National action plans for antimicrobial resistance and variations in surveillance data platforms.

Objective: To assess how national antimicrobial susceptibility data used to inform national action plans vary across surveillance platforms. Methods: We identified available open-access, supranational, interactive surveillance platforms and cross-checked their data in accordance with the World Health Organization's (WHO's) Data Quality Assurance: module 1. We compared platform usability and completeness of time-matched data on the antimicrobial susceptibilities of four blood isolate species: Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae from WHO's Global Antimicrobial Resistance and Use Surveillance System, European Centre for Disease Control's (ECDC's) network and Pfizer's Antimicrobial Testing Leadership and Surveillance database. Using Bland-Altman analysis, paired t-tests, and Wilcoxon signed-rank tests, we assessed susceptibility data and number of isolate concordances between platforms. Findings: Of 71 countries actively submitting data to WHO, 28 also submit to Pfizer's database; 19 to ECDC; and 16 to all three platforms. Limits of agreement between WHO's and Pfizer's platforms for organism-country susceptibility data ranged from -26% to 35%. While mean susceptibilities of WHO's and ECDC's platforms did not differ (bias: 0%, 95% confidence interval: -2 to 2), concordance between organism-country susceptibility was low (limits of agreement -18% to 18%). Significant differences exist in isolate numbers reported between WHO-Pfizer (mean of difference: 674, P-value: < 0.001, and WHO-ECDC (mean of difference: 192, P-value: 0.04) platforms. Conclusion: The considerable heterogeneity of nationally submitted data to commonly used antimicrobial resistance surveillance platforms compromises their validity, thus undermining local and global antimicrobial resistance strategies. Hence, we need to understand and address surveillance platform variability and its underlying mechanisms.

Effectiveness of BNT162b2 and ChAdOx-1 vaccines in residents of long-term care facilities in England using a time-varying proportional hazards model.

INTRODUCTION: residents of long-term care facilities (LTCFs) are at high risk of adverse outcomes from SARS-CoV-2. We aimed to estimate the vaccine effectiveness (VE) of one and two doses of BNT162b2 and ChAdOx-1 against SARS CoV-2 infection and COVID-19-related death in residents of LTCFs. METHODS: this observational study used testing, vaccination and mortality data for LTCF residents aged ≥ 65 years who were regularly tested regardless of symptoms from 8 December 2020 to 30 September 2021 in England. Adjusted VE, calculated as one minus adjusted hazard ratio, was estimated using time-varying Cox proportional hazards models for infection and death within 28 days of positive test result. Vaccine status was defined by receipt of one or two doses of vaccine and assessed over a range of intervals. RESULTS: of 197,885 LTCF residents, 47,087 (23.8%) had a positive test and 11,329 (5.8%) died within 28 days of a positive test during the study period. Relative to unvaccinated individuals, VE for infection was highest for ChAdOx-1 at 61% (40-74%) at 1-4 weeks and for BNT162b2 at 69% (52-80%) at 11-15 weeks following the second dose. Against death, VE was highest for ChAdOx-1 at 83% (58-94%) at 1-4 weeks and for BNT162b2 at 91% (75-97%) at 11-15 weeks following second dose. CONCLUSIONS: compared with unvaccinated residents, vaccination with one dose of BNT162b2 or ChAdOx-1 provided moderate protection against infection and death in residents of LTCFs. Protection against death improved after two doses. However, some waning of protection over time was noted.

Invasive Meningococcal Disease, 2011-2020, and Impact of the COVID-19 Pandemic, England.

Invasive meningococcal disease incidence in England declined from 1.93/100,000 persons (1,016 cases) in 2010-11 to 0.95/100,000 (530 cases) in 2018-19 and 0.74/100,000 in 2019-20 (419 cases). During national lockdown for the coronavirus disease pandemic (April-August 2020), incidence was 75% lower than during April-August 2019.

Robust antibody responses in 70-80-year-olds 3 weeks after the first or second doses of Pfizer/BioNTech COVID-19 vaccine, United Kingdom, January to February 2021.

