Journal of Infection

While socioeconomic status (SES) and migration background have been linked to complicated lower respiratory tract infections (LRTIs) in population-based studies, their predictive value in primary care remains unclear. Using routine care data from Dutch general practices (Leiden-The Hague-Zoetermeer region, n {approx} 750,000 adult patients, 2014 to 2023, excluding COVID-19 years), linked to sociodemographic and hospital claims data, we developed a multivariable logistic regression model to predict 30-day hospitalisation or death following LRTI. Among 186,094 LRTI episodes, 2.19% were classified as complicated. After adjusting for established clinical factors, SES was a strong predictor, whereas migration background was not. Patients in the lowest SES category had an adjusted odds ratio of 1.46 (95%CI: 1.31 - 1.62) for a complicated course compared to the highest. The incorporation of SES into clinical decision tools and guidelines has the potential to enhance risk-stratification of patients with LRTI in daily practice of primary care, thereby supporting more equitable care.

Human metapneumovirus is a common upper respiratory tract infection, routinely monitored as part of laboratory respiratory virus surveillance in England. Given the recent international interest in trends of hMPV, we describe the current and historical trends of hMPV in England overall and by age group using activity threshold methods.

BackgroundThe clinical diagnosis of sepsis is based on non-specific criteria and blood culture remains the gold standard confirmatory test. While early results are of wide clinical benefit delayed reports lead to prolonged anti-microbial therapy which fosters the emergence of antimicrobial resistance. Pre-analytical delay of a blood culture delays or decreases the chance of a positive report and a maximal four-hour delay between collection and incubation of the specimen is recommended by the United Kingdom Standards for Microbiology Investigations (UK SMI). This retrospective observational study documents compliance with this quality standard by National Health Service (NHS) hospitals across England. An appraisal is undertaken of the policies which governed laboratory centralisation and their impact on the microbiology service. MethodsFreedom of Information (FOI) applications were submitted to 116 NHS Trusts in England requesting retrospective audit data showing compliance with the recommended pre-analytical standard for blood cultures. Information relating to the configuration of microbiology services and global laboratory costs were also requested. ResultsReports were received from 89 Trusts (76.7%) comprising 146 acute hospitals. Only four hospitals (2.7%) showed full compliance with the four-hour pre-analytical standard. Service configurations varied widely. The anticipated savings resulting from centralisation have not been realised. ConclusionsThere was poor compliance with the quality standard for pre-analytical delay of blood cultures. Evidence is presented to show that the poor compliance rates reported are a result of the approach taken and the guiding policies applied when laboratory centralisation was imposed by NHS England. Reversal of these adverse effects will require mandatory implementation of UK SMIs and computing the cost of quality measures in the context of the overall health care benefit to the patient.

