Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic.

OBJECTIVE: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD. DESIGN: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study. RESULTS: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups. CONCLUSIONS: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Persistence of clinically relevant levels of SARS-CoV2 envelope gene subgenomic RNAs in non-immunocompromised individuals.

OBJECTIVES: This study aimed to evaluate the associations between COVID-19 severity and active viral load, and to characterize the dynamics of active SARS-CoV-2 clearance in a series of archival samples taken from patients in the first wave of COVID-19 infection in the South West of the UK. METHODS: Subgenomic RNA (sgRNA) and E-gene genomic sequences were measured in a retrospective collection of PCR-confirmed SARS-CoV-2-positive samples from 176 individuals, and related to disease severity. Viral clearance dynamics were then assessed in relation to symptom onset and last positive test. RESULTS: Whilst E-gene sgRNAs declined before E-gene genomic sequences, some individuals retained sgRNA positivity for up to 68 days. 13% of sgRNA-positive cases still exhibited clinically relevant levels of virus after 10 days, with no clinical features previously associated with prolonged viral clearance times. CONCLUSIONS: Our results suggest that potentially active virus can sometimes persist beyond a 10-day period, and could pose a potential risk of onward transmission. Where this would pose a serious public health threat, additional mitigation strategies may be necessary to reduce the risk of secondary cases in vulnerable settings.

Along came a spider: an unusual organism identified in a peritoneal dialysis patient, a case report and literature review.

BACKGROUND: Peritoneal dialysis-associated peritonitis can uncommonly be caused by fungal infections. When they do present, they are associated with significant mortality and morbidity. We describe a case where a sample of peritoneal dialysate fluid grew Rhodotorula muciliginosa, a yeast organism present in the normal environment which has previously been reported as rarely causing peritonitis. We believe this is the first case where the Rhodotorula spp. and its origin has been identified. CASE PRESENTATION: A 20 year old male grew Rhodotorula muciliginosa from his peritoneal dialysis fluid on three separate occasions when a fluid sample was sent following a disconnection and subsequent set change. He was not systemically unwell and his peritoneal dialysate was clear. As Rhodotorula spp. is exceedingly difficult to treat our patient had his Tenchkoff catheter removed. Subsequent samples of soil and sand from his bearded dragon and Chilean tarantula cases, kept in his bedroom where dialysis occurred, were tested. The tarantula sand was identified as the source of the Rhodotorula spp. Of note, Candida was isolated from sand from the bearded dragon case. Once his Tenchkoff was removed he was treated with an intravenous course of antifungal therapy. He has since had a new Tenchkoff catheter inserted and recommenced PD following education around pets and hygiene. CONCLUSIONS: In this era where people are keeping increasingly rare and unusual wildlife in their homes, this case highlights the need for clinician and nursing staff awareness of a patient's home environment and hobbies when they are undergoing peritoneal dialysis. Sand from our patient's tarantula case grew the colonising organism but interestingly soil from his bearded dragon case also isolated candida. This can also cause difficult to treat peritonitis.

Resolving Disagreement: A Multi-Jurisdictional Comparative Analysis of Disputes About Children's Medical Care.

Recently, the English courts have dealt with a number high-profile, emotive disputes over the care of very ill children, including Charlie Gard, Alfie Evans, and Tafida Raqeeb. It is perhaps fair to say such cases have become a regular feature of the courts in England. But is the situation similar in other jurisdictions? If not, are there lessons to be learned from these jurisdictions that do not seem to need to call on judges to resolve these otherwise intractable disputes? We argue that many of the differences we see between jurisdictions derive from cultural and social differences manifesting in both the legal rules in place, and how the various parties interact with, and defer to, one another. We further argue that while recourse to the courts is undesirable in many ways, it is also indicative of a society that permits difference of views and provides for these differences to be considered in a public manner following clear procedural and precedential rules. These are the hallmarks of a liberal democracy that allows for pluralism of values, while still remaining committed to protecting the most vulnerable parties in these disputes-children facing life-limiting conditions.

Snapshot PCR surveillance for SARS-CoV-2 in hospital staff in England.

BACKGROUND: Significant nosocomial transmission of SARS-CoV-2 has been demonstrated. Understanding the prevalence of SARS-CoV-2 carriage amongst HCWs at work is necessary to inform the development of HCW screening programmes to control nosocomial spread. METHODS: Cross-sectional 'snapshot' survey from April-May 2020; HCWs recruited from six UK hospitals. Participants self-completed a health questionnaire and underwent a combined viral nose and throat swab, tested by Polymerase Chain Reaction (PCR) for SARS-CoV-2 with viral culture on majority of positive samples. FINDINGS: Point prevalence of SARS-CoV-2 carriage across the sites was 2.0% (23/1152 participants), median cycle threshold value 35.70 (IQR:32.42-37.57). 17 were previously symptomatic, two currently symptomatic (isolated anosmia and sore throat); the remainder declared no prior or current symptoms. Symptoms in the past month were associated with threefold increased odds of testing positive (aOR 3.46, 95%CI 1.38-8.67; p = 0.008). SARS-CoV-2 virus was isolated from only one (5%) of nineteen cultured samples. A large proportion (39%) of participants reported symptoms in the past month. INTERPRETATION: The point-prevalence is similar to previous estimates for HCWs in April 2020, though a magnitude higher than in the general population. Based upon interpretation of symptom history and testing results including viral culture, the majority of those testing positive were unlikely to be infectious at time of sampling. Development of screening programmes must balance the potential to identify additional cases based upon likely prevalence, expanding the symptoms list to encourage HCW testing, with resource implications and risks of excluding those unlikely to be infectious with positive tests. FUNDING: Public Health England.

