48:861e865.
[25] Miller D, Oliveria S, Berlowitz D, Fincke B, Stang P, Lillienfeld D. Angioedema incidence in US veterans initiating angiotensin converting enzyme inhibitors.
 Establishment of reference centers in each country or region [26] Beltrami L, Zanichelli A, Zingale L, Vacchini R, Carugo S, Cicardi M. Long term follow up of 111 patients with angiotensin converting enzyme inhibitor related angioedema. J Hyperten. 2011;29:2273e2277.
 Expanded activities of patient support groups to reach out to [27] Zingale LC, Beltrami L, Zanichelli A, et al. Angioedema without urticaria: health care professionals and affected patients and their families.
a large clinical survey. CMAJ. 2006;175:1065e1070.
[28] Zuraw BL, Sugimoto S, Curd JG. The value of rocket immunoelectrophoresis for C4 activation in the evaluation of patients with angioedema or C1-inhibitor deficiency. J Allergy Clin Immunol. 1986;78:1115e1120.
[29] Gompels MM, Lock RJ, Morgan JE, Osborne J, Brown A, Virgo PF. A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 We thank the following individuals whose survey responses are inhibitor deficiency. J Clin Pathol. 2002;55:145e147.
described in this ICON: Jiu-Yao Wang (Taiwan), Fanny W. S. Ko (Hong [30] Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman Kong), Mimi Chang (Hong Kong), Hae-Sim Park (Korea), Suwat factor) gene in hereditary angioedema with normal C1 inhibitor. BiochemBiophys Res Commun. 2006;343:1286e1289.
Benjaponpitak (Thailand), Madeleine Sumpaico (Philippines), Heru [31] Duan QL, Binkley K, Rouleau GA. Genetic analysis of Factor XII and bradykinin Sundara (Indonesia), Ashok Shah (India), Manori Amarasekera (Sri catabolic enzymes in a family with estrogen-dependent inherited angioe- Lanka), Osman Yusuf (Pakistan), Sabiha Anis (Pakistan), and Tahir dema. J Allergy Clin Immunol. 2009;123:906e910.
[32] Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks.
J Allergy Clin Immunol. 2009;124:801e808.
[33] Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363:513e522.
[34] Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor [1] Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. 2005;53:373e392.
antagonist, in hereditary angioedema. N Engl J Med. 2010;363:532e541.
[2] Mehta D, Malik AB. Signaling mechanisms regulating endothelial perme- [35] Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the ability. Physiol Rev. 2006;86:279e367.
bradykinin B receptor antagonist icatibant for the treatment of acute attacks [3] Sandoval R, Malik AB, Minshall RD, Kouklis P, Ellis CA, Tiruppathi C. Ca(2þ) of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol.
signalling and PKCalpha activate increased endothelial permeability by disassembly of VE-cadherin junctions. J Physiol. 2001;533(pt 2):433e445.
[36] Zuraw B, Cicardi M, Levy RJ, et al. Recombinant human C1-inhibitor for the [4] Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency treatment of acute angioedema attacks in patients with hereditary angioe- and angioedema: molecular mechanisms and clinical progress. Trends Mol dema. J Allergy Clin Immunol. 2010;126:821e827, e14.
[37] Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with [5] Cugno M, Nussberger J, Cicardi M, Agostoni A. Bradykinin and the patho- a vapor-heated C1 inhibitor concentrate. N Engl J Med. 1996;334: physiology of angioedema. Int Immunopharmacol. 2003;3:311e317.
[6] Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in heredi- [38] Kunschak M, Engl W, Maritsch F, et al. A randomized, controlled trial to study tary angioedema. Ann Allergy Asthma Immunol. 2010;104:193e204.
the efficacy and safety of C1 inhibitor concentrate in treating hereditary [7] Cicardi M, Zanichelli A. The acquired deficiency of C1-inhibitor: lymphopro- angioedema. Transfusion. 1998;38:540e549.
liferation and angioedema. Curr Mol Med. 2010;10:354e360.
[39] Prematta M, Gibbs JG, Pratt EL, Stoughton TR, Craig TJ. Fresh frozen plasma for [8] Bork K, Wulff K, Hardt J, Witzke G, Staubach P. Hereditary angioedema caused the treatment of hereditary angioedema. Ann Allergy Asthma Immunol. 2007; by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol. 2009;124:129e134.
[40] Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary [9] Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol.
XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet.
