Search

Aims To characterise patients with systemic reactions and anaphylaxis with an acute serum tryptase of ⩾14 μg/L against recently published World Allergy Organisation (WAO) diagnostic criteria. To also perform a clinical audit to assess adherence to National Institute of Health and Care Excellence (NICE) guideline recommendations regarding serial tryptase measurements and specialist referral. Methods A systematic retrospective survey (2006-2010) was carried out (n=171; males=86; mean age±SD 48 ±20 years) and data were extracted from emergency department and specialist allergy clinic records. Results 34 patients (20%) had a grade 1 reaction, 61 (36%) grade 2, 46 (27%) grade 3 and 6 patients (4%) grade 4 (24 patients (13%) could not be graded due to lack of adequate clinical details) and 6% developed a biphasic response. Serial tryptase measurements were not available in 117 (69%) of the cohort. 97 (57%) patients were referred for specialist assessment, and 72 (74%) attended. 50% of cases were diagnosed with idiopathic systemic reactions/anaphylaxis and 28%, 14% and 8% triggered by drugs, foods and other allergies including disorders of mast cell overload, respectively. A weak positive correlation was detected between acute serum tryptase and severity. Conclusions The correlation between acute serum tryptase and severity of anaphylaxis/systemic reactions is weak. A significant proportion of patients with raised acute serum tryptase had mild reactions which did not meet WAO criteria for anaphylaxis and this may reduce the specificity of the test. The commonest aetiology in this cohort was idiopathic followed by drug and food allergies. NICE guidelines relating to serial tryptase measurements and specialist referral were not followed, and there is an urgent need to raise the awareness among clinicians involved in the management of anaphylaxis. [ABSTRACT FROM AUTHOR]

Presents a magnetic resonance image of cryoglobulinemia as an acute presentation of waldenstrom's macroglobulinemia. Manifestations of the condition; Features of hyperviscosity revealed by fundoscopy.

Background: Acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) is very rare compared to its prototype, hereditary angioedema. An updated characterisation of the AAE-C1-INH cohort in UK is required to inform management., Objectives: To describe the disease burden of AAE-C1-INH, long-term prophylaxis (LTP) and the clinical, immunochemical and treatment profiles of AAE-associated diseases in UK., Method: Retrospective data on 117 AAE-C1-INH patients were collected using a national survey proforma across 25/34 Adult Clinical Immunology and Allergy centres in UK. Other European cohorts were compared., Results: Median age at AAE-C1-INH diagnosis was 65 years with 3.4% of patients diagnosed below 40 years. The median delay in diagnosis was one year. Antifibrinolytics and attenuated androgens showed comparable efficacy as LTP 88.9% and 89.5%, respectively. A haematological disorder was identified in 83.8% AAE-C1-INH patients compared to 3.4% autoimmune diseases. The predominant haematological disorders were splenic marginal zone lymphoma (SZL) 34% followed by MGUS 16%. The severity of angioedema did not depend on the associated disease. Anti-C1INH-autoantibodies testing was limited at 23.1%. Rituximab monotherapy was effective in treating 9/9 SZL and 1/2 MGUS-associated AAE-C1-INH. Rituximab efficacy was independent of anti-C1INH-autoantibodies detection with response in 3/3 seronegative and 4/4 seropositive patients., Conclusion: The diagnosis of AAE-C1-INH should not be overlooked below the age of 40 years. The choice of oral LTP should be informed by propensity to side-effects. B-cell depletion could be considered in treating monoclonal B cell disorder-associated-AAE-C1-INH in the absence of haematological indications. Further studies are required to address the clinical utility of anti-C1INH-autoantibodies., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: In several countries, extended interval COVID-19 vaccination regimens are now used to accelerate population coverage, but the relative immunogenicity of different vaccines in older people remains uncertain. In this study we aimed to assess the antibody and cellular responses of older people after a single dose of either the BNT162b2 vaccine (tozinameran; Pfizer-BioNTech) or ChAdOx1 nCoV-19 vaccine (Oxford University-AstraZeneca)., Methods: Participants aged 80 years or older, who did not live in a residential or care home or require assisted living, and had received a single dose of either the BNT162b2 vaccine or ChAdOx1 nCoV-19 vaccine were eligible to participate. Participants were recruited through local primary care networks in the West Midlands, UK. Blood samples and dried blood spots were taken 5-6 weeks after vaccination to assess adaptive immune responses using Elecsys electrochemiluminescence immunoassay and cellular responses by ELISpot. Primary endpoints were percentage response and quantification of adaptive immunity., Findings: Between Dec 29, 2020, and Feb 28, 2021, 165 participants were recruited and included in the analysis. 76 participants had received BNT162b2 (median age 84 years, IQR 82-89; range 80-98) and 89 had received ChAdOx1 nCoV-19 (median age 84 years, 81-87; 80-99). Antibody responses against the spike protein were detectable in 69 (93%) of 74 BNT162b2 vaccine recipients and 77 (87%) of 89 ChAdOx1 nCoV-19 vaccine recipients. Median antibody titres were of 19·3 U/mL (7·4-79·4) in the BNT162b2 vaccine recipients and 19·6 U/mL (6·1-60·0) in the ChAdOx1 nCoV-19 vaccine recipients (p=0·41). Spike protein-specific T-cell responses were observed in nine (12%) of 73 BNT162b2 vaccine recipients and 27 (31%) of 88 ChAdOx1 nCoV-19 vaccine recipients, and median responses were three-times higher in ChAdOx1 nCoV-19 vaccine recipients (24 spots per 1 × 10 6 peripheral blood mononuclear cells) than BNT162b2 vaccine recipients (eight spots per 1 × 10 6 peripheral blood mononuclear cells; p<0·0001). Humoral and cellular immune responses against spike protein were correlated in both cohorts. Evidence of previous SARS-CoV-2 infection was seen in eight participants (n=5 BNT162b2 recipients and n=3 ChAdOx1 nCoV-19 recipients), and was associated with 691-times and four-times increase in humoral and cellular immune responses across the whole cohort., Interpretation: Single doses of either BNT162b2 or ChAdOx1 nCoV-19 in older people induces humoral immunity in most participants, and is markedly enhanced by previous infection. Cellular responses were weaker, but showed enhancement after the ChAdOx1 nCoV-19 vaccine at the 5-6 week timepoint., Funding: Medical Research Council, National Institute for Health Research, and National Core Studies., Competing Interests: We declare no competing interests., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

