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While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important. Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types. Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC. Post-acute sequelae of COVID-19 (PASC) has heterogenous presentation and complex etiology. Here the authors profile peripheral blood of patients with PASC and analyze by machine-learning to identify immune and serology features that allow the stratification of PASC into inflammatory and non-inflammatory types for better diagnosis and therapy-planning.

Background Several new treatments for severe asthma have become available in the last decade; yet, little data exist to guide their use in specific patient populations. Objective A network meta-analysis was conducted comparing the efficacy of FDA-approved monoclonal antibody therapies in preventing exacerbations in patients with severe eosinophilic asthma. Methods PubMed and Ovid were searched from inception until July 2019 for randomized controlled trials that studied the efficacy of benralizumab, dupilumab, mepolizumab, and reslizumab, in preventing acute exacerbations of asthma. Studies were included if they reported data for patients with severe eosinophilic asthma (defined in this meta-analysis as absolute eosinophil count ≥ 250 cells/μL). Annualized rate ratios for asthma exacerbations (during treatment) were calculated and converted to log rate ratios. Direct and indirect treatment estimates (for inter-drug differences) were analyzed using frequentist network meta-analysis methodology in R and treatments were ranked based on P -scores. Results In total, nine studies were included in the final analysis. Network meta-analysis revealed that all drugs were superior to placebo in preventing rates of asthma exacerbation in the study population and no inter-drug differences existed. Dupilumab was found to have the greatest magnitudes of effect on decreasing log rate ratio of asthma exacerbation based on P -score (0.83). Conclusion Benralizumab, dupilumab, mepolizumab, and reslizumab are all associated with decreased asthma exacerbations in patients with eosinophilic asthma, with no significant inter-drug differences.

Streptococcus pneumoniae infections cause morbidity and mortality worldwide. A rapid, simple diagnostic method could reduce the time needed to introduce definitive therapy potentially improving patient outcomes. We introduce two new methods for diagnosing S. pneumoniae infections by measuring the presence of newly activated, pathogen-specific, circulating Antibody Secreting Cells (ASC). First, ASC were detected by ELISpot assays that measure cells secreting antibodies specific for signature antigens. Second, the antibodies secreted by isolated ASC were collected in vitro in a novel matrix, MENSA (media enriched with newly synthesized antibodies) and antibodies against S. pneumoniae antigens were measured using Luminex immunoassays. Each assay was evaluated using blood from S. pneumoniae and non-S. pneumoniae-infected adult patients. We enrolled 23 patients with culture-confirmed S. pneumoniae infections and 24 controls consisting of 12 non-S. pneumoniae infections, 10 healthy donors and two colonized with S. pneumoniae. By ELISpot assays, twenty-one of 23 infected patients were positive, and all 24 controls were negative. Using MENSA samples, four of five S. pneumoniae-infected patients were positive by Luminex immunoassays while all five non-S. pneumoniae-infected patients were negative. Specific antibodies produced by activated ASC may provide a simple diagnostic for ongoing S. pneumoniae infections. This method has the potential to diagnose acute bacterial infections.

ObjectivesThe Steroid PRO is a treatment-specific patient-reported outcome questionnaire which measures the impact of glucocorticoids on health-related quality of life. It has 15 items grouped into 4 domains (Social impact, Impact on Appearance, Psychological Impact and Treatment Concerns). Initially developed and validated in rheumatic diseases, the Steroid PRO demonstrates potential for broader application in patients with other inflammatory conditions. The objective of this study was to assess face validity, content validity and feasibility of the Steroid PRO in (1) patients treated with glucocorticoids for inflammatory respiratory, dermatological and gastroenterological conditions and (2) clinicians working within these specialties in the UK and USA.DesignQualitative study with semistructured cognitive interview methods.SettingOnline or face-to-face interviews with participants from seven departments across three secondary care hospitals in the UK and USA.ParticipantsInclusion criteria: (1) Adult patients with inflammatory respiratory, gastroenterological and dermatological conditions treated with glucocorticoids and (2) healthcare professionals (HCPs) working in respiratory, dermatology and gastroenterology departments in the UK and USA.ResultsPurposive sampling to ensure a range of patient and HCP participants. A total of 42 patient participants were recruited, from respiratory/pulmonology (n=14, 33.3%), dermatology (n=13, 31.0%) and gastroenterology (n=15, 35.8%) medical departments; 32 in the UK and 10 from the USA. Mean age 48.2 years (range 22–71) and 19 (45.2%) were female. Patient participants had a range of inflammatory lung, skin and bowel conditions, with a spectrum of demographics and patterns of glucocorticoid use. 14 HCPs participated from the UK (9) and USA (5). Face validity: 97% (30/31) patients and 100% (14/14) HCPs reported the Steroid PRO was ‘relevant or very relevant’ to them and their disease. Feasibility: 97% (30/31) patients and 100% (14/14) HCPs reported the Steroid PRO was ‘easy or very easy to complete’. Patients reported that the four domains of the Steroid PRO had relevance to them and that it was validating to see their concerns represented: ‘It’s obvious you guys know what you’re talking about—these are my issues. It’s very validating when you realise it’s not just you. These problems are real and they matter.… These are not questions my doctor asks me about. Doctors never ask about psychosocial aspects. It would be really great if they used this’ (female patient with asthma). Patients and clinicians felt the Steroid PRO would be suitable for use in clinical practice within their specialties and would aid in understanding of the impact of glucocorticoids.ConclusionsThe Steroid PRO demonstrated face validity and content validity for assessing the impact of glucocorticoids in patients with inflammatory respiratory, gastroenterological and dermatological conditions. Additionally, the feasibility of using the Steroid PRO with both patients and HCPs has been established. Future work should include quantitative testing of the Steroid PRO as an outcome measure within clinical trials in these conditions.Trial registration numberNCT06314451.

