Prophylaxis in hereditary angioedema: a United Kingdom Delphi consensus.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent of episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalising patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding long-term prophylaxis as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone is too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient reported outcome measures have the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

Differential Diagnosis: Hepatic Complications in Inborn Errors of Immunity.

Inborn errors of immunity (IEIs) are a heterogeneous group of diverse clinical and genetic phenotypes that have an estimated combined prevalence as high as 1/1000. Increased risk of frequent, severe, or opportunistic infections is a common feature of IEIs, but there are also diverse immune-mediated, non-infective complications that are associated with significant morbidity and mortality. As patient survival increases, these are becoming more apparent within the liver. Hepatic involvement of IEIs may not only manifest as infections, but also nodular regenerative hyperplasia, granulomatous disease, autoimmune hepatitis and malignancy. As therapeutic options for patients are expanding, with both pharmaceutical treatments as well as haematopoietic stem cell transplant (HSCT), iatrogenic liver injury is increasingly common and important to identify. This review article summarises the spectrum of hepatic complications seen in IEIs, and highlights the challenges of management within this patient cohort, where immunosuppression is poorly tolerated. Early recognition and prompt diagnosis of potential hepatic complications is therefore crucial in ensuring potentially reversible causes are treated, but significant uncertainty remains regarding best practice for many features of immune dysregulation with limited high-quality evidence.

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.

Effects of Atrioventricular Optimization on Left Ventricular Reverse Remodeling With Cardiac Resynchronization Therapy: Results of the SMART-CRT Trial.

BACKGROUND: The role of atrioventricular optimization (AVO) to improve cardiac resynchronization therapy outcomes remains controversial. Previous post hoc analyses of a multicenter trial showed that measures of electrical dyssynchrony (right ventricular-left ventricular [LV] or LV electrical delay durations) are associated with patients who benefit from AVO. METHODS: This was a global, multicenter, prospective, randomized trial of de novo cardiac resynchronization therapy implant patients with an right ventricular-LV duration ≥70 ms to determine whether AVO results in greater reverse remodeling. Patients were randomized 1:1 for either an AVO algorithm (SmartDelay) that determines atrioventricular delay and pacing chamber, biventricular or LV only, or a fixed atrioventricular delay of 120 ms with biventricular pacing. Paired echocardiograms performed at baseline and 6 months were evaluated. The primary end point was echocardiographic cardiac resynchronization therapy response, defined dichotomously as a >15% reduction in LV end-systolic volume. RESULTS: A total of 310 patients (n=120 women) were randomized and had completed 6 months of follow-up. The echocardiographic cardiac resynchronization therapy response rate did not statistically differ between the groups (SmartDelay, 74.8%; fixed, 67.7%; P=0.17). Analyses of prespecified secondary end points demonstrated significant improvements in the absolute (median: SmartDelay, -41.0 mL; fixed, -33.0 mL; P=0.01) and relative change in LV end-systolic volume (SmartDelay, -38.3%; fixed, -27.8%; P=0.03) for patients with SmartDelay optimization. Similar results were observed for the relative improvement in LV ejection fraction (SmartDelay, 46.7%; fixed, 32.1%; P=0.050); absolute improvement in LV ejection fraction trended to be higher with SmartDelay (P=0.06). CONCLUSIONS: Analysis of reverse remodeling parameters demonstrated that AVO via SmartDelay, relative to the nonoptimized fixed atrioventricular delay comparator group, improved absolute and relative changes in LV function in patients with longer right ventricular-LV duration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03089281.

Resistant Chronic Spontaneous Urticaria - A Case Series Narrative Review of Treatment Options.

Background: Chronic spontaneous urticaria (CSU) can be extremely debilitating to the patient and challenging for the treating clinician. The National Institute of Health and Clinical Excellence (NICE) in the United Kingdom (UK) recommendation of omalizumab for patients who fail to respond to high-dose anti-histamines has improved treatment options and quality of life. However, there is still lack of clear guidelines for treatment of patients resistant to standard and anti-IgE therapies. Methods: We discuss the therapeutic strategies employed among nine extremely resistant CSU cases and the heterogeneity between guidelines from different societies. Results: Patients with anti-histamine-resistant urticaria either remained on omalizumab or started on immunosuppressive drugs (dapsone or ciclosporin) when they stopped responding to omalizumab. We used clinical assessment, skin biopsies (when available) and previous published reports to consider dapsone (for predominantly neutrophilic infiltration), or ciclosporin at doses between 2 and 4 mg/kg/day. One patient with ciclosporin-resistant urticaria responded to mycophenolate mofetil. Two patients remain on long-term omalizumab due to its relative safety and efficacy including 1 patient with underlying antibody deficiency where omalizumab was preferred over risks of using immunosuppressive medications. Conclusions: These case studies bring to light the real-world difficulties in managing patients with resistant CSU and the need for generating the evidence base on alternative therapeutic options such as synergistic use of biologics and immunosuppressive drugs.

