Objective Why about a quarter of patients with inflammatory bowel disease (IBD) suffer symptoms for more than a year before their diagnosis made is unclear. Low public awareness, embarrassment and ...the apprehension of invasive tests are cited. The anonymity of direct-to-public calprotectin testing may overcome these barriers. We sought to characterise what calprotectin testing is available directly to the public in the UK.Design/method We conducted a cross-sectional evaluation of the calprotectin assays available online in the UK. Collection kits were procured from eligible providers, and surplus stool tested to receive follow-up advice for known positive (>50–100 μg/g) and negative (<50 μg/g) stool samples. Results Half (54.5% (6/11)) of the available tests were home lateral flow tests and the remainder were laboratory-based ELISAs. The lateral flow tests were considerably cheaper than the laboratory-based tests (median (range) cost £14.20 (£7.85–21.00) vs £75.85 (£59–151), p<0.0001). The median turnaround time for the laboratory tests was 14 (range: 1–23) days. All but one provider used a positivity threshold of 50 μg/g. All tests included written and pictorial instructions with the testing kit. Contact with a physician was recommended for similar proportions of positive and negative calprotectin results (54.5% (6/11) vs 54.5% (6/11), p=1).Conclusion In the UK, the public can choose between inexpensive home-based lateral flow tests or send stool samples for gold-standard laboratory testing of calprotectin. The low cost and rapid turnaround times suggest that direct-to-public calprotectin testing could be promoted to try to reduce the time to IBD diagnosis.
Abstract
Background and Aims
Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory ...disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories. We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low volume Patient-led Remote IntraCapillary pharmacoKinetic Sampling fingerPRICKS compared to conventional venepuncture.
Methods
We undertook a cross-sectional blood sampling methods comparison study and compared sample types using linear regression models. Drug and antidrug antibody levels were measured using standard ELISAs. Acceptability was assessed using a purpose-designed questionnaire.
Results
Therapeutic drug monitoring requests for adalimumab (96.5 70.5–106 per week to 52 33.5–57.0, p < 0.001) but not infliximab (184.5 161.2–214.2 to 161 135–197.5, p = 0.34) reduced during the first UK stay-at-home lockdown compared with the preceding 6 months. Fingerprick sampling was equivalent to conventional venepuncture for adalimumab, infliximab, vedolizumab and ustekinumab drug, and anti-adalimumab and anti-infliximab antibody levels. The median interquartile range volume of serum obtained using intracapillary sampling was 195 µL 130–210. More than 87% 90/103 of patients agreed that intracapillary testing was easy and 69% 71/103 preferred it to conventional venepuncture. In routine care, 75.3% 58/77 of patients returned two blood samples within 14 days to permit remote assessment of biologic therapeutic drug monitoring.
Conclusions
Therapeutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.
the utility of glycated haemoglobin (HbA1c) for the diagnosis and monitoring of diabetes in sub-Saharan Africa is uncertain due to limited data on the performance of the available HbA1c assay methods ...in this population, which has a high prevalence of haemoglobin variants. We aimed to compare the diagnostic accuracy of the major HbA1c methodologies (Boronate Affinity, Capillary Electrophoresis, High Performance Liquid Chromatography, Immunoassay) in an African population, and assess the impact of the common haemoglobin variant HbAS (sickle cell trait).Introductionthe utility of glycated haemoglobin (HbA1c) for the diagnosis and monitoring of diabetes in sub-Saharan Africa is uncertain due to limited data on the performance of the available HbA1c assay methods in this population, which has a high prevalence of haemoglobin variants. We aimed to compare the diagnostic accuracy of the major HbA1c methodologies (Boronate Affinity, Capillary Electrophoresis, High Performance Liquid Chromatography, Immunoassay) in an African population, and assess the impact of the common haemoglobin variant HbAS (sickle cell trait).whole blood samples were obtained from 182 individuals living with type 2 diabetes in Uganda. HbA1c values for each method were compared to average glucose measured over 14 days by continuous glucose monitoring (CGM). To determine concordance, the three HbA1c assay methods were compared to the capillary electrophoresis method.Methodswhole blood samples were obtained from 182 individuals living with type 2 diabetes in Uganda. HbA1c values for each method were compared to average glucose measured over 14 days by continuous glucose monitoring (CGM). To determine concordance, the three HbA1c assay methods were compared to the capillary electrophoresis method.there was a strong correlation between CGM average glucose levels and all four HbA1c methodologies (r=0.81-0.89) which did not differ in those with and without HbAS (present in 37/182 participants). The presence of HbAS did not alter the relationship between HbA1c and CGM glucose for any assay (p for interaction >0.2 for all methods). Diagnostic accuracy for CGM average glucose thresholds of 7 and 10mmol/L was similar across methods (area under the receiver operating characteristic curve 0.80-0.84 and 0.76-0.84 respectively). The maximum bias between the HbA1c assay methodologies was 2 mmol/mol (2.07%).Resultsthere was a strong correlation between CGM average glucose levels and all four HbA1c methodologies (r=0.81-0.89) which did not differ in those with and without HbAS (present in 37/182 participants). The presence of HbAS did not alter the relationship between HbA1c and CGM glucose for any assay (p for interaction >0.2 for all methods). Diagnostic accuracy for CGM average glucose thresholds of 7 and 10mmol/L was similar across methods (area under the receiver operating characteristic curve 0.80-0.84 and 0.76-0.84 respectively). The maximum bias between the HbA1c assay methodologies was 2 mmol/mol (2.07%).all major HbA1c technologies offer accurate and comparable HbA1c measurement even in this population with high prevalence of haemoglobin variants.Conclusionall major HbA1c technologies offer accurate and comparable HbA1c measurement even in this population with high prevalence of haemoglobin variants.
COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether ...immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose.
VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain RBD) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data.
Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL geometric SD 4·3; p<0·0001), infliximab plus thiopurine (1818·3 U/mL 6·7; p<0·0001), and tofacitinib (8071·5 U/mL 3·1; p=0·0018) compared with the healthy control group (16 774·2 U/mL 2·6). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL 2·2; p=0·099), ustekinumab (11 089·3 U/mL 2·8; p=0·060), or vedolizumab (13 564·9 U/mL 2·4; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 95% CI 0·11-0·21; p<0·0001), tofacitinib (0·52 CI 0·31-0·87; p=0·012), and thiopurine (0·69 0·51-0·95; p=0·021), but not with ustekinumab (0·64 0·39-1·06; p=0·083), or vedolizumab (0·84 0·54-1·30; p=0·43). Previous SARS-CoV-2 infection (1·58 1·22-2·05; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 0·80-0·97; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021).
A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors.
Pfizer.
We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with inflammatory bowel ...disease IBD.
We conducted a prospective study including 213 IBD patients and 53 healthy controls: 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab, or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination, and interval between vaccination and sampling.
Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (geometric mean ratio 0.35 95% confidence interval 0.20-0.60, p = 0.0002), combination of infliximab and thiopurine therapy (0.46 0.27-0.79, p = 0.0050), and tofacitinib (0.28 0.14-0.57, p = 0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 0.15-0.56, p = 0.0003), combination of infliximab and thiopurine therapy (0.34 0.17-0.66, p = 0.0016), thiopurine monotherapy (0.46 0.24-0.87, p = 0.017), and tofacitinib (0.23 0.10-0.56, p = 0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 r = 0.27; p = 0.0004 and H1N1 r = 0.33; p < 0.0001.
Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to influenza/A, similar to COVID-19 vaccine-induced antibody responses.
Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional ...metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients.
Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination.
Forty-three infliximab-treated patients with IBD were recruited (30 Crohn's disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.037). Bilophila abundance was associated with better serological response, while Streptococcus was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R2X 0.25, R2Y 0.26, Q2 0.15; CV-ANOVA p = 0.038). Trimethylamine, isobutyrate and omega-muricholic acid were associated with better response, while succinate, phenylalanine, taurolithocholate and taurodeoxycholate were associated with poorer response.
Our data suggest that there is an association between the gut microbiota and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine may be important in mitigating anti-TNF-induced attenuation of the immune response.
JLA is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-502), funded by Imperial College London and The Joyce and Norman Freed Charitable Trust. BHM is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-002). The Division of Digestive Diseases at Imperial College London receives financial and infrastructure support from the NIHR Imperial Biomedical Research Centre (BRC) based at Imperial College Healthcare NHS Trust and Imperial College London. Metabolomics studies were performed at the MRC-NIHR National Phenome Centre at Imperial College London; this work was supported by the Medical Research Council (MRC), the National Institute of Health Research (NIHR) (grant number MC_PC_12025) and infrastructure support was provided by the NIHR Imperial Biomedical Research Centre (BRC). The NIHR Exeter Clinical Research Facility is a partnership between the University of Exeter Medical School College of Medicine and Health, and Royal Devon and Exeter NHS Foundation Trust. This project is supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.
Abstract Objective Identifying factors associated with school functioning of abused children is important in prevention of long-term negative outcomes associated with school failure. The purpose of ...this study was to examine the degree to which parent emotional expressiveness and children's self-regulation predicted early school behavior of abused children. Methods The sample included 92 physically abused children ages 4–7 and one of their parents (95.7% mothers). Parents completed a measure of their own emotional expressiveness, and parents and teachers provided reports of children's self-regulatory skills. Children's school functioning was measured by observations of playground aggression and teacher reports of aggression and classroom behavior. Results Parents’ expression of positive and negative emotions was associated with various aspects of children's self-regulation and functioning in the school setting. Links between self-regulation and children's school adjustment were robust; poor self-regulation was associated with higher aggression and lower cooperation and self-directed behavior in the classroom. There was minimal support for a mediating role of children's self-regulation in links between parent expressiveness and children's behavior. Practice implications Findings point to the relevance of parent emotional expressivity and children's self-regulatory processes in understanding physically abused children's functioning at the transition to school. Although further research is needed, findings indicate that increasing parental expression of positive emotion should be a focus in treatment along with reduction in negativity of abusive parents. Further, addressing children's self-regulation could be important in efforts to reduce aggression and enhance children's classroom competence.
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