Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

The Icatibant Outcome Survey: 10 years of experience with icatibant for patients with hereditary angioedema.

In patients with hereditary angioedema (HAE), bradykinin causes swelling episodes by activating bradykinin B2 receptors. Icatibant, a selective bradykinin B2 receptor antagonist, is approved for on-demand treatment of HAE attacks. The Icatibant Outcome Survey (IOS; NCT01034969) is an ongoing observational registry initiated in 2009 to monitor the effectiveness/safety of icatibant in routine clinical practice. As of March 2019, 549 patients with HAE type 1 or 2 from the IOS registry had been treated of 5995 total attacks. This article reviews data published from IOS over time which have demonstrated that the effectiveness of icatibant in a real-world setting is comparable to efficacy in clinical trials; one dose is effective for the majority of attacks; early treatment (facilitated by self-administration) leads to faster resolution and shorter attack duration; effectiveness/safety of icatibant has been shown across a broad range of patient subgroups, including children/adolescents and patients with HAE with normal C1 inhibitor levels; and tolerability has been demonstrated in patients aged ≥65 years. Additionally, this review highlights how IOS data have provided valuable insights into patients' diagnostic journeys and treatment behaviours across individual countries. Such findings have helped to inform clinical strategies and guidelines to optimise HAE management and limit disease burden. This research was sponsored by Takeda Development Center Americas, Inc. Takeda Development Center Americas, Inc., provided funding to Excel Medical Affairs for support in writing and editing this manuscript.

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

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Consensus on treatment goals in hereditary angioedema: A global Delphi initiative.

BACKGROUND: Hereditary angioedema (HAE) is a rare, life-threatening genetic disorder characterized by recurrent episodes of subcutaneous or submucosal angioedema. The ultimate goals of treatment for HAE remain ill-defined. OBJECTIVES: The aim of this Delphi process was to define the goals of HAE treatment and to examine which factors should be considered when assessing disease control and normalization of the patient's life. METHODS: The Delphi panel comprised 23 participants who were selected based on involvement with scientific research on HAE or coauthorship of the most recent update and revision of the World Allergy Organization/European Academy of Allergy and Clinical Immunology guideline on HAE. The process comprised 3 rounds of voting. The final round aimed to aggregate the opinions of the expert panel and to achieve consensus. RESULTS: Two direct consensus questions were posed in round 2, based on the responses received in round 1, and the panel agreed that the goals of treatment are to achieve total control of the disease and to normalize the patient's life. For the third round of voting, 21 statements were considered, with the participants reaching consensus on 18. It is clear from the wide-ranging consensus statements that the burdens of disease and treatment should be considered when assessing disease control and normalization of patients' lives. CONCLUSIONS: The ultimate goal for HAE treatment is to achieve no angioedema attacks. The availability of improved treatments and disease management over the last decade now makes complete control of HAE a realistic possibility for most patients.

Management of hereditary angioedema type I and homozygous MTHFR mutation during pregnancy.

Hereditary angioedema (HAE) is an autosomal dominant disease, characterized by edema attacks resulting from quantitative and/or functional deficiency of the C1 inhibitor (C1-INH), which acts in controlling the complement, coagulation, fibrinolysis, and contact systems. The exacerbation of these systems results in decreased circulating levels of kallikrein and conversion of bradykinin. In addition, thrombophilia is related to the deficiency of methylenetetrahydrofolate reductase (MTHFR) enzyme, causing an increase in homocysteine, accumulation of atheromatous plaques, and arterial and venous thrombosis. The association of these conditions in related systems brings greater clinical risks to the patient. We report a female patient, aged 23 years, with HAE and homozygous MTHFR mutation, G2A1, carrier of HAE with crises since early childhood. The first pregnancy terminated with abortion due to gestational sac detachment. In the second pregnancy, at 5.1 weeks, she had bleeding and partial detachment of gestational sac. Thrombophilia tests confirmed homozygosity for the MTHFR enzyme. At the beginning of gestation, she had attacks of angioedema treated with fresh plasma, and at one occasion, she received treatment with a plasma-derived C1-INH esterase. During breastfeeding, she received prophylaxis with plasma-derived C1-INHdp. The course of HAE during pregnancy worsened. There are studies that discuss the occurrence of abortion due to attacks of angioedema. The patient's disease was associated with a homozygous MTHFR mutation, which probably caused the miscarriage. The control of both clinical situations is important for the success of pregnancy, so a combined action plan between obstetricians and HAE treatment specialists is essential.

European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management.

This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for ~5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disorders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning.