Recurrent Campylobacter jejuni Infection in an Immunodeficient Patient Treated with Repeated Faecal Microbiota Transplant (FMT)-A Case Report.

There is limited evidence to guide successful treatment of recurrent Campylobacter infection in patients with common variable immunodeficiency (CVID) already managed on regular immunoglobulin therapy. The role of faecal microbiota transplant (FMT) is uncertain. We report a case of recurrent Campylobacter jejuni infection in a patient with CVID treated with repeated FMT with 18 months of symptom resolution prior to relapse.

A meta-analysis on allergen-specific immunotherapy using MCT® (MicroCrystalline Tyrosine)-adsorbed allergoids in pollen allergic patients suffering from allergic rhinoconjunctivitis.

BACKGROUND: The World Allergy Organization and the European Academy of Allergy and Clinical Immunology recommend to perform product-specific meta-analyses for allergen-specific immunotherapies because of the high degree of heterogeneity between individual products. This meta-analysis evaluates the efficacy and safety of Glutaraldehyde-modified and MCT® (MicroCrystalline Tyrosine)-adsorbed allergoids (MATA). METHODS: The databases MEDLINE, LILACS, embase, LIVIVO, Web of Science and Google (Scholar) were searched for publications on MATA up to June 2019. Primary endpoint was the combined symptom and medication score (CSMS). Secondary endpoints were single scores, immunogenicity and improvement of allergic condition. Secondary safety endpoints were the occurrence of side effects. A random effects model was applied with (standardized) mean differences ([S]MDs) including confidence intervals (CI). Heterogeneity was analyzed using the I2 index and publication bias using Egger's test and Funnel plots. Subgroups were analyzed regarding age and asthma status. RESULTS: Eight randomized double-blind placebo-controlled trials were selected for efficacy and 43 publications for safety analysis. In total, 4531 patients were included in this analysis including eight studies containing data on children and adolescents. AIT with MATA significantly reduced allergic symptoms and medication use with a SMD for CSMS of -0.8 (CI: -1.24, -0.36) in comparison to placebo. Heterogeneity was moderate between the studies. The total symptom score (-1.2 [CI: -2.11, -0.29]) and the total medication score (-2.2 [CI: -3.65, -0.74]) were also significantly reduced after MATA treatment. Patient's condition improved significantly after treatment with MATA, with an odds ratio of 3.05 (CI: 1.90, 4.90) when compared to placebo. The proportion of patients, who developed side effects was 38% (CI: 19%, 57%). No serious side effects occurred. Safety in the subgroups of asthmatic patients, children and adolescents did not differ from the overall patient population. CONCLUSIONS: This meta-analysis reveals a large body of evidence from publications investigating MATA. MATA significantly improved allergic symptoms and reduced the use of anti-allergic medication in comparison to placebo, with an excellent safety profile. Especially for children and asthmatic patients, the use of MATAs can be considered as safe, because the safety profiles in these groups did not differ from the total patient population.

Assessment of primary prevention patients receiving an ICD - Systematic evaluation of ATP: APPRAISE ATP.

BACKGROUND: The value of antitachycardia pacing (ATP) in the overall cohort of primary prevention patients who receive implantable cardioverter-defibrillators (ICDs) remains uncertain. ATP success reported in prior trials potentially included a large number of patients receiving unnecessary ATP for arrhythmias that may have self-terminated owing to the prematurity of the intervention. Although some patients derive benefit from initial ATP in terminating rapid ventricular arrhythmias and thereby preventing shocks, there are limited data allowing us to identify those patients a priori. OBJECTIVE: The purpose of APPRAISE ATP is to understand the role of ATP in primary prevention patients currently indicated for ICD therapy in a large prospective randomized controlled trial with modern programming parameters. METHODS: The study is a global, prospective, randomized, multicenter clinical trial conducted at up to 150 sites globally, enrolling approximately 2600 subjects The primary endpoint of the trial is time to first all-cause shock in a 2-arm study with an equivalent study design in which the incidence of all-cause shocks will be compared between primary prevention subjects programmed with shocks only vs subjects programmed to standard therapy (ATP and shock). RESULTS: An Electrogram and Device Interrogation Core Laboratory will review interrogation data to determine primary endpoints that occur in APPRAISE ATP. Their decisions are based on independent physician review of the data from device interrogation. CONCLUSION: The ultimate purpose of the study is to aid clinicians in the selection of ICD technologies based on hard endpoint evidence across the spectrum of indications for primary prevention implantation.

The first reported cases of meat allergy following tick bites in the UK.

