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 complexities of decision-making associated with on-demand treatment of hereditary angioedema (HAE) attacks.

BACKGROUND: Hereditary angioedema (HAE) is characterized by debilitating attacks of tissue swelling in various locations. While guidelines recommend the importance of early on-demand treatment, recent data indicate that many patients delay or do not treat their attacks. OBJECTIVE: This survey aimed to investigate patient behavior and evaluate the key factors that drive on-demand treatment decision-making, as reported by those living with HAE. METHODS: People living with HAE were recruited by the US Hereditary Angioedema Association (HAEA) to complete a 20-minute online survey between September 6, and October 19, 2022. RESULTS: Respondents included 107 people with HAE, 80% female, 98% adults (≥ 18 years). Attack management included on-demand therapy only (50%, n = 53) or prophylaxis with on-demand therapy (50%, n = 54). Most patients (63.6%) reported that they did not carry on-demand treatment at all times when away from home. The most common reason for not carrying on-demand treatment when away from home was 'prefer to treat at home' (72.1%). Overall, 86% of respondents reported delaying on-demand treatment, despite recognizing the initial onset of an HAE attack and despite 97% of patients agreeing that it is important to recover quickly from an HAE attack. Reasons for non-treatment or treatment delay included 'the attack is not severe enough to treat' (91.9% and 88.0%, respectively), 'cost of treatment' (31.1% and 40.2%, respectively), anxiety about refilling the prescription for on-demand treatment quickly (31.1% and 37.0%, respectively), the pain (injection or burning) associated with their on-demand treatment (18.9% and 28.3%, respectively), the lack of a suitable/private area to administer on-demand treatment (17.6% and 27.2%, respectively), lack of time to prepare on-demand treatment (16.2% and 16.3%, respectively), and a 'fear of needles' (13% and 12.2%, respectively). Survey findings from the patient perspective revealed that when on-demand treatment was delayed, 75% experienced HAE attacks that progressed in severity, and 80% reported longer attack recovery. CONCLUSIONS: Survey results highlight that decision-making regarding on-demand treatment in HAE is more complicated than expected. The burden associated with current parenteral on-demand therapies is often the cause of treatment delay, despite acknowledgment that delays may result in progression of HAE attacks and longer time to recovery.

Hereditary Angioedema: A Review of the Current and Evolving Treatment Landscape.

Hereditary angioedema (HAE) is a rare disease characterized by sudden and often unprovoked episodes of swelling that can be potentially life-threatening when it involves the upper airway. The treatment options for both acute episodes of HAE and LTP, used to minimize the frequency and severity of angioedema attacks, were limited historically to very few options, had considerable side effects, and/or had considerable burden of treatment. Fortunately, through the elucidation of the pathophysiology of HAE, the development of newer targeted therapies has been possible both for acute therapy and long-term prophylaxis and even more are on the horizon. Because of the rapid development of these therapies, it can be challenging for clinicians to keep abreast of newer and developing treatments for HAE. This review article will outline the current and potential future treatments for HAE. It will also highlight important considerations when treating special HAE patient populations including women and pediatric patients.

Second-dose mRNA COVID-19 vaccine safety in patients with immediate reactions after the first dose: A case series.

Background: The rates of suspected allergic reactions to the first dose of the coronavirus disease 2019 (COVID-19) mRNA vaccines have been reported to be as high as 2%, with an anaphylaxis incidence up to 2.5 per 10,000 individuals. Anaphylaxis in response to the first dose may be considered a contraindication to administration of the second dose, even though the second dose is necessary for optimal protection against severe disease. Many individuals with anaphylactic reactions to the first dose still want to receive a second dose. However, there are few published data to support the safety of administration of a second dose in this population. Objective: The primary objective of this study was to determine the percentage of patients tolerating a second COVID-19 mRNA vaccine dose after an immediate reaction to the first dose. Methods: This was a retrospective chart review of 47 patients at a Canadian hospital who had immediate, suspected allergic reactions following their first COVID-19 mRNA vaccine dose and received a second dose within our allergy clinic. Results: Of 47 patients, 46 tolerated the second dose; 43% of patients developed mild, transient symptoms. There were no patients who developed anaphylaxis or needed epinephrine after the second dose. Conclusion: Our case series adds to current evidence that administration of a second COVID-19 mRNA vaccine dose has a good safety profile in patients with a history of immediate reactions after the first dose, including those with a history of anaphylaxis in response to the first dose.