Sera were collected from 185 adults aged ≥ 70 years in London to evaluate the immune response to COVID-19 vaccines. A single dose of Pfizer/BioNtech vaccine resulted in > 94% seropositivity after 3 weeks in naïve individuals using the Roche Spike antibody assay, while two doses produced very high spike antibody levels, significantly higher than convalescent sera from mild-to-moderate PCR-confirmed adult cases. Our findings support the United Kingdom's approach of prioritising the first dose and delaying the second dose of COVID-19 vaccine.

Trends in laboratory-confirmed bacterial meningitis (2012-2019): national observational study, England.

Background: Bacterial meningitis is associated with significant morbidity and mortality worldwide. We aimed to describe the epidemiology, aetiology, trends over time and outcomes of laboratory-confirmed bacterial meningitis in England during 2012-2019. Methods: UK Health Security Agency routinely receives electronic notifications of confirmed infections from National Health Service hospital laboratories in England. Data were extracted for positive bacterial cultures, PCR-positive results for Neisseria meningitidis or Streptococcus pneumoniae from cerebrospinal fluid and positive blood cultures in patients with clinical meningitis. Findings: During 2012-19, there were 6554 laboratory-confirmed cases. Mean annual incidence was 1.49/100,000, which remained stable throughout the surveillance period (p = 0.745). There were 155 different bacterial species identified, including 68.4% (106/1550) Gram-negative and 31.6% (49/155) Gram-positive bacteria. After excluding coagulase-negative staphylococci (2481/6554, 37.9%), the main pathogens causing meningitis were Streptococcus pneumoniae (811/4073, 19.9%), Neisseria meningitidis (497/4073, 12.2%), Staphylococcus aureus (467/4073, 11.5%), Escherichia coli (314/4073, 7.7%) and group B streptococcus (268/4073, 6.6%). Pneumococcal meningitis incidence increased significantly during 2012-9, while meningococcal, group A streptococcal and tuberculous meningitis declined. Infants aged <3 months had the highest mean incidence (55.6/100,000; 95% CI, 47.7-63.5) driven mainly by group B streptococci, followed by 3-11 month-olds (8.1/100,000; 95% CI 7.1-9.0), where pneumococcal and meningitis predominated. The 30-day case-fatality rate (CFR) was 10.0% (71/6554). Group A streptococcal meningitis had the highest CFR (47/85, 55.3%). The probability of surviving at 30 days was 95.3% (95% CI, 93.4-97.3%) for infants and 80.0% for older adults (77-84%). Interpretation: The incidence of bacterial meningitis has remained stable. The high CFR highlights a need for prevention through vaccination. Funding: PHE.

Vaccine effectiveness of the first dose of ChAdOx1 nCoV-19 and BNT162b2 against SARS-CoV-2 infection in residents of long-term care facilities in England (VIVALDI): a prospective cohort study.