[41] Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term [10] Zuraw BL. Clincal practice: hereditary angioedema. N Engl J Med. 2008;359: prophylaxis with attenuated androgens in hereditary angioedema: compar- ison of treated and untreated patients. J Allergy Clin Immunol. 1997;99: [11] Grumach AS, Valle SO, Toledo E, et al, on behalf of group interested on HAE (GINHA). Hereditary angioedema: first report of the Brazilian registry and [42] Sloane DE, Lee CW, Sheffer AL. Hereditary angioedema: safety of long-term challenges [published online ahead of print August 7, 2012]. J Eur Acad Der- stanozolol therapy. J Allergy Clin Immunol. 2007;120:654e658.
matol Venereol. doi: 10.1111/j.1468-3083.2012.04670.x.
[43] Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus [12] Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings document. Clin Exp Immunol. 2005;139:379e394.
concerning symptoms, affected organs, and course. Am J Med. 2006;119:267.
[44] Frank MM, Sergent JS, Kane MA, Alling DW. Epsilon aminocaproic acid [13] Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical therapy of hereditary angioneurotic edema: a double-blind study. N Engl J syndrome and its management. Ann Intern Med. 1976;84:586e593.
[14] Bowen T, Cicardi M, Bork K, et al. Hereditary angiodema: a current state-of- [45] Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired the-art review, VII: Canadian Hungarian 2007 International Consensus angioedema: problems and progress: proceedings of the third C1 esterase Algorithm for the Diagnosis, Therapy, and Management of Hereditary inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114(3 Angioedema. Ann Allergy Asthma Immunol. 2008;100(1 suppl 2):S30eS40.
[15] Farkas H, Varga L, Szeplaki G, Visy B, Harmat G, Bowen T. Management of [46] Jaffe CJ, Atkinson JP, Gelfand JA, Frank MM. Hereditary angioedema: the use of hereditary angioedema in pediatric patients. Pediatrics. 2007;120:e713ee722.
fresh frozen plasma for prophylaxis in patients undergoing oral surgery.
[16] Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: bio- J Allergy Clin Immunol. 1975;55:386e393.
logical and clinical characteristics in 235 patients. Medicine (Baltimore). 1992; [47] Bork K, Hardt J, Staubach-Renz P, Witzke G. Risk of laryngeal edema and facial swellings after tooth extraction in patients with hereditary angioe- [17] Prematta MJ, Kemp JG, Gibbs JG, Mende C, Rhoads C, Craig TJ. Frequency, dema with and without prophylaxis with C1 inhibitor concentrate: a retro- timing, and type of prodromal symptoms associated with hereditary spective study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112: angioedema attacks. Allergy Asthma Proc. 2009;30:506e511.
[18] Bork K. Diagnosis and treatment of hereditary angioedema with normal C1 [48] De Serres J, Groner A, Lindner J. Safety and efficacy of pasteurized C1 inhibitor inhibitor. Allergy Asthma Clin Immunol. 2010;6:15.
concentrate in hereditary angioedema: a review. Transfus Apher Sci. 2003;29: [19] Bork K. Hereditary angioedema with normal c1 inhibition. Curr Allergy Asthma [49] Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary [20] Bork K, Gul D, Hardt J, Dewald G. Hereditary angioedema with normal C1 angioedema with danazol: reversal of clinical and biochemical abnormalities.
inhibitor: clinical symptoms and course. Am J Med. 2007;120:987e992.
D.M. Lang et al. / Ann Allergy Asthma Immunol 109 (2012) 395e402 [50] Craig TJ. Appraisal of danazol prophylaxis for hereditary angioedema. Allergy [66] Cupido C, Rayner B. Life-threatening angio-oedema and death associated with the ACE inhibitor enalapril. S Afr Med J. 2007;97:244e245.
[51] Bouillet L, Longhurst H, Boccon-Gibod I, et al. Disease expression in women [67] Bas M, Greve J, Stelter K, et al. Therapeutic efficacy of icatibant in angioedema with hereditary angioedema. Am J Obstet Gynecol. 2008;199:484, e1e4.
induced by angiotensin-converting enzyme inhibitors: a case series. Ann [52] Czaller I, Visy B, Csuka D, Fust G, Toth F, Farkas H. The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor [68] Schmidt PW, Hirschl MM, Trautinger F. Treatment of angiotensin-converting concentrate during pregnancy: a long-term survey. Eur J Obstet Gynecol enzyme inhibitor-related angioedema with the bradykinin B2 receptor antagonist icatibant. J Am Acad Derm. 2010;63:913e914.