Hereditary Angioedema in Pregnancy.

IMPORTANCE: Hereditary angioedema is a rare disease of potentially life-threatening attacks of angioedema that can affect patients of all ages, including women of childbearing age. Pregnancy can affect the course of the disease and the choice of treatment used. It is important for the care providers to recognize this disease and understand its mechanism in order to provide appropriate care for the patients. OBJECTIVE: The goal of this article is to provide an overview of hereditary angioedema and guideline for management of pregnant patients with hereditary angioedema. EVIDENCE ACQUISITION: A search of the available English language literature was performed on PubMed and Ovid MEDLINE using the key words hereditary angioedema and pregnancy. Additional articles were selected from the reference lists of the reviewed articles. RESULTS: The data for hereditary angioedema in pregnant patients come from observational studies, case reports, retrospective reviews, and questionnaires. The course of hereditary angioedema can be variable between different patients and pregnancies. Plasma-derived C1 inhibitor concentrate is both safe and effective as treatment for attacks and as preventive therapy in pregnancy. With proper recognition, understanding of the disease, and appropriate medical management, most patients will undergo successful pregnancy and delivery. CONCLUSIONS AND RELEVANCE: Clinicians should maintain high suspicion for this disease when patients present with recurrent episodes of angioedema without urticaria or severe abdominal pains of unclear etiology. Treatment plans during pregnancy and delivery should be individualized, and the patient's care should be shared by a clinician experienced in the management of this disease.

Vaccine response following anti-CD20 therapy: a systematic review and meta-analysis of 905 patients.

The objective of this study was to perform a systematic review of the literature on vaccine responsiveness in patients who have received anti-CD20 therapy. PubMed and EMBASE were searched up to 4 January 2021 to identify studies of vaccine immunogenicity in patients treated with anti-CD20 therapy, including patients with hematologic malignancy or autoimmune disease. The primary outcomes were seroprotection (SP), seroconversion (SC), and/or seroresponse rates for each type of vaccine reported. As the pandemic influenza vaccine (2009 H1N1) has standardized definitions for SP and SC, and represented a novel primary antigen similar to the COVID-19 vaccine, meta-analysis was conducted for SC of studies of this vaccine. Pooled estimates, relative benefit ratios (RBs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-eight studies (905 patients treated with anti-CD20 therapy) were included (19 studies of patients with hematologic malignancies). Patients on active (<3 months since last dose) anti-CD20 therapy had poor responses to all types of vaccines. The pooled estimate for SC after 1 pandemic influenza vaccine dose in these patients was 3% (95% CI, 0% to 9%), with an RB of 0.05 (95% CI, 0-0.73) compared with healthy controls and 0.22 (95% CI, 0.09-0.56) compared with disease controls. SC compared with controls seems abrogated for at least 6 months following treatment (3-6 months post anti-CD20 therapy with an RB of 0.50 [95% CI, 0.24-1.06] compared with healthy and of 0.44 [95% CI, 0.23-0.84] compared with disease controls). For all vaccine types, response to vaccination improves incrementally over time, but may not reach the level of healthy controls even 12 months after therapy.

Impact of lanadelumab in hereditary angioedema: a case series of 12 patients in Canada.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disease resulting in recurring episodes of swelling, leading to considerable patient morbidity and mortality. Lanadelumab is a plasma kallikrein inhibitor that is approved as 1st line therapy in Canada for long term prophylaxis of HAE attacks. OBJECTIVE: To describe our clinical findings from a case series of adult patients with HAE type 1/2 who have been initiated on lanadelumab. METHODS: A chart review of HAE type 1/2 patients at three academic centers in Canada was undertaken with demographic and clinical data extracted. Patients were included if they had been receiving lanadelumab for at least 6 months. Patients with other causes of angioedema were excluded. RESULTS: 12 patients meeting enrollment criteria were identified. Compared to pre-lanadelumab, patients had mean reductions of 72% and 62% in attack rate and treated attack rate respectively. 3 patients reported complete remission from attacks after starting lanadelumab. Most patients had significant improvements in HAE impact on social outings. CONCLUSION: Our case series findings support the 2019 International/Canadian HAE guideline that lanadelumab is an effective therapy for long term prophylaxis. In our patient population, initiation of lanadelumab improved disease control, minimized the burden of treatment and improved HAE impact on social outings.