A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling. Sanz and colleagues examine B cell subsets in a cohort of patients with COVID-19. Severely ill patients have higher frequencies of activated extrafollicular T-bet + B cells that form antibody-secreting cells, the majority of which express germline sequences and are reminiscent of antibody responses observed in patients with systemic lupus erythematosus during flares.

Abstract Although significant strides have been made in the understanding of pulmonary immunology, much work remains to be done to comprehensively explain coordinated immune responses in the lung. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic only served to highlight the inadequacy of current models of host–pathogen interactions and reinforced the need for current and future generations of immunologists to unravel complex biological questions. As part of that effort, the 64th Annual Thomas L. Petty Aspen Lung Conference was themed “Bridging the Gap between Innate and Adaptive Immunity in the Lung” and featured exciting work from renowned immunologists. This report summarizes the proceedings of the 2022 Aspen Lung Conference, which was convened to discuss the roles played by innate and adaptive immunity in disease pathogenesis, evaluate the interface between the innate and adaptive immune responses, assess the role of adaptive immunity in the development of autoimmunity and autoimmune lung disease, discuss lessons learned from immunologic cancer treatments and approaches, and define new paradigms to harness the immune system to prevent and treat lung diseases.

Aberrant immune response is a hallmark of asthma, with 5%–10% of patients suffering from severe disease exhibiting poor response to standard treatment. A better understanding of the immune responses contributing to disease heterogeneity is critical for improving asthma management. T cells are major players in the orchestration of asthma, in both mild and severe disease, but it is unclear whether specific T cell subsets influence asthma symptom duration. Here we show a significant association of airway CD8 + effector memory T cells re-expressing CD45RA (TEMRAs), but not CD8 + CD45RO + or tissue-resident memory T cells, with asthma duration in patients with severe asthma (SA) but not mild to moderate asthma (MMA). Higher frequencies of IFN-γ + CD8 + TEMRAs compared with IFN-γ + CD45RO + T cells were detected in SA airways, and the TEMRAs from patients with SA but not MMA proliferated ex vivo, although both expressed cellular senescence-associated biomarkers. Prompted by the transcriptomic profile of SA CD8 + TEMRAs and proliferative response to IL-15, airway IL15 expression was higher in patients with SA compared with MMA. Additionally, IL15 expression in asthmatic airways negatively correlated with lung function. Our findings add what we believe is a new dimension to understanding asthma heterogeneity, identifying IL-15 as a potential target for treatment.

Ultrasound (US)-guided central venous catheter (CVC) insertion is a procedure that carries the risk of significant complications. Simulation provides a safe learning atmosphere, but most CVC simulators are not available outside of simulation centers. To explore longitudinal trends in US-guided CVC insertion competency in internal medicine (IM) interns, we studied the use of a low-fidelity, gelatin-based, US-guided CVC insertion simulation model combined with a simulation curriculum. This prospective observational study of IM interns was performed over the course of one academic year. Interns (n = 56) underwent model-based, US-guided procedure simulation training program and a repeated training course prior to their intensive care unit (ICU) rotation. CVC insertion competency at different timepoints was recorded. Survey data about intern experience and attitudes were also collected. Out of the 56 interns initially trained, 40 were included in the final analysis. Across all outcomes, interns experienced skill atrophy between initial training and the beginning of their ICU month. However, by the end of the month, there was a significant improvement in competency as compared to initial procedural training, which then waned by the end of the intern year. Attitudes toward the model were generally positive and self-reported confidence improved throughout the course of the year and correlated with objective measures of competency. Over the course of their intern year, which included simulation training using a gelatin-based model, interns demonstrated consistent competency trends. The use of a gelatin-based CVC insertion simulation model warrants further study as an adjunctive aid to existing simulation training.

Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.

Ramonell argues on the study of Allie SR and colleague's The Establishment of Resident Memory B Cells in the Lung Requires Local Antigen Encounter. He said that Allie and colleagues demonstrate not only that BRM cells are distinct from circulating memory B cells but also that these cells' differentiation into antigen-specific antibody-secreting cells (ASCs) after secondary infection requires local antigen encounter. They also show that BRM cells play an important role in protective immunity with secondary viral infection. These investigators designed a model of influenza infection in C57BL/6 mice using influenza nucleoprotein and hemagglutinin protein tetramers conjugated to fluorochromes that allowed detection in flow cytometric assays. Their new study elucidates the characteristics, origins and function of a novel layer of protective memory B cells localized in infected tissues, the BRM cells.