Otitis Media and Inborn Errors of Immunity.

PURPOSE OF REVIEW: The aim of this review is as follows: (1) to present the role of otitis as a warning sign for inborn errors of immunity (IEI), (2) to establish which patients presenting otitis should be investigated for IEI, (3) to review data about main IEI associated with otitis-prone patients. RECENT FINDINGS: Otitis media is a very common infection in general population. The concept of otitis-prone children established a certain frequency of the infections in order to look for conditions leading to them. The confirmation of middle ear impairment by specialists has demonstrated better confiability. The hallmarks for immunologic evaluation are the presence of complications as mastoiditis and membrane perforation, failure to thrive, and additional respiratory symptoms. Humoral immunodeficiencies have been more frequently described in association with otitis-prone patients, for example, hypogammaglobulinemia, MBL deficiency, and IEI associated with major syndromes. Most of the patients with confirmed IEI present otitis as one of the recurrent infections. It is suggested the investigation of immune defects in patients with otitis, and the following warning signs are suggested: Otitis evolving with mastoiditis, abscesses, or systemic infections; no response to appropriate antibiotic therapy; otitis media associated with other infections; recurrent otitis leading to failure to thrive and general developmental delay; and family history of primary immunodeficiency and/or consanguinity.

Latin American consensus on the supportive management of patients with severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 "agreed" and 38 "nonagreed" statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.

Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency.

Autosomal recessive (AR) CARD9 (caspase recruitment domain-containing protein 9) deficiency underlies invasive infections by fungi of the ascomycete phylum in previously healthy individuals at almost any age. Although CARD9 is expressed mostly by myeloid cells, the cellular basis of fungal infections in patients with inherited CARD9 deficiency is unclear. Therapy for fungal infections is challenging, with at least 20% premature mortality. We report two unrelated patients from Brazil and Morocco with AR CARD9 deficiency, both successfully treated with hematopoietic stem cell transplantation (HSCT). From childhood onward, the patients had invasive dermatophytic disease, which persisted or recurred despite multiple courses of antifungal treatment. Sanger sequencing identified homozygous missense CARD9 variants at the same residue, c.302G>T (p.R101L) in the Brazilian patient and c.301C>T (p.R101C) in the Moroccan patient. At the ages of 25 and 44 years, respectively, they received a HSCT. The first patient received a HLA-matched HSCT from his CARD9-mutated heterozygous sister. There was 100% donor chimerism at D + 100. The other patient received a T cell-depleted haploidentical HSCT from his CARD9-mutated heterozygous brother. A second HSCT from the same donor was performed due to severe amegakaryocytic thrombocytopenia despite achieving full donor chimerism (100%). At last follow-up, more than 3 years after HSCT, both patients have achieved complete clinical remission and stopped antifungal therapy. HSCT might be a life-saving therapeutic option in patients with AR CARD9 deficiency. This observation strongly suggests that the pathogenesis of fungal infections in these patients is largely due to the disruption of leukocyte-mediated CARD9 immunity.

A homozygous CARD9 mutation in a Brazilian patient with deep dermatophytosis.

Deep dermatophytosis has been described in HIV and immunosuppressed patients. Recently, CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in individuals with deep dermatophytosis previously classified as "immunocompetent". We report a 24-year-old Brazilian male patient with deep dermatophytosis born to an apparently non-consanguineous family. The symptoms started with oral candidiasis when he was 3 years old, persistent although treated. At 11 years old, well delimited, desquamative and pruriginous skin lesions appeared in the mandibular area; ketoconazole and itraconazole were introduced and maintained for 5 years. At 12 years of age, the lesions, which initially affected the face, started to spread to thoracic and back of the body (15 cm of diameter) and became ulcerative, secretive and painful. Terbinafine was introduced without any improvement. Trichophyton mentagrophytes was isolated from the skin lesions. A novel homozygous mutation in CARD9 (R101L) was identified in the patient, resulting in impaired neutrophil fungal killing. Both parents, one brother (with persistent superficial but not deep dermatophytosis) and one sister were heterozygous for this mutation, while another brother was found to be homozygous for the CARD9 wild-type allele. This is the first report of CARD9 deficiency in Latin America.

First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes.

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

Angioedema With Normal Complement Studies: What Do We Know?

Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue caused by increased vascular permeability and extravasation of intravascular fluid. It can occur via a variety of mechanisms. A number of clinical conditions (masqueraders) are occasionally mistaken for angioedema. Clinical classification of the various angioedema forms begins with noting the presence or absence of concurrent urticaria or wheals. Pathogenesis can be considered through two broad categories: mast cell-mediated with release of vasoactive mediators causing angioedema usually associated with urticaria or in the context of an anaphylactic reaction; and bradykinin (BK)-driven, in which increased vascular permeability is mediated by BK. BK-mediated angioedema does not occur with urticaria, nor does it respond to antiallergic medications. The various forms of hereditary angioedema are included in this category, requiring specific tests of C4 and C1 inhibitor level and function to confirm the diagnosis. Angiotensin converting enzyme inhibitors, which impair the degradation of BK, account for up to a third of all patients with angioedema presenting to the emergency department. Finally, angioedema may occur by yet unknown mechanisms; under this circumstance, it is difficult to manage.

Current challenges and future opportunities in patient-focused management of hereditary angioedema: A narrative review.

Patients with hereditary angioedema (HAE) experience a high burden of disease due to unpredictable, painful, disfiguring, and potentially life-threatening HAE attacks. Multiple HAE-specific medications for the on-demand treatment, short-term and long-term prophylaxis of HAE attacks have entered the market in recent years; however, the availability and access to these medications may vary between different countries. For this review, PubMed and EMBASE databases were searched for guidelines, consensus statements, and other publications on HAE management as well as publications on quality of life in patients with HAE. The current guidelines and recent literature on HAE management in specific countries are summarized with the aim to highlight the similarities and differences between guideline recommendations and the country-specific clinical practice. Improvement in quality of life, which is a key goal in HAE management, is also discussed and the country-specific trends are highlighted. Finally, the ways to achieve a more patient-centric approach to HAE management within the framework set by the clinical management guidelines are examined.

Are pediatricians familiar with hereditary angioedema?

Background: Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of subcutaneous or mucosal edema caused by excess bradykinin. The aim of the present study was to assess the knowledge of pediatricians about hereditary angioedema. Methods: An online survey with 12 HAE-related and 14 demographics-related questions was e-mailed to all pediatricians who were members of the Brazilian Society of Pediatrics (n = 17 145) once a week during the months of June and July 2021. The electronic questionnaire assessed clinical manifestations, diagnosis, and treatment of hereditary angioedema in children and adolescents. Results: Four hundred and fifty-five pediatricians responded to the questionnaire (2.6%), of whom 55 (12.1%) were board certified in Allergy and Immunology (A/I), while 400 (87.9%) were not (N-A/I). Three hundred and sixty-eight (80.9%) were female, 289 (55.7%) were under 50 years of age, 286 (62.9%) graduated from Medical School more than 10 years previously, 83 (18.2%) held an MSc/PhD degree, and 253 (55.6%) were living in the Southeast Region of Brazil. The median number of correct answers to the questions related to HAE among A/I was 7 out of 12 (58.3%), with median ranging from 4.5 to 8 correct answers, while for N-A/I it was 3 (25%), with median ranging from 2.5 to 4 correct answers (p < 0.001). Conclusion: Knowledge about HAE among Brazilian pediatricians, whether board certified in Allergy and Immunology or not, was unsatisfactory. HAE is a rare disease, largely unknown among physicians; therefore, increasing awareness may lead to improvement in diagnosis and treatment.

Lymphocyte transformation assay for C neoformans antigen is not reliable for detecting cellular impairment in patients with neurocryptococcosis.

BACKGROUND: Cryptococcus neoformans causes meningitis and disseminated infection in healthy individuals, but more commonly in hosts with defective immune responses. Cell-mediated immunity is an important component of the immune response to a great variety of infections, including yeast infections. We aimed to evaluate a specific lymphocyte transformation assay to Cryptococcus neoformans in order to identify immunodeficiency associated to neurocryptococcosis (NCC) as primary cause of the mycosis. METHODS: Healthy volunteers, poultry growers, and HIV-seronegative patients with neurocryptococcosis were tested for cellular immune response. Cryptococcal meningitis was diagnosed by India ink staining of cerebrospinal fluid and cryptococcal antigen test (Immunomycol-Inc, SP, Brazil). Isolated peripheral blood mononuclear cells were stimulated with C. neoformans antigen, C. albicans antigen, and pokeweed mitogen. The amount of 3H-thymidine incorporated was assessed, and the results were expressed as stimulation index (SI) and log SI, sensitivity, specificity, and cut-off value (receiver operating characteristics curve). We applied unpaired Student t tests to compare data and considered significant differences for p<0.05. RESULTS: The lymphotoxin alpha showed a low capacity with all the stimuli for classifying patients as responders and non-responders. Lymphotoxin alpha stimulated by heated-killed antigen from patients with neurocryptococcosis was not affected by TCD4+ cell count, and the intensity of response did not correlate with the clinical evolution of neurocryptococcosis. CONCLUSION: Response to lymphocyte transformation assay should be analyzed based on a normal range and using more than one stimulator. The use of a cut-off value to classify patients with neurocryptococcosis is inadequate. Statistical analysis should be based on the log transformation of SI. A more purified antigen for evaluating specific response to C. neoformans is needed.