BACKGROUND: The effectiveness of SARS-CoV-2 vaccines in older adults living in long-term care facilities is uncertain. We investigated the protective effect of the first dose of the Oxford-AstraZeneca non-replicating viral-vectored vaccine (ChAdOx1 nCoV-19; AZD1222) and the Pfizer-BioNTech mRNA-based vaccine (BNT162b2) in residents of long-term care facilities in terms of PCR-confirmed SARS-CoV-2 infection over time since vaccination. METHODS: The VIVALDI study is a prospective cohort study that commenced recruitment on June 11, 2020, to investigate SARS-CoV-2 transmission, infection outcomes, and immunity in residents and staff in long-term care facilities in England that provide residential or nursing care for adults aged 65 years and older. In this cohort study, we included long-term care facility residents undergoing routine asymptomatic SARS-CoV-2 testing between Dec 8, 2020 (the date the vaccine was first deployed in a long-term care facility), and March 15, 2021, using national testing data linked within the COVID-19 Datastore. Using Cox proportional hazards regression, we estimated the relative hazard of PCR-positive infection at 0-6 days, 7-13 days, 14-20 days, 21-27 days, 28-34 days, 35-48 days, and 49 days and beyond after vaccination, comparing unvaccinated and vaccinated person-time from the same cohort of residents, adjusting for age, sex, previous infection, local SARS-CoV-2 incidence, long-term care facility bed capacity, and clustering by long-term care facility. We also compared mean PCR cycle threshold (Ct) values for positive swabs obtained before and after vaccination. The study is registered with ISRCTN, number 14447421. FINDINGS: 10 412 care home residents aged 65 years and older from 310 LTCFs were included in this analysis. The median participant age was 86 years (IQR 80-91), 7247 (69·6%) of 10 412 residents were female, and 1155 residents (11·1%) had evidence of previous SARS-CoV-2 infection. 9160 (88·0%) residents received at least one vaccine dose, of whom 6138 (67·0%) received ChAdOx1 and 3022 (33·0%) received BNT162b2. Between Dec 8, 2020, and March 15, 2021, there were 36 352 PCR results in 670 628 person-days, and 1335 PCR-positive infections (713 in unvaccinated residents and 612 in vaccinated residents) were included. Adjusted hazard ratios (HRs) for PCR-positive infection relative to unvaccinated residents declined from 28 days after the first vaccine dose to 0·44 (95% CI 0·24-0·81) at 28-34 days and 0·38 (0·19-0·77) at 35-48 days. Similar effect sizes were seen for ChAdOx1 (adjusted HR 0·32, 95% CI 0·15-0·66) and BNT162b2 (0·35, 0·17-0·71) vaccines at 35-48 days. Mean PCR Ct values were higher for infections that occurred at least 28 days after vaccination than for those occurring before vaccination (31·3 [SD 8·7] in 107 PCR-positive tests vs 26·6 [6·6] in 552 PCR-positive tests; p<0·0001). INTERPRETATION: Single-dose vaccination with BNT162b2 and ChAdOx1 vaccines provides substantial protection against infection in older adults from 4-7 weeks after vaccination and might reduce SARS-CoV-2 transmission. However, the risk of infection is not eliminated, highlighting the ongoing need for non-pharmaceutical interventions to prevent transmission in long-term care facilities. FUNDING: UK Government Department of Health and Social Care.

Respiratory samples to diagnose tuberculosis in the absence of chest x-ray abnormalities.

BACKGROUND: The World Health Organisation states that the chest x-ray (CXR) has a 'high sensitivity for pulmonary tuberculosis (TB)' [1] and as such, is relied on worldwide as the cornerstone of screening for active pulmonary TB (pTB). METHOD: This is a retrospective analysis of plain chest radiographs and microbiological yield in all patients who were diagnosed with pTB or intra-thoracic nodal tuberculosis (ITLN) in two London NHS Trusts. RESULTS: Between 2011 and 2017 8% of those diagnosed with pTB and 32% with ITLN TB had normal CXR appearances in the 6 weeks preceding diagnosis. DISCUSSION: Pulmomary TB was diagnosed in an additional 51 people based on CT scan and 43 people based on respiratory samples. ITLN TB was also diagnosed in a further 20 people using CT but only an extra 3 people from standard respiratory sampling. Our data suggests that CT imaging and respiratory samples should be sent on all suspected cases of pTB and ITLN TB even if the CXR is normal.

Serological responses and vaccine effectiveness for extended COVID-19 vaccine schedules in England.

The UK prioritised delivery of the first dose of BNT162b2 (Pfizer/BioNTech) and AZD1222 (AstraZeneca) vaccines by extending the interval between doses up to 12 weeks. In 750 participants aged 50-89 years, we here compare serological responses after BNT162b2 and AZD1222 vaccination with varying dose intervals, and evaluate these against real-world national vaccine effectiveness (VE) estimates against COVID-19 in England. We show that antibody levels 14-35 days after dose two are higher in BNT162b2 recipients with an extended vaccine interval (65-84 days) compared with those vaccinated with a standard (19-29 days) interval. Following the extended schedule, antibody levels were 6-fold higher at 14-35 days post dose 2 for BNT162b2 than AZD1222. For both vaccines, VE was higher across all age-groups from 14 days after dose two compared to one dose, but the magnitude varied with dose interval. Higher dose two VE was observed with >6 week interval between BNT162b2 doses compared to the standard schedule. Our findings suggest higher effectiveness against infection using an extended vaccine schedule. Given global vaccine constraints these results are relevant to policymakers.

Genetic and pharmacological inhibition of inflammasomes reduces the survival of Mycobacterium tuberculosis strains in macrophages.