BackgroundDelay in COVID-19 detection has led to a major pandemic. We report rapid early detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction (RT-PCR), comparing it to the serostatus of convalescent infection, at an Austrian National Sentinel Surveillance Practice in an isolated ski-resort serving a population of 22,829 people. MethodsRetrospective dataset of all 73 patients presenting with mild to moderate flu-like symptoms to a sentinel practice in the ski-resort of Schladming-Dachstein, Austria, between 24 February and 03 April, 2020. We split the outbreak in two halves, by dividing the period from the first to the last case by two, to characterise the following three cohorts of patients with confirmed infection: people with reactive RT-PCR presenting during the first half (early acute infection) vs. those presenting in the second half (late acute), and people with non-reactive RT-PCR (late convalescent). For each cohort we report the number of cases detected, the accuracy of RT-PCR and the duration of symptoms. We also report multivariate regression of 15 clinical symptoms as covariates, comparing all people with convalescent infection to those with acute infection. FindingsAll 73 patients had SARS-CoV-2 RT-PCR testing. 22 patients were diagnosed with COVID-19, comprising: 8 patients presenting early acute, and 7 presenting late acute and 7 late convalescent respectively; 44 patients tested SARS-COV-2 negative, and 7 were excluded. RT-PCR sensitivity was high (100%) among acute presenters, but dropped to 50% in the second half of the outbreak; specificity was 100%. The mean duration of symptoms was 2 days (range 1-4) among early acute presenters, and 4.4 days (1-7) among late acute and 8 days (2-12) among late convalescent presenters respectively. Convalescent infection was only associated with loss of taste (ORs=6.02;p=0.047). Acute infection was associated with loss of taste (OR=571.72;p=0.029), nausea and vomiting (OR=370.11;p=0.018), breathlessness (OR=134.46;p=0.049), and myalgia (OR=121.82;p=0.032); but not loss of smell, fever or cough. InterpretationRT-PCR rapidly and reliably detects early COVID-19 among people presenting with viral illness and multiple symptoms in primary care, particularly during the early phase of an outbreak. RT-PCR testing in primary care should be prioritised for effective COVID-19 prevention and control. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSA comprehensive and effective test-trace-isolate (TTI) strategy is necessary to keep track of current and future COVID-19 infection in the UK and avoid a secondary wave later this year, as society reopens. As part of a wider TTI strategy, it is important to assess the feasibility of COVID-19 testing in primary care. We searched PubMed for implementation of SARS-CoV-2 testing in primary care using the following search terms: ("SARS-CoV-2" OR "COVID-19") AND "testing" AND ("primary care" OR "general practice"). We did not find any studies that met these criteria. Added value of this studyTo our knowledge, our study provides first evidence that extension of a National Influenza Surveillance Programme to include SARS-CoV-2 RT-PCR testing in primary care leads to viral detection among patients presenting with mild to moderate flu-like illness during a local outbreak of COVID-19. We show that the sensitivity of reverse transcriptase-polymerase chain reaction (RT-PCR), the technique to detect viral RNA, is high (100%) in the initial phase of the outbreak and among patients who were acutely unwell. Acute infection was associated with multiply symptoms: loss of taste, nausea and vomiting, breathlessness, myalgia and sore throat; but not loss of smell, fever or cough. We also show high correlation between reactive RT-PCR and seropositivity. Implications of all available evidenceOur findings suggest that RT-PCR can rapidly and reliably detect early COVID-19 among people presenting with viral illness and multiple symptoms in primary care, particularly during the early phase of an outbreak. Furthermore RT-PCR testing in primary care can effectively detect new COVID-19 clusters in the community and should be included in any strategy for prevention and control of the disease.

BackgroundRecurrent sore throat affects a small minority of adults but can cause substantial morbidity. Evidence to guide tonsillectomy eligibility in adults is limited, and current criteria are extrapolated from paediatric populations. We aimed to describe the epidemiology, management, and prognosis of adult sore throat in UK primary care. MethodsUsing CPRD Aurum (2010-2020 adults with a first coded episode of sore throat or tonsillitis were identified and matched to controls. Episode frequency, antibiotic use, ENT referral, and tonsillectomy were analysed. Predictors of recurrent episodes ([≥]3 in 365 days), referral, and tonsillectomy were assessed using time-to-event, multinomial logistic, and multilevel mixed-effects regression models. FindingsOf 4.45 million adults, 1.70 million (38.3%) had [≥]1 episode; most (61.5%) had only one, but 4.1% experienced [≥]3 within 1 year. Recurrent episodes were more common in younger females and those from more deprived areas. Only 21,869 patients (0.5% of the exposed cohort) underwent tonsillectomy, and just 25.7% of these met Paradise criteria at any time; conversely, only 13.9% of those meeting criteria underwent surgery. Patients who had a tonsillectomy tended to be younger, female, and from less deprived areas. Pre-tonsillectomy episode rates were unexpectedly low, but the data indicated that individuals with high baseline burden continue to experience elevated episode rates over several years. ConclusionsRecurrent sore throat is uncommon, but those affected face substantial disease burden. Current tonsillectomy patterns are poorly aligned with disease burden and show inequities by deprivation. Earlier identification of adults likely to develop recurrent episodes, and more timely surgical intervention, may improve patient outcomes and the cost-effectiveness of tonsillectomy.

Examination of the chronology, location and size of waves of SARS-CoV-2 infection across England could shed light on the inter-play between the 1st and the 2nd Waves. From mid-October onwards such an analysis becomes increasingly difficult due to the emergence of a new strain (VOC-202012/01) and in light of the differential implementation of lockdown measures and tiers. Therefore, we sought to examine trends and correlations in virus prevalence and covid-related deaths spanning the start of the UK pandemic in March 2020 through to early November 2020 - i.e., including the first growth period of the 2nd Wave. We found striking regional relationships between the 1st and the 2nd Wave that are difficult to explain other than by involving some role for changing levels of immunity in the population affecting the progression of the pandemic.