Inhibitors of the tyrosine kinase Btk have been proposed as novel antiplatelet agents. In this study we show that low concentrations of the Btk inhibitor ibrutinib block CLEC-2-mediated activation and tyrosine phosphorylation including Syk and PLCγ2 in human platelets. Activation is also blocked in patients with X-linked agammaglobulinemia (XLA) caused by a deficiency or absence of Btk. In contrast, the response to GPVI is delayed in the presence of low concentrations of ibrutinib or in patients with XLA, and tyrosine phosphorylation of Syk is preserved. A similar set of results is seen with the second-generation inhibitor, acalabrutinib. The differential effect of Btk inhibition in CLEC-2 relative to GPVI signalling is explained by the positive feedback role involving Btk itself, as well as ADP and thromboxane A2 mediated activation of P2Y12 and TP receptors, respectively. This feedback role is not seen in mouse platelets and, consistent with this, CLEC-2-mediated activation is blocked by high but not by low concentrations of ibrutinib. Nevertheless, thrombosis was absent in 8 out of 13 mice treated with ibrutinib. These results show that Btk inhibitors selectively block activation of human platelets by CLEC-2 relative to GPVI suggesting that they can be used at 'low dose' in patients to target CLEC-2 in thrombo-inflammatory disease.

Background: Assessment of pure polysaccharide response to the 23-valent pneumococcal polysaccharide vaccine (PPV23) can be biased by previous exposure to the conjugate vaccine (PCV). We applied pre-analytical modification to the existing ELISA by pre-incubating serum with PCV., Methods: PCV-adsorbed and non-adsorbed sera were prepared before measuring the concentration of anti-pneumococcal capsular polysaccharide (PCP) IgG antibodies by the whole pneumococcal ELISA. Paired pre and post-pneumococcal vaccination sera from 73 subjects were analyzed and the baseline anti-PCP IgG for each sample was subtracted from the post-vaccination value to measure vaccine responses. Absolute change in titers and fold changes were then compared between both methods., Results: In the PCV-vaccinated group (n = 28), pre-adsorption with PCV significantly reduced the vaccine responses compared to non-adsorbed sera [median increase in anti-PCP titers: 27.55 mg/l and 45.98 mg/l, respectively]. In addition, the median fold change dropped significantly from 3.026 to 2.313. In PPV23-vaccinated immunocompetent subjects (n = 28) there was a significant difference in anti-PCP responses with PCV adsorption [median values: 73.71 mg/l without and 51.04 mg/l with adsorption]. All the antibody deficiency patients (n = 17) displayed poor PPV23 responses. Although PPV23 responsiveness was not statistically different between both methods, we have observed a trend for lower anti-PCP IgG titers in PCV-adsorbed sera compared to non-adsorbed ones. Serotype-specific IgG analysis using a multiplexed bead-based immunoassay performed on 10 paired samples confirmed that the adsorption observed is specific to PCV serotypes., Conclusion: Pre-analytical modification to the conventional ELISA by removing the PCV-specific serotypes may differentiate true polysaccharide response from recall response induced by previous PCV vaccination., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies 1-3 . Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed 4 ) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

Background: Detecting antibody responses during and after SARS-CoV-2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect., Methods: We systemically developed an ELISA assay, optimising different antigens and amplification steps, in serum and saliva from symptomatic and asymptomatic SARS-CoV-2-infected subjects., Results: Using trimeric spike glycoprotein, rather than nucleocapsid enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti-spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti-spike, but not nucleocapsid, IgG, IgA and IgM antibody responses were readily detectable in saliva from non-hospitalized symptomatic and asymptomatic individuals. Antibody responses in saliva and serum were largely independent of each other and symptom reporting., Conclusions: Detecting antibody responses in both saliva and serum is optimal for determining virus exposure and understanding immune responses after SARS-CoV-2 infection., Funding: This work was funded by the University of Birmingham, the National Institute for Health Research (UK), the NIH National Institute for Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation and the University of Southampton.