Tom Bowen

WAO Guideline for the Management of Hereditary Angioedema

Hereditary Angioedema (HAE) is a rare disease and for this reason proper diagnosis and appropriate therapy are often unknown or not available for physicians and other health care providers. For this reason we convened a group of specialists that focus upon HAE from around the world to develop not only a consensus on diagnosis and management of HAE, but to also provide evidence based grades, strength of evidence and classification for the consensus. Since both consensus and evidence grading were adhered to the document meets criteria as a guideline. The outcome of the guideline is to improve diagnosis and management of patients with HAE throughout the world and to help initiate uniform care and availability of therapies to all with the diagnosis no matter where the residence of the individual with HAE exists.

Management of hereditary angioedema in pediatric patients

Hereditary angioneurotic edema is a rare disorder caused by the congenital deficiency of C1 inhibitor. Recurring angioedematous paroxysms that most commonly involve the subcutis (eg, extremities, face, trunk, and genitals) or the submucosa (eg, intestines and larynx) are the hallmarks of hereditary angioneurotic edema. Edema formation is related to reduction or dysfunction of C1 inhibitor, and conventional therapy with antihistamines and corticosteroids is ineffective. Manifestations occur during the initial 2 decades of life, but even today there is a long delay between the onset of initial symptoms and the diagnosis of hereditary angioneurotic edema. Although a variety of reviews have been published during the last 3 decades on the general management of hereditary angioneurotic edema, little has been published regarding management of pediatric hereditary angioneurotic edema. Thus, we review our experience and published data to provide an approach to hereditary angioneurotic edema in childhood.

The Use of Immunoglobulin Therapy for Patients With Primary Immune Deficiency: An Evidence-Based Practice Guideline

The standard treatment for patients with primary antibody deficiency is immunoglobulin (IG), but the care of these patients is complex. These guidelines, initiated by the Canadian Blood Services and the National Advisory Committee on Blood and Blood Products, have been developed to facilitate and standardize the care of these patients by the various physician specialties that are responsible for their care. A panel of national expert immunologists and methodologists developed salient clinical questions; and a systematic, expert, and bibliography literature search up to July 2008 was conducted. One thousand eighty-seven citations were retrieved, and 102 reports were used in the preparation of this guideline. The recommendations provide guidance (1) on the complexity of the treatment of these patients; (2) the established benefits of IG on morbidity and mortality; (3) dosage, routes of administration, and management of reactions; (4) the various IG formulations available; (5) vaccination of these patients; and (6) research priorities.

Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis

BACKGROUND Sublingual swallow immunotherapy has been increasingly recognized as a safe and efficacious alternative to parenteral specific immunotherapy. OBJECTIVE To determine the safety and efficacy of sublingual swallow immunotherapy ragweed allergen extract for rhinoconjunctivitis treatment starting just before and continuing through the ragweed pollen season. METHODS This randomized, double-blind, placebo-controlled study was performed in children and adults with a documented history of allergic rhinoconjunctivitis during ragweed season at 9 Canadian allergy centers. Active treatment was standardized extract of ragweed allergen administered as sublingual swallow drops at increasing doses starting shortly before the pollen season and maintenance doses continued daily during the season. Primary efficacy variables were symptom and medication scores, and secondary variables included global evaluation of efficacy and immunologic measurements. RESULTS Eighty-three patients were included in the safety analysis; 76 patients were included in the intent-to-treat analysis. Nine placebo recipients and 1 treatment recipient withdrew for lack of efficacy (P = .004). Nine patients in the treatment group withdrew because of adverse events, none serious (P = .003). Investigator evaluation of efficacy showed that significantly more patients improved and fewer deteriorated in the treatment group vs the placebo group (P = .047). Ragweed IgE and IgG4 levels increased significantly in treatment recipients vs placebo users (P < .001). Sneezing and nasal pruritus approached significant improvement in the treatment group vs the placebo group (P = .09 and .06, respectively). Quebec City experienced low pollen counts. Excluding Quebec City, significant improvement was seen for these 2 symptoms (P = .04). CONCLUSION Sublingual swallow immunotherapy seems to be safe and efficacious for ragweed rhinoconjunctivitis even when started immediately before the ragweed pollen season.

Canadian hereditary angioedema guideline

Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

Hereditary angioedema: beyond international consensus - circa December 2010 - The Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture

BackgroundThe 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema was published earlier this year in this Journal (Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24 - http://www.aacijournal.com/content/6/1/24). Since that publication, there have been multiple phase III clinical trials published on either prophylaxis or therapy of hereditary angioedema and some of these products have changed approval status in various countries. This manuscript was prepared to review and update the management of hereditary angioedema.ObjectiveTo review approaches for the diagnosis and management of hereditary angioedema (HAE) circa December 2010 and present thoughts on moving from HAE management from international evidence-based consensus to facilitate more local health unit considerations balancing costs, efficacies of treatments, and risk benefits. Thoughts will reflect Canadian and international experiences.MethodsPubMed searches including hereditary angioedema and diagnosis, therapy, management and consensus were reviewed as well as press releases from various pharmaceutical companies to early December 2010.ResultsThe 2010 International Consensus Algorithms for the Diagnosis, Therapy and Management of Hereditary Angioedema is reviewed in light of the newly published phase III Clinical trials for prevention and therapy of HAE. Management approaches and models are discussed.ConclusionsConsensus approach and double-blind placebo controlled trials are only interim guides to a complex disorder such as HAE and should be replaced as soon as possible with large phase IV clinical trials, meta analyses, data base registry validation of approaches including quality of life and cost benefit analyses, safety, and head-to-head clinical trials investigating superiority or non-inferiority comparisons of available approaches. Since not all therapeutic products are available in all jurisdictions and since health care delivery approaches and philosophy vary between countries, each health care delivery sector will likely devise their own algorithms based on local practicalities for implementing evidence-based guidelines and standards for HAE disease management. Quality-of-life and cost affordability benefit conclusions will likely vary between countries and health care units. Data base registries for rare disorders like HAE should be used to detect early adverse events for new therapies and to facilitate phase IV clinical trials and encourage superiority and non-inferiority comparisons of HAE management approaches.

International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency

The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1‐INH‐HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1‐INH‐HAE.

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up‐to‐date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1‐inhibitor (type 1) and HAE with dysfunctional C1‐inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE‐1/2 be defined and classified?, (2) How should HAE‐1/2 be diagnosed?, (3) Should HAE‐1/2 patients receive prophylactic and/or on‐demand treatment and what treatment options should be used?, (4) Should HAE‐1/2 management be different for special HAE‐1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE‐1/2 management incorporate self‐administration of therapies and patient support measures?

Hereditary Angioedema Consensus 2010

Editorial The 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema was arrived at during the Canadian Hereditary Angioedema Network (CHAEN)/Reseau Canadien d’angioedeme hereditaire (RCAH) second meeting held May 15/16, 2010, Toronto, Canada and was cosponsored by CHAEN/RCAH, the Canadian Society of Allergy and Clinical Immunology, and the University of Calgary and was funded through an unrestricted educational grant from CSL Behring. This is the third international consensus and is meant to be a living document requiring continual updating and rethinking. The first consensus conference was scheduled for Toronto, Ontario, Canada in April 2003 but was SARSed out. That conference was rescheduled and held in Toronto in October 2003 and published in 2004. The next consensus was again held in Toronto Canada in 2006 and rediscussed in Budapest in 2007 and published in 2008. This third consensus conference was in danger of being ashed out from the volcanic activity in Iceland making planning of such meetings a challenge. Rare disorders such as Hereditary Angioedema require international collaboration to push ahead with progress in the management of the disorders. The Hungarian group under Dr. Henriette Farkas and the Italian group under Dr. Marco Cicardi have certainly led the way in organizing these essential get-togethers. Patient Group participation in these discussions has been strongly encouraged and the Consensus Algorithms have been signed off by various National Patient Organizations. The patients should decide how they wish to be treated. I usually bore audiences with my motto: It can be done It must be done for the sake of our patients. This concept continues in this third consensus algorithm development. We have moved from 2003 from only a few controlled trials in prophylaxis and treatment in HAE-Types I and II to now several clinical trials in various stages of publication. Prophylaxis options have moved from anti-fibrinolytics and androgens to include consideration of plasma-derived C1-inhibitor (pdC1INH) prophylaxis. Therapy options have broadened from pdC1INH to now include bradykinin receptor antagonist Icatibant and kallikrein antagonist Ecallantide and recombinant C1INH under clinical trial. These phase III clinical trials will move this current consensus algorithm approach to evidence-based approach and Dr. Marco Cicardi is moving this along with an important meeting in Italy in September 2010. Clinical trials in rare disorders are difficult at the best of times but exceptionally difficult in HAE where swelling events are unpredictable and require quick intervention at all hours of day, night, weekends. These clinical trials are difficult for patients and clinic staff alike and it is to the credit of the Patients and the Research Clinics that these studies have moved along and are either now published or in stages of publication. However, phase IV clinical trials and head-to-head evaluation of prophylactic and therapeutic approaches including cost benefit and quality of life are still lacking. To date, the clinical trials have been small and these data may change when larger trials are undertaken. For example, for many years Berinert (Berinert P in the past and now just called Berinert) has been used for therapy at doses of one or two vials (500 to 1000 units; close to 10 units per kg) in thousands of infusions and appear safe and appear to have successfully treated most HAE episodes with second infusions uncommon. However, when the small clinical phase III trial was conducted, results showed benefit from 20 units/kg but not 10 units/kg. Since this was the phase III clinical trial, dose licensing for this drug is 20 units/kg. This recommendation has great economic impact on the therapy of this disorder increasing the cost of treatment by considerable amount. It is essential for national and international networks of clinics to undertake phase IV clinical trials to retest this dose-finding. Plasma derivatives such as pdC1INH are precious resources donated from dedicated blood donors needing conservation when possible and such products are costly for individual patients or treatment programs. The extensive European clinical experience in hundreds of thousands of infusions would indicate a lower dose used early in a swelling Correspondence: tbowen@pol.net Department of Medicine and Paediatrics, University of Calgary, Calgary, Alberta, Canada Bowen Allergy, Asthma & Clinical Immunology 2010, 6:13 http://www.aacijournal.com/content/6/1/13 ALLERGY, ASTHMA & CLINICAL IMMUNOLOGY