Icatibant use in Brazilian patients with hereditary angioedema (HAE) type 1 or 2 and HAE with normal C1-INH levels: findings from the Icatibant Outcome Survey Registry Study.

BACKGROUND: Hereditary angioedema can be caused by C1-Inhibitor (C1-INH) deficiency and/or dysfunction (HAE-1/2) or can occur in patients with normal C1-INH (HAE nC1-INH). METHODS: The Icatibant Outcome Survey (IOS; NCT01034969) registry monitors the safety and effectiveness of icatibant for treating acute angioedema. OBJECTIVE: Present findings from Brazilian patients with HAE-1/2 and HAE nC1-INH participating in IOS. RESULTS: 42 patients were enrolled (HAE-1/2, n = 26; HAE nC1-INH, n = 16). Median age at symptom onset was significantly lower with HAE-1/2 vs. HAE nC1-INH (10.0 vs. 16.5y, respectively; p = 0.0105), whereas median age at diagnosis (31.1 vs. 40.9y; p = 0.1276) and the median time between symptom onset and diagnosis (15.0 vs. 23.8y; p = 0.6680) were numerically lower vs. HAE nC1-INH, respectively. One icatibant dose was used for > 95% of HAE attacks. Median (range) time-to-event outcomes were shorter for patients with HAE nC1-INH vs. HAE-1/2, including time to first administration (0.5 [0-96.0] vs. 1.0 [0-94.0]h, respectively), time from first administration to complete resolution (1.0 [0-88.0] vs. 5.5 [0-96.0]h, respectively), and total attack duration (7.0 [0.3-99.0] vs. 18.5 [0.1-100.0]h, respectively). Mean (SD) time from attack onset to resolution was significantly shorter for patients with HAE nC1-INH vs. HAE-1/2 (9.8 [18.7] vs. 19.6 [24.0]h, respectively; p = 0.0174). 83 adverse events (AEs) in 42 patients were reported; most were mild (66.3%) or moderate (13.3%) and non-serious (75.9%). The most common icatibant-related AE was injection site erythema (HAE-1/2, 34.6%; HAE nC1-INH, 18.8%). STUDY LIMITATIONS: This was an observational study without a treatment comparator and that relied on patient recall. CONCLUSIONS: Findings demonstrate effectiveness and tolerability of icatibant in Brazilian HAE patients.

Pregnancy in Patients With Hereditary Angioedema and Normal C1 Inhibitor.

Background: HAE with normal C1 inhibitor (HAE-nC1-INH) has been identified as a bradykinin mediated angioedema. Estrogens are one of the main trigger factors. Pregnancy in HAE with C1 inhibitor deficiency showed variable course, however, few reports are available for HAE-nC1-INH. We evaluated the course of pregnancies in women diagnosed with HAE-nC1-INH. Methods: Women with diagnosis of HAE-nC1-INH according to the following criteria: clinical manifestations similar to HAE-C1-INH, normal biochemical evaluation and family history were included. A questionnaire about pregnancies was applied after consent. Genetic evaluation for known mutations was performed in all patients. Results: A total of 45 pregnancies occurring in 26 HAE-nC1-INH patients were evaluated (7/26 patients with F12 variant). Spontaneous abortion was reported in 8/45 (17.8%) pregnancies. Onset of attacks started before the pregnancy in 18/26 patients; during the pregnancy in 2/26; and after the pregnancy in 6/26. HAE attacks occurred in 24/37 pregnancies (64,7%): during the 1st trimester in 41.7%; 2nd trimester in 12.5%; 3rd trimester in 20.8%; 1st and 3rd trimesters in 4.2% and during the whole pregnancy in 20.8%. Among 15/18 patients who had attacks before pregnancy, symptoms persisted with worsening in 9/15; improvement in 4/15; no change in 1/15, and no response in 1/15. Conclusions: The occurrence of abortion in HAE-nC1-INH was similar to the expected for not affected women. The 1st trimester of the pregnancy was more symptomatic for HAE-nC1-INH women. Considering the strong relevance of estrogens in HAE-nC1-INH, pregnancy could worsen the course of disease.

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

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.