The Exeter Knee Infection Multi Disciplinary Team approach to managing prosthetic knee infections: A qualitative analysis.

BACKGROUND: A Knee Infection Multi-Disciplinary Team meeting was established in Exeter. This study was designed to qualitatively evaluate the impact of the MDT on those involved. MATERIALS AND METHODS: Semi-structured interviews of all members of the MDT at Exeter were undertaken and analysed using Nvivo software. Data was coded to identify common patterns and trends. RESULTS: The common themes identified were improved communication and standardisation of care. The main challenges identified were the timing of the meetings and funding. CONCLUSION: This study has used established qualitative techniques to evaluate the impact of the Exeter Knee Infection MDT.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.

Protecting me from my Directive: Ensuring Appropriate Safeguards for Advance Directives in Dementia.

With one in six people over 80 now suffering from dementia, advance directives provide an important means of empowerment. Upholding directives in the context of dementia, however, raises extra challenges, given the potential for the directive to conflict with an assessment of what is in the person's current best interests. Given the profound harm that tying a person with dementia to their previous wishes can do, it is essential that we have sufficient safeguards in place to ensure that we only uphold such directives where we can be sure they are truly autonomous and are intended to apply to the situation at hand-safeguards which are at present, severely lacking. This article will consider various mechanisms by which safeguards can be built into the legal regime to ensure that the original decision is autonomous, including making it mandatory for the person to undergo a consultation with a healthcare professional, which would involve a contemporaneous capacity assessment. Clinicians must also be confident that the directive applies to the situation at hand. Introducing formalities, including a standardised (though not mandatory) proforma, may help to enhance specificity about when the directive is triggered, and to what treatments it relates, to enable clinicians to better assess the directive's applicability. A national registry for advance directives might also be beneficial. It will be argued that health care professionals will have to play a much greater role in the drafting and registering of advance directives, if we are to feel comfortable in upholding them.

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment.

Association between Propionibacterium acnes and frozen shoulder: a pilot study.

BACKGROUND: Frozen shoulder has not previously been shown to be associated with infection. The present study set out to confirm the null hypothesis that there is no relationship between infection and frozen shoulder using two modern scientific methods, extended culture and polymerase chain reaction (PCR) for bacterial nucleic acids. METHODS: A prospective cohort of 10 patients undergoing arthroscopic release for stage II idiopathic frozen shoulder had two biopsies of tissue taken from the affected shoulder joint capsule at the time of surgery, along with control biopsies of subdermal fat. The biopsies and controls were examined with extended culture and PCR for microbial nucleic acid. RESULTS: Eight of the 10 patients had positive findings on extended culture in their shoulder capsule and, in six of these, Propionibacterium acnes was present. CONCLUSIONS: The findings mean that we must reject the null hypothesis that there is no relationship between infection and frozen shoulder. More studies are urgently needed to confirm or refute these findings. If they are confirmed, this could potentially lead to new and effective treatments for this common, painful and disabling condition. Could P. acnes be the Helicobacter of frozen shoulder?

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): study protocol for a randomised controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and serious infection, with an associated mortality of ~25%. Once in the blood, S. aureus can disseminate to infect almost any organ, but bones, joints and heart valves are most frequently affected. Despite the infection's severity, the evidence guiding optimal antibiotic therapy is weak: fewer than 1,500 patients have been included in 16 randomised controlled trials investigating S. aureus bacteraemia treatment. It is uncertain which antibiotics are most effective, their route of administration and duration, and whether antibiotic combinations are better than single agents. We hypothesise that adjunctive rifampicin, given in combination with a standard first-line antibiotic, will enhance killing of S. aureus early in the treatment course, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. Our aim is to determine whether adjunctive rifampicin reduces all-cause mortality within 14 days and bacteriological failure or death within 12 weeks from randomisation. METHODS: We will perform a parallel group, randomised (1:1), blinded, placebo-controlled trial in NHS hospitals across the UK. Adults (≥ 18 years) with S. aureus (meticillin-susceptible or resistant) grown from at least one blood culture who have received ≤ 96 h of active antibiotic therapy for the current infection and do not have contraindications to the use of rifampicin will be eligible for inclusion. Participants will be randomised to adjunctive rifampicin (600-900 mg/day; orally or intravenously) or placebo for the first 14 days of therapy in combination with standard single-agent antibiotic therapy. The co-primary outcome measures will be all-cause mortality up to 14 days from randomisation and bacteriological failure/death (all-cause) up to 12 weeks from randomisation. 940 patients will be recruited, providing >80% power to detect 45% and 30% reductions in the two co-primary endpoints of death by 14 days and bacteriological failure/death by 12 weeks respectively. DISCUSSION: This pragmatic trial addresses the long-standing hypothesis that adjunctive rifampicin improves outcome from S. aureus bacteraemia through enhanced early bacterial killing. If proven correct, it will provide a paradigm through which further improvements in outcome from S. aureus bacteraemia can be explored.