Allergy transfer with hematopoietic cell transplantation from an unrelated donor

Allergy may be transferred from an allergic donor to a nonallergic recipient of hematopoietic cell transplantation (reviewed by Khan et al.). It is generally thought that this is due to the adoptive transfer of allergen-specific B cells (differentiating into IgE plasma cells) or allergen-specific T cells (helping allergen-specific B cells to differentiate into IgE plasma cells). This is supported by reports that typically detected the presence of IgE for the same allergen in the donor and in the recipient post transplant. There is also an alternative explanation for the acquisition of allergy through hematopoietic cell transplantation from an allergic donor: transfer of hematolymphatic system prone to support differentiation of B cells into IgE plasma cells in general. In this scenario, the donor and the recipient, post transplant, would not need to be allergic to the same allergen(s). A total of 18 cases have been reported in whom transfer of allergy by hematopoietic cell transplantation was suspected. However, due to missing data (for example, on the allergy status of the recipient before transplant), the transfer was conclusively documented in only five patients. In all the 18 patients, the donor was a sibling. Given that predisposition to allergy is genetically determined, it can be argued that the post transplant diagnosis of allergy in a pretransplant nonallergic recipient of hematopoietic cell transplantation from an allergic donor does not necessarily imply the transfer of allergy, but rather the development of allergy in a genetically predisposed individual. However, here we present a case of allergy transfer from an unrelated donor. A 50-year-old man with acute myeloid leukemia in remission underwent filgrastim-mobilized blood SCT from an HLA-A, B, C, DRB1 and DQB1 allele-matched unrelated donor. Conditioning and GVHD prophylaxis included BU, fludarabine, antithymocyte globulin, CYA and MTX. There were no major transplant complications. CYA was discontinued at 3 months post transplant. The donor had asthma, which was triggered by exposure to dogs and cats. The asthma was treated with inhaled fluticasone regularly and inhaled albuterol/salbutamol as needed. The donor also had a history of recurrent anaphylactic reactions triggered by eating nuts, including pecans and walnuts, and fish. These required self-injections of epinephrine and emergency room visits. The last emergency room visit was 2 months before the stem cell collection and was for nut-triggered anaphylaxis. The recipient had no history of allergic disease. Allergen-specific IgE in donor serum was positive for peanut, pecan, walnut, codfish, cat and dog but negative in the recipient (both donor and recipient blood were collected within 1 month pretransplant; Table 1). Post transplant, the recipient abstained from eating nuts for 19 months, despite negative supervised food challenge at 6 months. He had been eating fish. Given that both allergenspecific IgE and skin prick tests were negative for peanuts, walnuts, hazelnuts, almonds and pecans at 19 months, the patient began to eat nuts without symptoms. The patient was again evaluated at 29 months. Skin tests showed no reaction to peanuts, hazelnuts, almonds and pecans, but a minor reaction to walnuts. However, the patient had been eating nuts without symptoms. The patient had no allergy symptoms after exposure to dogs or cats, despite repeated exposure until approximately 20 months post transplant when he developed swelling, itching and hives on being licked by a dog, and on other occasions developed hives after touching dogs and no symptoms after touching cats. The patient continued eating nuts without symptoms. By 37 months post transplant, the patient developed asthma triggered by exposure to dogs (not cats) and began to use inhaled fluticasone and salmeterol regularly and inhaled albuterol/salbutamol as needed. As shown in Table 1, serum IgE for nuts and fish remained undetectable throughout the follow-up, whereas IgE for dogs and cats became elevated by 29 months post transplant. This case is important for three reasons: it describes transfer of allergy from an unrelated rather than related donor, suggesting a true transfer rather than development of allergy in a genetically predisposed recipient. This conclusion is moderated by the fact that the recipient was adopted, so it was impossible to ascertain whether his family history was positive for allergy. Another caveat is that the donor was HLA-matched and certain HLA-DR and DQ loci have been associated with allergy. However, HLA genes constitute only a minor fraction of genes associated with allergy. This case also shows that the recipient does not have to become allergic to the same allergen(s) as the donor. The donor was allergic to peanuts, pecans and codfish, but the recipient post transplant did not become allergic to these, suggesting transfer of hematolymphatic system prone to allergy in general rather than transfer of B/T cells specific for certain allergen(s). This case also shows that the clinical manifestation of allergy may be different in the donor pretransplant vs the recipient post transplant (in this case, anaphylaxis and asthma in the donor vs urticaria and asthma in the recipient).