Measurement of C1-Inhibitor function alone is sufficient for diagnosis of hereditary angioedema

The World Allergy Organisiation/European Academy of Allergy and Clinical Immunology (WAO/EAACI) 2017/2018 guidelines recommend measuring complement4 levels, followed by C1-inhibitor level and function for diagnosis of hereditary angioedema (HAE). We analysed 6 months’ worth of data generated in our laboratory which is a specialist regional immunology service and also provides laboratory service for the Barts Health immunology department, which is a GA2LEN/HAEi-Angioedema Centre of Excellence and Reference (ACARE) and hence, investigates a large number of patients for HAE. We found that an efficient and sensitive approach for laboratory diagnosis of HAE is to only test the C1-inhibitor function. This approach had a sensitivity of 100% and reduced the cost of laboratory investigations for HAE diagnosis by 45%

Real-world outcomes in hereditary angioedema: first experience from the Icatibant Outcome Survey in the United Kingdom

Background Hereditary angioedema (HAE) is a potentially life-threatening, bradykinin-mediated disease, often misdiagnosed and under-treated, with long diagnostic delays. There are limited real-world data on best-practice management of HAE in the UK. Objectives To characterize the clinical profile, management and outcomes of patients with HAE type I and II from three specialist centres in the UK using data from the Icatibant Outcome Survey (IOS; Shire, Zug, Switzerland), an international observational study monitoring safety and effectiveness of icatibant, a selective bradykinin B2 receptor antagonist. Methods We performed retrospective analyses of IOS data for patients with HAE type I and II from three centres in the UK and compared UK data with pooled IOS data from 10 countries (48 centres). Results Analyses included 73 UK and 579 non-UK patients with HAE type I or II. Median diagnostic delay was 6.2 and 5.9 years, respectively. Analysis of data collected from February 2008 to July 2016 included 286 icatibant-treated attacks in 58 UK patients and 2553 icatibant-treated attacks in 436 non-UK patients (median of 3.0 attacks per patient in both groups). More attacks were treated by icatibant self-administration in UK patients (95.8%) than in non-UK patients (86.8%, p < 0.001). Time to icatibant treatment, time to resolution and attack duration were not significantly different in the UK versus non-UK patients. Conclusion UK patients from the specialist centres studied report similar diagnostic delay and similar icatibant treatment outcomes to their non-UK counterparts. However, improvements in the timely diagnosis of HAE are still required

Primary vs. Secondary Antibody Deficiency: Clinical Features and Infection Outcomes of Immunoglobulin Replacement

<div><p>Secondary antibody deficiency can occur as a result of haematological malignancies or certain medications, but not much is known about the clinical and immunological features of this group of patients as a whole. Here we describe a cohort of 167 patients with primary or secondary antibody deficiencies on immunoglobulin (Ig)-replacement treatment. The demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, and infection frequency were analysed retrospectively. Chemotherapy for B cell lymphoma and the use of Rituximab, corticosteroids or immunosuppressive medications were the most common causes of secondary antibody deficiency in this cohort. There was no difference in diagnostic delay or bronchiectasis between primary and secondary antibody deficiency patients, and both groups experienced disorders associated with immune dysregulation. Secondary antibody deficiency patients had similar baseline levels of serum IgG, but higher IgM and IgA, and a higher frequency of switched memory B cells than primary antibody deficiency patients. Serious and non-serious infections before and after Ig-replacement were also compared in both groups. Although secondary antibody deficiency patients had more serious infections before initiation of Ig-replacement, treatment resulted in a significant reduction of serious and non-serious infections in both primary and secondary antibody deficiency patients. Patients with secondary antibody deficiency experience similar delays in diagnosis as primary antibody deficiency patients and can also benefit from immunoglobulin-replacement treatment.</p></div

British Society for Immunology & United Kingdom Primary Immunodeficiency Network (UKPIN) consensus guideline for the management of immunoglobulin replacement therapy

Currently there is no guideline to support the use of immunoglobulin replacement therapy (IgRT) in primary and secondary immunodeficiency disorders in UK. The UK Primary Immunodeficiency Network (UK-PIN) and the British Society of Immunology (BSI) joined forces to address this need. Given the paucity of evidence a modified Delphi approach was employed covering statements for the initiation, monitoring, discontinuation of IgRT as well as home therapy programme. A group of 6 consultant immunologists and 3 nurse specialists created the statements, reviewed responses and feedback and agreed on final recommendations. This guideline includes 22 statements for initiation, 22 statements for monitoring, 11 statement for home therapy and 19 statements for discontinuation of IgRT. Further areas of research are proposed to improve future delivery of care

Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sj\uf6gren Syndrome (CRESS) and Sj\uf6gren Tool for Assessing Response (STAR) to B Cell–Targeted Therapy in the Trial of Anti–B Cell Therapy in Patients With Primary Sj\uf6gren Syndrome (TRACTISS)

\ua9 2023 The Authors. Arthritis &amp; Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.Objective: This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sj\uf6gren Syndrome (cCRESS) and candidate Sj\uf6gren Tool for Assessing Response (STAR) composite endpoints. Methods: Longitudinal analysis of peripheral blood and SG biopsies was performed pre- and post-treatment from the Trial of Anti–B Cell Therapy in Patients With Primary Sj\uf6gren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing. Results: Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class-switched memory B cells within the SG. Furthermore, rituximab significantly down-regulated genes involved in immune-cell recruitment, lymphoid organization alongside antigen presentation, and T cell co-stimulatory pathways. In the peripheral compartment, rituximab down-regulated immunoglobulins and auto-antibodies together with pro-inflammatory cytokines and chemokines. Interestingly, patients classified as responders according to STAR displayed significantly higher baseline levels of C-X-C motif chemokine ligand-13 (CXCL13), interleukin (IL)-22, IL-17A, IL-17F, and tumor necrosis factor-α (TNF-α), whereas a longitudinal analysis of serum T cell–related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS-responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ-receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration. Conclusion: Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification. (Figure presented.)

Pedagogical Agents for Fostering Question-Asking Skills in Children

Question asking is an important tool for constructing academic knowledge, and a self-reinforcing driver of curiosity. However, research has found that question asking is infrequent in the classroom and children's questions are often superficial, lacking deep reasoning. In this work, we developed a pedagogical agent that encourages children to ask divergent-thinking questions, a more complex form of questions that is associated with curiosity. We conducted a study with 95 fifth grade students, who interacted with an agent that encourages either convergent-thinking or divergent-thinking questions. Results showed that both interventions increased the number of divergent-thinking questions and the fluency of question asking, while they did not significantly alter children's perception of curiosity despite their high intrinsic motivation scores. In addition, children's curiosity trait has a mediating effect on question asking under the divergent-thinking agent, suggesting that question-asking interventions must be personalized to each student based on their tendency to be curious.Comment: Accepted at CHI 202

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients