Understanding the extent of, and reasons for, diagnostic delay in inflammatory bowel disease

Background: Inflammatory Bowel Disease (IBD) is a complex chronic condition affecting the gastrointestinal (GI) system and is sub-classified into Crohn’s Disease (CD) and Ulcerative Colitis (UC). Patients with IBD can present with a multitude of symptoms, making the diagnosis challenging and frequently resulting in delays. Aim & objective: The aim of this research was to better understand the extent of, and reasons for, diagnostic delay in IBD. The first objective was to establish the extent of which the diagnosis of IBD is typically delayed and any characteristics which may be related to this. The second objective was to explore the individual experience of delay, including possible contributing factors for delay as well as any impact of delay on the patient. Methods: Two distinct methods were used. A systematic review was conducted to identify articles that reported a time-period of diagnostic delay of IBD. A narrative synthesis was then used to present the extent of IBD and explore consultation and healthcare factors for delay, which is defined below. Secondly, interviews were conducted with participants who self-reported a delay in IBD diagnosis, in order to explore this delay from their perspective. Participants were asked their opinions on factors which may have contributed to their delay and any consequences of this delay. Misdiagnoses they had been given before their IBD diagnosis was also discussed. Thematic analysis was applied to this dataset. Results: For the systematic review, 7570 articles were sourced from the search following de-duplication. 5127 and 2143 articles were excluded following title and abstract review respectively. Of the remaining 284 articles for full-text review, 35 met the inclusion criteria. The median values of diagnostic delay were between 2 and 5.3 months for IBD, 2 to 26.4 months for CD and 2 to 12 months for UC. Consultation delays, defined as the time between the onset of patient symptoms and them seeking medical advice, ranged from 1 to 8.6 months in CD and 0.7 to 1.9 months in UC. Healthcare delays, the time between patients seeking medical advice to receiving a diagnosis, were 0.7 to 20.8 months and 0.2 to 1.1 months for CD and UC respectively. From interviews with sixteen participants, irritable bowel syndrome (IBS), gastroenteritis and mental health conditions were commonly reported misdiagnoses. Participants cited a perceived insignificance of symptoms, fear and embarrassment as reasons why they delayed seeking medical advice. Patient-reported reasons for healthcare delays included GP reluctance to refer to secondary care and prolonged, ineffective management. Participants described experiencing issues with waiting lists for appointments and delayed diagnostic procedures. Some participants felt their delay had negatively impacted on their diagnosis, including a need for stronger medication or surgery. Discussion: The overall diagnostic delay of IBD is extensive but varies considerably. Delay seems to be worse in CD than UC, particularly regarding healthcare delays. This is also supported by the interview findings

Impact of naturally spawning captive-bred Atlantic salmon on wild populations: depressed recruitment and increased risk of climate-mediated extinction

The assessment report of the 4th International Panel on Climate Change confirms that global warming is strongly affecting biological systems and that 20–30% of species risk extinction from projected future increases in temperature. It is essential that any measures taken to conserve individual species and their constituent populations against climate-mediated declines are appropriate. The release of captive bred animals to augment wild populations is a widespread management strategy for many species but has proven controversial. Using a regression model based on a 37-year study of wild and sea ranched Atlantic salmon (Salmo salar) spawning together in the wild, we show that the escape of captive bred animals into the wild can substantially depress recruitment and more specifically disrupt the capacity of natural populations to adapt to higher winter water temperatures associated with climate variability. We speculate the mechanisms underlying this seasonal response and suggest that an explanation based on bio-energetic processes with physiological responses synchronized by photoperiod is plausible. Furthermore, we predict, by running the model forward using projected future climate scenarios, that these cultured fish substantially increase the risk of extinction for the studied population within 20 generations. In contrast, we show that positive outcomes to climate change are possible if captive bred animals are prevented from breeding in the wild. Rather than imposing an additional genetic load on wild populations by releasing maladapted captive bred animals, we propose that conservation efforts should focus on optimizing conditions for adaptation to occur by reducing exploitation and protecting critical habitats. Our findings are likely to hold true for most poikilothermic species where captive breeding programmes are used in population management

Bioengineering commensal bacteria-derived outer membrane vesicles for delivery of biologics to the gastrointestinal and respiratory tract

Gram-negative bacteria naturally produce and secrete nanosized outer membrane vesicles (OMVs). In the human gastrointestinal tract, OMVs produced by commensal Gram-negative bacteria can mediate interactions amongst host cells (including between epithelial cells and immune cells) and maintain microbial homeostasis. This OMV-mediated pathway for host-microbe interactions could be exploited to deliver biologically active proteins to the body. To test this we engineered the Gram-negative bacterium Bacteroides thetaiotaomicron (Bt), a prominent member of the intestinal microbiota of all animals, to incorporate bacteria-, virus- and human-derived proteins into its OMVs. We then used the engineered Bt OMVs to deliver these proteins to the respiratory and gastrointestinal (GI)-tract to protect against infection, tissue inflammation and injury. Our findings demonstrate the ability to express and package both Salmonella enterica ser. Typhimurium-derived vaccine antigens and influenza A virus (IAV)-derived vaccine antigens within or on the outer membrane of Bt OMVs. These antigens were in a form capable of eliciting antigen-specific immune and antibody responses in both mucosal tissues and systemically. Furthermore, immunisation with OMVs containing the core stalk region of the IAV H5 hemagglutinin from an H5N1 strain induced heterotypic protection in mice to a 10-fold lethal dose of an unrelated subtype (H1N1) of IAV. We also showed that OMVs could express the human therapeutic protein, keratinocyte growth factor-2 (KGF-2), in a stable form that, when delivered orally, reduced disease severity and promoted intestinal epithelial repair and recovery in animals administered colitis-inducing dextran sodium sulfate. Collectively, our data demonstrates the utility and effectiveness of using Bt OMVs as a mucosal biologics and drug delivery platform technology

Clinical and Immunologic Features of Ultra-short Celiac Disease

BACKGROUND & AIMS: The clinical effects of gluten-sensitive enteropathy with villous atrophy limited to the duodenal bulb (D1) have not been delineated in adults with celiac disease. We investigated the sensitivity of D1 biopsy analysis in the detection of celiac disease, the number and sites of biopsies required to detect ultra-short celiac disease (USCD, villous atrophy limited to D1), and the clinical phenotype of USCD. METHODS: We performed a prospective study of 1378 patients (mean age, 50.3 y; 62% female) who underwent endoscopy at a tertiary medical center in the United Kingdom from 2008 through 2014; routine duodenal biopsy specimens were collected from D1 and the second part of the duodenum (D2). Quadrantic D1 biopsy specimens were collected from 171 consecutive patients with a high suspicion of celiac disease (mean age, 46.5 y; 64% female). Clinical data from patients diagnosed with USCD, based on biopsy analysis, were compared with those from patients with conventional celiac disease (CCD) (villous atrophy beyond D1) and individuals without celiac disease (controls). The number of intraepithelial lymphocytes (IELs) and immune phenotypes were compared between D1 vs D2 in patients with celiac disease. RESULTS: Of the 1378 patients assessed, 268 (19.4%) were diagnosed with celiac disease; 9.7% of these patients had villous atrophy confined to D1 (USCD; P < .0001). Collection of a single additional biopsy specimen from any D1 site increased the sensitivity of celiac disease detection by 9.3%–10.8% (P < .0001). Patients with USCD were younger (P ¼ .03), had lower titers of tissue transglutaminase antibody (P ¼ .001), and less frequently presented with diarrhea (P ¼ .001) than patients with CCD. Higher proportions of patients with CCD had ferritin deficiency (P ¼ .007) or folate deficiency (P ¼ .003) than patients with USCD or controls. Patients with celiac disease had a median of 50 IELs/100 enterocytes in D1 and a median of 48 IELs/100 enterocytes (P ¼ .7) in D2. The phenotype of IELs from patients with D1 celiac disease was indistinguishable from those of patients with D2 celiac disease. CONCLUSIONS: Collection of a single additional biopsy specimen from any site in the D1 intestine increases the sensitivity of detection for celiac disease. Patients with USCD may have early stage or limited celiac disease, with a mild clinical phenotype and infrequent nutritional deficiencies

Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens

BACKGROUND: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. METHODS: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. FINDINGS: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. CONCLUSIONS: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease

The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity

T cell phenotypes in COVID-19 - a living review

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation

Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure

The Omicron, or Pango lineage B.1.1.529, variant of SARS-CoV-2 carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection from severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple mRNA vaccinated healthcare workers (HCW) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple vaccinated individuals, but magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants, but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529

Quantitative, multiplexed, targeted proteomics for ascertaining variant specific SARS-CoV-2 antibody response

Determining the protection an individual has to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VoCs) is crucial for future immune surveillance, vaccine development, and understanding of the changing immune response. We devised an informative assay to current ELISA-based serology using multiplexed, baited, targeted proteomics for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. Serum from individuals collected after infection or first- and second-dose vaccination demonstrates this approach and shows concordance with existing serology and neutralization. Our assays show altered responses of both immunoglobulins and complement to the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.1) VoCs and a reduced response to Omicron (B1.1.1529). We were able to identify individuals who had prior infection, and observed that C1q is closely associated with IgG1 (r > 0.82) and may better reflect neutralization to VoCs. Analyzing additional immunoproteins beyond immunoglobulin (Ig) G, provides important information about our understanding of the response to infection and vaccination