Gastrointestinal Disease in Patients with Common Variable Immunodeficiency: A Retrospective Observational Study.

BACKGROUND: Gastrointestinal (GI) symptoms are common among patients with common variable immunodeficiency disorder (CVID) yet remain poorly understood. AIMS: The aim of this study was to characterize the demographic, clinical, endoscopic and histologic features of patients with CVID and GI symptoms. METHODS: We conducted a retrospective observational study of all patients with CVID at a large Canadian tertiary care centre between January 2000 and May 2018. RESULTS: We included 95 patients with CVID. The mean age of patients at the time of CVID diagnosis was 38.2(±16.0). Fifty-three (56%) patients were female. Sixty-four (67%) patients had GI symptoms, with a mean age of onset for GI symptoms of 43.4(±15.1) years. The most common symptoms were bowel movement changes (n = 55 [58%]) and abdominal pain (n = 44 [46%]). Patients with GI symptoms were more likely to have anemia (n = 23 [36%] versus n = 3 [10%], P = 0.0129), iron deficiency (n = 16 [25%] versus n = 2 [7%], P = 0.0481), and have received GI antibiotics (n = 37 [58%] versus n = 0, P < 0.0001) and proton pump inhibitors for reflux (n = 24 [38%] versus n = 3 [10%], P = 0.0067). The most common GI infections were Giardia lamblia (n = 14 [15%]) and Clostridium difficile (n = 4 [4%]). Forty-three (45%) patients with GI symptoms underwent colonoscopy, esophagogastroduodenoscopy or both. The most common findings were inflammation, nodular lymphoid hyperplasia, reduced plasma cells and increased intraepithelial lymphocytes. CONCLUSIONS: This is the largest study on CVID patients in a North American setting. The majority of patients experienced GI symptoms. Future studies should study response to treatment for GI disease among patients with CVID.

Timing of infections in patients with primary immunodeficiencies treated with intravenous immunoglobulin (IVIg).

PURPOSE: Patients with common variable immune deficiency and X-linked agammaglobulinemia are unable to produce their own antibodies thus leading to a higher incidence of recurrent infections, particularly those involving the sinuses and lungs. Treatment with intravenous immunoglobulin therapy aims to reduce the incidence of infections; however, as serum IgG approaches its trough during the third and fourth week after infusion, we hypothesized that the rate of infection would be higher during this time period. METHODS: Patients with a diagnosis of either common variable immunodeficiency (CVID) or X-linked agammaglobulinemia (XLA) treated with intravenous immunoglobulin (IVIg) were analyzed in a prospective cohort study. Data was obtained as to the timing of symptom onset post infusion, the type of infection, as well as timing of the initiation of antibiotics. Descriptive analyses were conducted to explore the patterns of the data at each month and then over the course of the study year. RESULTS: Twenty-three patients with a diagnosis of either CVID (n = 22), or XLA (n = 1) were enrolled with a mean follow duration of 11.3 months. The mean number of days to infection after IVIg infusion, the primary endpoint, was 17.0 days with the most common infections reported as sinusitis and upper respiratory tract infections. There was no statistically significant difference (p = 0.70) in the rates of infection when considering the weeks post-infusion. CONCLUSIONS: We believe that this pilot study is the first reported prospective study to examine the timing of infections after IVIg infusion in individuals with CVID and XLA. Further multi-centered research with a larger sample size is required into the comparison of infection rates in primary immunodeficiency patients treated with IVIg versus subcutaneous immunoglobulin therapy, where serum IgG levels remain at steady state.

Urticaria and angioedema.

Urticaria (hives) is a common disorder that often presents with angioedema (swelling that occurs beneath the skin). It is generally classified as acute or chronic. Second-generation, non-sedating, non-impairing histamine type 1 (H1)-receptor antihistamines represent the mainstay of therapy for both acute and chronic urticaria. Angioedema can occur in the absence of urticaria and can be broadly divided into histamine-mediated and non-histamine-mediated angioedema. Histamine-mediated angioedema can be allergic, pseudoallergic or idiopathic. Non-histamine mediated angioedema is largely driven by bradykinin and can be hereditary, acquired or drug-induced, such as with angiotensin-converting enzyme inhibitors. Although bradykinin-mediated angioedema is often self-limited, laryngeal involvement can lead to fatal asphyxiation. The mainstay of management for angioedema is to avoid specific triggers, if possible. For hereditary angioedema, there are specifically licensed treatments that can be used for the management of acute attacks, or for prophylaxis in order to prevent attacks. In this article, the authors will review the causes, diagnosis and management of urticaria (with or without angioedema) and isolated angioedema. The diagnostic and therapeutic approaches to these two conditions are considerably different, and this review is designed to highlight these differences to the reader.