Allergic reactions frequently involve the production of immunoglobulin E (IgE) antibodies to proteins. However, reactions directed against carbohydrate moieties are increasingly being recognised. Tick bites can contribute to the development of immunoglobulin E to the galactose-1,3-galactose (alpha-gal) moiety on tick salivary proteins. These IgE molecules can cross-react with alpha-gal found in red meats, causing Type I IgE-mediated hypersensitivity reactions to these foods. We present three cases of delayed reactions to beef, pork and lamb in patients with prior tick bites and in the presence of a positive-specific IgE to alpha-gal. Patients were advised to avoid red meat consumption and to carry emergency treatment in the form of anti-histamines with or without adrenaline autoinjector devices. This is the first published report of red meat allergy caused by tick bites suffered in the UK.

No Venous Thromboembolism Increase Among Transgender Female Patients Remaining on Estrogen for Gender-Affirming Surgery.

BACKGROUND: Both surgery and exogenous estrogen use are associated with increased risk of venous thromboembolism (VTE). However, it is not known whether estrogen hormone therapy (HT) exacerbates the surgery-associated risk among transgender and gender nonbinary (TGNB) individuals. The lack of published data has contributed to heterogeneity in perioperative protocols regarding estrogen HT administration for TGNB patients undergoing gender-affirming surgery. METHODS: A single-center retrospective chart review was performed on all TGNB patients who underwent gender-affirming surgery between November 2015 and August 2019. Surgery type, preoperative HT regimen, perioperative HT regimen, VTE prophylaxis management, outcomes, and demographic data were recorded. RESULTS: A total of 919 TGNB patients underwent 1858 surgical procedures representing 1396 unique cases, of which 407 cases were transfeminine patients undergoing primary vaginoplasty. Of the latter, 190 cases were performed with estrogen suspended for 1 week prior to surgery, and 212 cases were performed with HT continued throughout. Of all cases, 1 patient presented with VTE, from the cohort of transfeminine patients whose estrogen HT was suspended prior to surgery. No VTE events were noted among those who continued HT. Mean postoperative follow-up was 285 days. CONCLUSIONS: Perioperative VTE was not a significant risk in a large, homogenously treated cohort of TGNB patients independent of whether HT was suspended or not prior to surgery.

Reassessing the role of antitachycardia pacing in fast ventricular arrhythmias in primary prevention implantable cardioverter-defibrillator recipients: Results from MADIT-RIT.

BACKGROUND: In Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy (MADIT-RIT), high-rate cutoff (arm B) and delayed therapy (arm C) reduced the risk of inappropriate implantable cardioverter-defibrillator (ICD) interventions when compared with conventional programming (arm A); however, appropriate but unnecessary therapies were not evaluated. OBJECTIVE: The purpose of this study was to assess the value of antitachycardia pacing (ATP) for fast ventricular arrhythmias (VAs) ≥ 200 beats/min in patients with primary prevention ICD. METHODS: We compared ATP only, ATP and shock, and shock only rates in patients in MADIT-RIT treated for VAs ≥ 200 beats/min. The only difference between these randomized groups was the time delay between ventricular tachycardia detection and therapy (3.4 seconds vs 4.9 seconds vs 14.4 seconds). RESULTS: In arm A, 11.5% patients had events, the initial therapy was ATP in 10.5% and shock in 1%, and the final therapy was ATP in 8% and shock in 3.5%. In arm B, 6.6% had events, 4.2% were initially treated with ATP and 2.4% with shock, and the final therapy was ATP in 2.8% and shock in 3.8%. In arm C, 4.7% had events, 2.5% were initially treated with ATP and 2.3% with shock, and the final therapy was ATP in 1.4% and shock in 3.3%. The final shock rate was similar in arm A vs arm B (3.5% vs 3.8%; P = .800) and in arm A vs arm C (3.5% vs 3.3%; P = .855) despite the marked discrepancy in initial ATP therapy utilization. CONCLUSION: In MADIT-RIT, there was a significant reduction in ATP interventions with therapy delays due to spontaneous termination, with no difference in shock therapies, suggesting that earlier interventions for VAs ≥ 200 beats/min are likely unnecessary, leading to an overestimation of the value of ATP in primary prevention ICD recipients.

Illustrative Case Series and Narrative Review of Therapeutic Failure of Immunotherapy for Allergic Rhinitis.

This is a series of 4 cases (3 therapeutic failure and 1 early relapse) in adult patients treated with allergen immunotherapy (AIT) for allergic rhinitis (AR) in our immunotherapy clinic, which treats 110 new patients per year. AIT includes both subcutaneous and sublingual routes. The current national/international AIT recommendations and the literature have been searched to identify guidance for the optimal management of therapeutic failure of AIT in AR. There is scant information available to support clinicians when treatment failure and/or intolerable side effects occur. The importance is highlighted for developing the guidance and evidence base for the benefit of this patient subgroup. The potential strategies that clinicians have proposed are discussed in this article, though it is acknowledged that these are mostly not evidence-based.

A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination-deficient Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated with heterogeneous responses. EXPERIMENTAL DESIGN: We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were gBRCA mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers. RESULTS: We found that biallelic inactivation of BRCA1/BRCA2 is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17). CONCLUSIONS: In summary, we propose a predictive and prognostic model of gBRCA-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.