Clinical and immunologic risk factors for meningococcal C conjugate vaccine failure in the United Kingdom.

BACKGROUND: The meningococcal serogroup C conjugate (MCC) vaccine was introduced into the United Kingdom with licensure based on immunogenicity data not efficacy data. METHODS: All subjects with laboratory-confirmed meningococcal serogroup C (MenC) disease from January 2000 to December 2003 in England and Wales were followed up. A vaccine failure was defined as a laboratory-confirmed case of MenC disease occurring > or =10 days after the subject's last scheduled dose of MCC vaccine. Total immunoglobulins, serum bactericidal antibody (SBA) titers, MCC anticapsular antibody levels, and avidity indices (AIs) were measured in acute and convalescent serum samples from subjects with vaccine failure and unvaccinated subjects with MenC disease. RESULTS: Of 465 subjects with confirmed MenC disease identified among those eligible for vaccination, information on vaccination history was obtained for 462 (99.4%); of these, 53 were subjects with vaccine failure. SBA titers in convalescent serum samples and AIs in acute serum samples were significantly higher in subjects with vaccine failure than in unvaccinated subjects, (6.1-fold higher for SBA titers [P=.03] and 3.2-fold higher for AIs [P=.001]). CONCLUSIONS: The antibody response in the subjects with vaccine failure was consistent with an anamnestic response, suggesting that MenC disease occurred despite the MCC vaccine priming for immune memory. Persistence of antibodies may be a more appropriate correlate of long-term protection for MCC vaccines than the ability to generate a booster response on exposure.

Immunoglobulin G subclass response to a meningococcal quadrivalent polysaccharide-diphtheria toxoid conjugate vaccine.

Changes in the immunoglobulin G1 (IgG1)/IgG2 ratio following vaccination can indicate the activation of cellular control mechanisms typical of a T-cell-dependent response. We examined IgG subclass ratios in 17 healthy adults (26 to 55 years of age) before and 4 to 6 weeks following immunization with a quadrivalent meningococcal-polysaccharide diphtheria toxoid conjugate vaccine against serogroups A, C, Y, and W135. Serologic responses were determined by serum bactericidal antibody assay and serogroup-specific IgG, IgG1, and IgG2 enzyme-linked immunosorbent assay. Prevaccination serogroup A-specific IgG1/IgG2 ratios were <1 for all subjects and differed by subject for C, Y, and W-135. Postvaccination, significant increases in IgG, IgG1, and IgG2, were observed for all serogroups. Serogroup-specific IgG1/IgG2 ratios increased for group A (14/17 subjects, 88%), decreased in more than half of subjects for groups C (9/17, 53%) and W135 (12/17, 71%) and decreased for serogroup Y (16/17, 94%). IgG1/IgG2 ratios differed between individual vaccinees and were similar to the responses of adults who received pneumococcal conjugate vaccines or a monovalent C conjugate vaccine. Further studies on IgG subclasses following meningococcal polysaccharide and conjugate vaccination are needed.

Reactions to small pox vaccine in naïve and previously-vaccinated individuals.

Two hundred health care workers in England and Wales were vaccinated with the Lister/Elstree strain of the vaccinia virus, and completed health diaries for 21 days or until the lesion had scabbed over. Pain and temperature were measured daily, and all other symptoms recorded freehand by the vaccinee. One hundred and forty two (71%) vaccinees reported pain, of which 25% considered it to be moderate or severe; 32 vaccinees (16%) recorded a temperature of >37.7 degrees C, two of which exceeded 39 degrees C. Other, mainly trivial, adverse events were common; itch was reported in 72%, erythema in 27%, axillary pain or lymphadenopathy in 38%, malaise or flu-like symptoms in 40% and headache in 23%. The incidences of minor adverse events were lower in re-vaccinees, compared with naïve vaccine recipients, significantly so in the case of erythema and general malaise (p=0.001 and 0.006, respectively), perhaps reflecting pre-existing immunity. Major adverse events occurred in two vaccinees (hospital admission, one with cellulitis and one with headache and possible encephalitis), and a further five were treated with antibiotics for local cellulitis. This is the first study to report results derived from active follow-up by diaries in recipients of the Lister/Elstree strain of vaccinia, and to document reductions in trivial adverse events in re-vaccinees.