The Clinical Evaluation of Angioedema.

The clinical evaluation of angioedema is reliant on obtaining a thorough patient and family history with an assessment of risk factors and presenting symptoms unique to each subtype. It is important to distinguish between angioedema with and without urticaria as a primary step in the evaluation; thereafter, laboratory parameters and investigations allow for subsequent stratification. There is a significant disease burden associated with angioedema and thus it is essential for health care practitioners to establish a prompt and accurate diagnosis, and a comprehensive care plan that addresses the patient's physical and mental well-being alike.

Anaphylaxis in laboratory workers because of rodent handling: two case reports.

INTRODUCTION: Occupational allergy to rodents among laboratory animal workers is common. Most patients generally experience allergic symptoms after the first few years of work. Associated symptoms are usually mild, such as rhinoconjunctivits, urticaria, and asthma. Anaphylaxis, although rare, could be severe and life threatening. METHODS: We have described in this study two cases of laboratory workers that developed skin and respiratory reactions following laboratory rat and mouse bites, consistent with anaphylaxis. RESULTS: Skin testing was found positive for rat epithelium in the patient with anaphylaxis due to rat bite. Elevated levels of specific IgE antibodies against rat and mouse epitheliums were also detected in both the patients. CONCLUSION: These cases illustrate a severe hypersensitivity reaction that could potentially occur in occupational workers that are in close contact with rodents. Reduction of allergen exposure, regular screening, and job modification could be beneficial for affected individuals. Health care workers should be made aware that anaphylaxis could be a serious consequence of laboratory animal bites, particularly in those already sensitized.

Clinical Experience with Octagam® 10 %, a solvent detergent virus inactivated intravenous immunoglobulin: a Canadian retrospective review of utilization.

In Canada, intravenous immune globulin (IVIg) products are licensed for six disease indications, however it has been demonstrated that patients with a number of other conditions also benefit from IVIg. Here we report the routine clinical use of Octagam(®) 10 % across three Canadian institutions. A total of 135 patients were treated with Octagam(®), for conditions represented by five distinct indication groups. The results of this review indicate that Octagam(®) has been well adopted and is prescribed to Canadian patients similar to other IVIg products. In alignment with current practices, 85 % of Octagam's utilization was classified as appropriate based on Canadian IVIg guidelines.

Implications to payers of switch from hospital-based intravenous immunoglobulin to home-based subcutaneous immunoglobulin therapy in patients with primary and secondary immunodeficiencies in Canada.

BACKGROUND: Switching primary/secondary immunodeficiency (PID/SID) patients from intravenous immunoglobulin (IVIg) to home-based subcutaneous immunoglobulin (SCIg) therapy reduces nurse time. A nurse shortage in Canada provides an important context to estimate the net economic benefit, the number of patients needed to switch to SCIg to recoup one full-time equivalent (FTE), and potential population-wide savings of reduced nurse time to a payer. METHODS: The net economic benefit was estimated by multiplying the hourly compensation for nurses in Canada by the hours required for each administration route. The number needed to switch to SCIg to gain one nurse FTE was estimated by dividing the work hours in a year by the average annual savings in nursing time in a PID population in Canada. The prevalence of treated PID/SID in Canada was calculated using provincial IgG audit data to extrapolate the potential population-wide savings of switching patients to SCIg therapy. FINDINGS: The net economic gain from switching one patient to home-based SCIg care would be C$2,603 (Canadian Dollars) in year 1 and C$2,948 each year thereafter. Switching 37 IVIg patients to SCIg would gain one nurse FTE. Switching 50% of the estimated 5,486 PID and SID patients in Canada receiving IVIg therapy to SCIg has the potential to save 223.3 nurse FTEs (C$23.2 million in labor costs). CONCLUSIONS: A shift from IVIg to less labor-intensive SCIg has the potential to help alleviate nurse shortages and reduce overall health care costs in Canada. Health care professionals might consider advocating for home-based SCIg therapy for PID/SID patients when clinically appropriate.