BackgroundA new variant of SARS-CoV-2, B.1.1.7/VOC202012/01, was identified in the UK in December-2020. Direct estimates of its potential to enhance transmission are limited. MethodsNose and throat swabs from 28-September-2020 to 2-January-2021 in the UKs nationally representative surveillance study were tested by RT-PCR for three genes (N, S and ORF1ab). Those positive only on ORF1ab+N, S-gene target failures (SGTF), are compatible with B.1.1.7/VOC202012/01. We investigated cycle threshold (Ct) values (a proxy for viral load), percentage of positives, population positivity and growth rates in SGTF vs non-SGTF positives. Results15,166(0.98%) of 1,553,687 swabs were PCR-positive, 8,545(56%) with three genes detected and 3,531(23%) SGTF. SGTF comprised an increasing, and triple-gene positives a decreasing, percentage of infections from late-November in most UK regions/countries, e.g. from 15% to 38% to 81% over 1.5 months in London. SGTF Ct values correspondingly declined substantially to similar levels to triple-gene positives. Population-level SGTF positivity remained low (<0.25%) in all regions/countries until late-November, when marked increases with and without self-reported symptoms occurred in southern England (to 1.5-3%), despite stable rates of non-SGTF cases. SGTF positivity rates increased on average 6% more rapidly than rates of non-SGTF positives (95% CI 4-9%) supporting addition rather than replacement with B.1.1.7/VOC202012/01. Excess growth rates for SGTF vs non-SGTF positives were similar in those up to high school age (5% (1-8%)) and older individuals (6% (4-9%)). ConclusionsDirect population-representative estimates show that the B.1.1.7/VOC202012/01 SARS-CoV-2 variant leads to higher infection rates, but does not seem particularly adapted to any age group.

BackgroundTwice-weekly lateral flow device (LFD) testing was introduced for routine asymptomatic testing of healthcare workers (HCWs) in the National Health Service (NHS) in England in November 2020, with the primary aim of reducing nosocomial infections among staff and patients and a secondary aim of reducing absenteeism among HCWs. Here, we describe the burdens of HCW absenteeism and nosocomial infections in NHS acute trusts and the reported testing intensity of LFDs and associated costs from October 2020 to March 2022 and assess the impact of LFD testing on reducing these burdens. Methods and FindingsWe collected 16 million LFD testing results (total cost GBP 1.64 billion) reported in NHS acute trusts through Englands Pillar 1 and 2 testing programmes from 1 October 2020 to 30 March 2022. We estimated the prevalence of nosocomial COVID-19 infections in NHS acute trusts using data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC). Testing data were linked with nosocomial infections and full-time equivalent (FTE) days lost by trust for NHS acute trusts. We used a mixed-effects linear model to examine the association between FTE days lost and LFD test coverage. The relationship between weekly prevalence of nosocomial infections and LFD test coverage in the previous week was modelled using logistic regression weighted by the number of new COVID-19 cases reported in the ISARIC dataset for that week. We adjusted both models for community prevalence of COVID-19 infections, average income deprivation score, prevalence of variants of concern and LFD test positivity. FTE days lost among HCWs varied considerably by trust type, staff group, geographical location of trusts, and progress of the pandemic in England. Increased LFD test coverage was associated with decreases in FTE days lost due to COVID-19 from November 2020 to July 2021, with no association observed from August 2021 to March 2022. Higher community prevalence levels were associated with significant increases in FTE days lost due to COVID-19 in all periods except the pre-vaccination period (last two months of 2020). The model predicted that changes in testing levels (50-150%) would have resulted in modest changes in FTE days lost due to COVID-19 for all time periods. We identified 3,794 nosocomial infections (if patients developed COVID-19 symptoms 7 days or more after their hospital admission) among 106,377 hospitalised COVID-19 patients in 136 NHS acute trusts. The proportion of nosocomial infections among new weekly cases in hospitalised patients was negatively associated with reported LFD testing levels. The strength of the association varied over time and was estimated to be highest during the Omicron period, although no effect of testing on HCW absenteeism was found. The observed HCW testing/reporting was estimated to be associated with a 16.8% (95% confidence interval 8.2%, 18.8%) reduction in nosocomial infections compared with a hypothetical testing scenario at 25% of actual levels, translating to a cost saving per quality-adjusted life-year (QALY) gained of GBP 18,500-46,400. ConclusionsLFD testing was an impactful public health intervention for reducing HCW absenteeism and nosocomial infections in NHS acute trusts and was cost effective in preventing nosocomial infections. Author SummaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIIn any pandemic response, mass diagnostic testing plays a key role. C_LIO_LIWe sought to evaluate the burdens of healthcare worker absenteeism and nosocomial infections in NHS acute trusts, the reported testing intensity using lateral flow devices (LFDs) and associated costs, and the impact of LFD testing on reducing these burdens. C_LI What did the researchers do and find?O_LIWe collected 16 million LFD testing results and full-time equivalent (FTE) days lost due to COVID-19, obtained from healthcare workers (HCWs) in NHS acute trusts in England between 1 October 2020 and 30 March 2022. C_LIO_LIWe estimated the number of nosocomial COVID-19 infections in NHS acute trusts using data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC). C_LIO_LITesting data were linked with nosocomial infections and FTE days lost due to COVID-19 by trust for NHS acute trusts. C_LIO_LIWe used a mixed-effects linear model to examine the association between FTE days lost due to COVID-19 and LFD test coverage and applied a logistic regression to assess the association between nosocomial infections and LFD test coverage. C_LIO_LIWe found that LFD testing in the healthcare setting was an impactful public health intervention. C_LIO_LILFD testing reduced HCW absenteeism and nosocomial infections in NHS acute trusts; it was also cost effective in preventing nosocomial infections. C_LI What do these findings mean?O_LIOur analysis of the available data indicated that testing HCWs had varying impacts (on both nosocomial infections and HCW FTE days lost due to COVID-19) throughout the pandemic, possibly influenced by external factors such as community prevalence and vaccination. C_LIO_LIIn any future pandemic, HCW testing interventions should incorporate collection of and/or timely access to relevant data, including HCW absenteeism, routine test results, community prevalence, and hospitalisation and mortality data. C_LIO_LIThe lessons learnt from this study could be used by relevant authorities to support the real-time assessment of any testing service and adjustment of the testing regimen; they could also be used to help develop more targeted and agile testing systems, which operationally would require the ability to turn mass testing off and on as an epidemic progressed. C_LI

Respiratory Syncytial Virus (RSV) burden in adults is of interest due to recently-licensed vaccines, however, estimates are affected by test characteristics. We conducted a prospective cohort study of adults with acute lower respiratory tract disease (aLRTD) hospitalised in Bristol from April 2022-March 2023. RSV was detected by RT-PCR at standard-of-care and by additional nasopharyngeal, saliva, and sputum samples. Latent class analysis quantified and adjusted for test error and multiple testing. 6906/11445 aLRTD cases (60%) were tested and 251 were positive (3.6%). Test-positivity peaked in December (7.9-12.7%). Among cases, 43% had pneumonia and 55% had non-pneumonic infection. Due to low positivity-rates and imperfect specificity, test-positivity (3.6%) overestimated true prevalence (2.3%). Adjusted adult population incidence/1000-person-years was 0.33 (0.21-0.49), and 2.02 (1.10-3.06) in [&ge;]75-year-olds. RSV vaccines could reduce morbidity of hospitalised adult aLRTD, including non-pneumonic infection. Adult RSV burden accuracy is improved by adjustment for test characteristics, particularly estimates out-of-season.