[53] Sheffer AL, Fearon DT, Austen KF. Hereditary angioedema: a decade of [69] Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated management with stanozolol. J Allergy Clin Immunol. 1987;80:855e860.
with angiotensin-converting enzyme inhibitor use: outcome after switching [54] Farkas H, Jakab L, Temesszentandrasi G, et al. Hereditary angioedema: to a different treatment. Arch Intern Med. 2004;164:910e913.
a decade of human C1-inhibitor concentrate therapy. J Allergy Clin Immunol.
[70] Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated [55] Kreuz W, Rusicke E, Martinez-Saguer I, Aygoren-Pursun E, Heller C, with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Klingebiel T. Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema. Transfusion. 2012;52:100e107.
[71] Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT. The [56] Levi M, Choi G, Picavet C, Hack C. Self-administration of C1-inhibitor humanistic burden of hereditary angioedema: impact on health-related concentrate in patients with hereditary or acquired angioedema caused by quality of life, productivity, and depression. Allergy Asthma Proc. 2010;31: C1-inhibitor deficiency. J Allergy Clin Immunol. 2006;117:904e908.
[57] Zanichelli A, Badini M, Nataloni I, Montano N, Cicardi M. Treatment of acquired [72] Khallil ME, Basher AW, Brown EJ, Alhaddad IA. A remarkable medical story: angioedema with icatibant: a case report. Intern Emerg Med. 2011;6:279e280.
benefits of angiotensin converting enzyme inhibitors in cardiac patients. J Am [58] Cicardi M, Zanichelli A. Acquired angioedema. Allergy Asthma Clin Immunol.
[73] Huggett B. Companies line up for hereditary angioedema market. Nat Bio- [59] Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema. Lancet. 1998;351:1693e1697.
[74] Grumach AS, Valle SOR, Toledo E, et al, on behalf of group interested on HAE [60] Blais C Jr, Rouleau JL, Brown NJ, et al. Serum metabolism of bradykinin and (GINHA). First report of 210 patients with hereditary angioedema from Bra- zilian registry [published online ahead of print August 7, 2012]. J Eur Acad inhibitor-associated angioedema. Immunopharmacology. 1999;43:293e302.
Dermatol Venereol. doi: 10.1111/j.1468e3083.2012.04670.x.
[61] Adam A, Cugno M, Molinaro G, Perez M, Lepage Y, Agostoni A. Aminopepti- [75] en HL, Zhang HY. Clinical features of hereditary angioedema: analysis of 133 dase P in individuals with a history of angio-oedema on ACE inhibitors.
cases [in Chinese]. Zhonghua Yi Xue Za Zhi. 2007;87:2772e2776.
[76] Tang R, Chen S, Zhang HY. Fresh frozen plasma for the treatment of hereditary [62] Byrd JB, Woodard-Grice A, Stone E, et al. Association of angiotensin- angioedema acute attacks. Chin Med Sci J. 2012;27:92e95.
converting enzyme inhibitor-associated angioedema with transplant and [77] Markovic SN, Inwards DJ, Frigas EA, Phyliky RP. Acquired C1 inhibitor defi- immunosuppressant use. Allergy. 2010;65:1381e1387.
ciency. Ann Intern Med. 2000;132:144e150.
[63] Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in [78] van Dulmen S, Sluijs E, van Dijk L, Ridder D, Heerdink R, Bensing J. Patient patients with angiotensin-converting enzyme inhibitor-induced angioedema.
adherence to medical treatment: a review of reviews. BMC Health Serv Res.
Ann Pharmacotherapy. 2011;45:520e524.
[64] White WB, Bresalier R, Kaplan AP, et al. Safety and tolerability of the direct renin [79] Wood B. Medication Adherence: The real problem when treating chronic inhibitor aliskiren: a pooled analysis of clinical experience in more than 12,000 conditions. US Pharm. 2012;37(4 Compliance suppl):3e6.
patients with hypertension. J Clin Hypers (Greenwich). 2010;12:765e775.
[80] World Health Organization. Adherence to long-term therapies: evidence for [65] Jason DR. Fatal angioedema associated with captopril. J Forensic Sci. 1992;37:

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A novel two-step kit for topical treatment of tinea pedis –an open studyA Shemer,† MH Grunwald,‡ B Davidovici,§ N Nathansohn,† B Amichai†,*†Department of Dermatology, Sheba Medical Center, Tel-Hashomer, ‡Soroka University Medical Center, Ben-Gurion University,Beer-Sheva, and §Dermatology Unit, Kaplan Medical Center, Rehovot, Israel*Correspondence: B Amichai. E-mail: boazam@clali

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