Mycobacterium tuberculosis infection causes high rates of morbidity and mortality. Host-directed therapy may enhance the immune response, reduce tissue damage and shorten treatment duration. The inflammasome is integral to innate immune responses but over-activation has been described in tuberculosis (TB) pathology and TB-immune reconstitution syndrome. Here we explore how clinical isolates differentially activate the inflammasome and how inflammasome inhibition can lead to enhanced bacterial clearance. Wild-type, Nlrp3-/-/Aim2-/-, Casp1/11-/- and Asc-/- murine bone-marrow derived macrophages (BMDMs) were infected with laboratory strain M. tuberculosis H37Rv or clinical isolates from various lineages. Inflammasome activation and bacterial numbers were measured, and pharmacological inhibition of NLRP3 was achieved using MCC950. Clinical isolates of M. tuberculosis differed in their ability to activate inflammasomes. Beijing isolates had contrasting effects on IL-1ß and caspase-1 activation, but all clinical isolates induced lower IL-1ß release than H37Rv. Our studies suggest the involvement of NLRP3, AIM2 and an additional unknown sensor in IL-1ß maturation. Pharmacological blockade of NLRP3 with MCC950 reduced bacterial survival, and combined treatment with the antimycobacterial drug rifampicin enhanced the effect. Modulating the inflammasome is an attractive adjunct to current anti-mycobacterial therapy that warrants further investigation.

Raised Venous Lactate and Markers of Intestinal Translocation Are Associated With Mortality Among In-Patients With HIV-Associated TB in Rural South Africa.

INTRODUCTION: Case fatality among in-patients with HIV-associated tuberculosis (HIV-TB) in Africa is high. We investigated the factors associated with mortality in a rural South African hospital. METHODS: This was a prospective observational study of HIV-TB in-patients, with death by 8 weeks the endpoint. RESULTS: Of 99 patients (median CD4 count 72 cells/mm³), 32 (32%) died after median 8-day TB treatment. TB was diagnosed microbiologically in 75/99 and clinico-radiologically in 24, with no mortality difference between these groups [31% versus 38% (P = 0.53)]. Median venous lactate was 5.5 mmol/L (interquartile range 3.9-6.2) in those who died and 3.1 mmol/L (interquartile range 2.2-4.1) in survivors (P < 0.001). In multivariable analysis, lactate ≥4 mmol/L [adjusted odds ratio (aOR) 9.8, 95% confidence interval (CI): 3.0 to 32.2], Glasgow Coma Score <15 (aOR 6.6, 95% CI: 1.5 to 29.6), CD4 count <50 cells per cubic millimeter (aOR 5.5, 95% CI: 1.6 to 18.5), and age ≥50 (aOR 7.7, 95% CI: 1.2 to 46.9) independently predicted death. In a nested case-control study, comparing those who died versus CD4-matched survivors, median plasma lipopolysaccharide concentrations were 93 and 57 pg/mL (P = 0.026) and intestinal fatty acid-binding protein, 132 and 0 pg/mL (P = 0.002). CONCLUSIONS: Mortality was high and predicted by elevated lactate, likely reflecting a sepsis-syndrome secondary to TB or bacterial coinfection with intestinal barrier dysfunction appearing to contribute.

Cytomegalovirus proctitis mimicking rectal cancer in an immunocompetent elderly patient: a case report.

BACKGROUND: Cytomegalovirus infection is associated with significant morbidity and mortality in immunocompromised patients, but its impact on immunocompetent patients is still poorly understood. Furthermore, there is increasing evidence implying that chronic infection may contribute to a heightened cardiovascular risk. CASE PRESENTATION: We describe the case of incidental diagnosis of Cytomegalovirus proctitis in an immune-competent white British elderly gentleman, admitted following a stroke and investigated for rectal cancer following the development of bloody diarrhoea and persistent systemic inflammatory response. CONCLUSION: This raised some several interesting points; firstly that we must revise our approach to investigating the immunocompetent elderly patient, secondly, could chronic Cytomegalovirus infection have contributed to the presentation of stroke in this patient and lastly what are the existing evidence for treatment in this population? We use this opportunity to try and address some of these questions and feel that this would be of benefit to the wider audience.We discuss the risk factors for disease in immune-competent patients and also a brief overview of the benefits of treatment in this population.