Control of SARS-CoV-2 transmission is complicated by the emergence of variants, especially those containing mutations in the spike protein. By enhancing infectivity and evading immunity, infection with these variants might result in more severe clinical outcomes as well as being more resistant to vaccines developed on the basis of the original prototypic virus variant. One such example is the alpha variant (B.1.1.7), which has been detected in more than 100 countries and rapidly become the dominant strain in the UK in late 2020 and early 2021. There is an urgent need to develop appropriate surveillance programmes to rapidly monitor the spread of variants and to better understand the role of variants in disease outcomes and immune evasion. The nucleotide sequencing method, the gold standard of variant detection, is unsuitable as a fast-response surveillance tool by frontline diagnostic services which require detection methods with short turnaround times. We developed a screening protocol based of sequential allele-specific qPCR for detection of the N501Y mutation and H69/V70 deletion present in the alpha/B.1.1.7 variant. We tested this protocol in previously confirmed positive samples from the Pathology Dept, University Hospital Coventry and Warwickshire during the second wave period in the UK (December 2020-March 2021). In these samples variant identity was confirmed by NGS sequencing via COG-UK. Our results identified increased incidence of variants containing both N501Y and {Delta}69/70 HV mutations, especially in patients admitted during January and early February 2021. This approach, which yields results within 3 hours, can be used as an initial rapid screening step with NGS as confirmatory follow-up. We also report that the increased prevalence of alpha/B.1.1.7 variant in admitted patients since mid-January 2021, a period that characterised peaked mortality rates, was associated with a sharp 2.5-fold rise in the mean circulating IL-6 level and to a lesser extent Troponin-T. More detailed biomarker analysis of a small cohort of patients (n=83), where variant status and clinical outcomes were available, demonstrated that deceased patients infected with the alpha/B.1.1.7 variant had significantly higher levels of inflammation and cell injury markers, especially IL-6 and LDH, compared to deceased patients infected with a non-alpha/B.1.1.7 variant, pointing towards a more severe inflammatory disease phenotype. In contrast, both groups survivors most biomarker exhibited levels below the group average, with distinct patterns of modified z-scores present.

BackgroundSeveral community-based studies have assessed the ability of different symptoms to identify COVID-19 infections, but few have compared symptoms over time (reflecting SARS-CoV-2 variants) and by vaccination status. MethodsUsing data and samples collected by the COVID-19 Infection Survey at regular visits to representative households across the UK, we compared symptoms in new PCR-positives and comparator test-negative controls. ResultsFrom 26/4/2020-7/8/2021, 27,869 SARS-CoV-2 PCR-positive episodes occurred in 27,692 participants (median 42 years (IQR 22-58)); 13,427 (48%) self-reported symptoms ("symptomatic positive episodes"). The comparator group comprised 3,806,692 test-negative visits (457,215 participants); 130,612 (3%) self-reported symptoms ("symptomatic negative visit"). Reporting of any symptoms in positive episodes varied over calendar time, reflecting changes in prevalence of variants, incidental changes (e.g. seasonal pathogens, schools re-opening) and vaccination roll-out. There was a small increase in sore throat reporting in symptomatic positive episodes and negative visits from April-2021. After May-2021 when Delta emerged there were substantial increases in headache and fever in positives, but not in negatives. Although specific symptom reporting in symptomatic positive episodes vs. negative visits varied by age, sex, and ethnicity, only small improvements in symptom-based infection detection were obtained; e.g. adding fatigue/weakness or all eight symptoms to the classic four symptoms (cough, fever, loss of taste/smell) increased sensitivity from 74% to 81% to 90% but tests per positive from 4.6 to 5.3 to 8.7. ConclusionsWhilst SARS-CoV-2-associated symptoms vary by variant, vaccination status and demographics, differences are modest and do not warrant large-scale changes to targeted testing approaches given resource implications. SummaryWithin the COVID-19 Infection Survey, recruiting representative households across the UK general population, SARS-CoV-2-associated symptoms varied by viral variant, vaccination status and demographics. However, differences are modest and do not currently warrant large-scale changes to targeted testing approaches.

We investigated anti-spike IgG antibody responses and correlates of protection following second doses of ChAdOx1 or BNT162b2 SARS-CoV-2 vaccines in the UK general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, while declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2-3 months after two ChAdOx1 doses and 5-8 months after two BNT162b2 doses in those without prior infection, and 1-2 years for those unvaccinated after natural infection. A third booster dose may be needed, prioritised to ChAdOx1 recipients and those more clinically vulnerable.

Polymerase Chain Reaction ("PCR") tests have been used to identify cases of COVID-19 during the course of the pandemic. Notably, PCR alone cannot differentiate between the presence of whole viruses (which can be transmitted and infect individuals) and small fragments of genetic material that are not infectious. A feature of PCR known as the cycle threshold (Ct) can be used to discriminate between these states, but the relationship between Ct and infectiousness is still poorly understood. This well-known limitation of the test compromises the identification of cases and their trends, and consequently those measures to interrupt transmission (such as isolation) that are undertaken on the basis of reliably identifying infectious individuals. Here, we interrogate the public authorities understanding of PCR testing for SARS-CoV-2 in the UK by accessing Freedom of Information requests submitted in 2020-21.We searched WhatDoTheyKnow and found 300 FOI requests, from over 150 individuals. We grouped their questions into four themes addressing the number of tests in use, the reporting of cycle thresholds ( Ct), the Ct values themselves, and the accuracy of tests. The number of validated tests in use in the UK is currently not clear: In FOI responses, Public Health England (PHE) report it may be "80" or "85". However, European regulations suggest there could be over 400 different CE marked tests available on the market and available for use. Laboratories have a statutory duty to report positive cases to PHE, but they do not have to advise which tests they are using nor submit Ct values. Only two FOI responses provided answers on Ct values, indicating that in a set time span, 24-38% of the Ct values were over 30. The most common FOI asked if there was a cycle threshold for positivity. In those that responded, the Ct for a positive result varied from 30 to 45. We found limited information on the technical accuracy of the tests. Several responses stated there is no static, specific or standard cycle threshold. The current system requires significant changes to ensure it offers accurate diagnostic data to enable effective clinical management of SARS-CoV-2. PCR is an important and powerful tool, but its systematic misuse and misreporting risk undermining its usefulness and credibility.

The Omicron sub-lineages BA.4 and BA.5 were first detected in England in April 2022. A case surge followed despite England having recently experienced waves with BA.1 and BA.2. This study used a whole population test-negative case-control study design to estimate the effectiveness of the vaccines currently in use as part of the UK COVID-19 vaccination programme against hospitalisation following infection with BA.4 and BA.5 as compared to BA.2 during a period of co-circulation. Incremental VE was estimated in those vaccinated with either a third or fourth dose as compared to individuals with waned immunity who had received their second dose at least 25 weeks prior. Vaccination status was included as an independent variable and effectiveness was defined as 1-odds of vaccination in cases/odds of vaccination in controls. During the study period, there were 32,845 eligible tests from hospitalised individuals. Of these, 25,862 were negative (controls), 3,432 were BA.2, 273 were BA.4, 947 were BA.5 and 2,331 were either BA.4 or BA.5 cases. There was no evidence of reduced VE against hospitalisation for BA.4 or BA.5 as compared to BA.2. The incremental VE was 56.8% (95% C.I.; 24.0-75.4%), 59.9% (95% C.I.; 45.6-70.5%) and 52.4% (95% C.I.; 43.2-60.1%) for BA.4, BA.5 and BA.2, respectively, at 2 to 14 weeks after a third or fourth dose. VE against hospitalisation with BA.4/5 or BA.2 was slightly higher for the mRNA-1273 booster than the BNT162b2 booster at all time-points investigated, but confidence intervals overlapped. These data provide reassuring evidence of the protection conferred by the current vaccines against severe disease with BA.4 and BA.5.

IntroductionSeveral viral respiratory infections - notably influenza - are associated with secondary bacterial infection and additional pathology. The extent to which this applies for COVID-19 is unknown. Accordingly, we aimed to define the bacteria causing secondary pneumonias in COVID-19 ICU patients using the FilmArray Pneumonia Panel, and to determine this tests potential in COVID-19 management. MethodsCOVID-19 ICU patients with clinically-suspected secondary infection at 5 UK hospitals were tested with the FilmArray at point of care. We collected patient demographic data and compared FilmArray results with routine culture. ResultsWe report results of 110 FilmArray tests on 94 patients (16 had 2 tests): 69 patients (73%) were male, the median age was 59 yrs; 92 were ventilated. Median hospital stay before testing was 14 days (range 1-38). Fifty-nine (54%) tests were positive, with 141 bacteria detected. Most were Enterobacterales (n=55, including Klebsiella spp. [n= 35]) or Staphylococcus aureus (n=13), as is typical of hospital and ventilator pneumonia. Community pathogens, including Haemophilus influenzae (n=8) and Streptococcus pneumoniae (n=1), were rarer. FilmArray detected one additional virus (Rhinovirus/Enterovirus) and no atypical bacteria. Fewer samples (28 % vs. 54%) were positive by routine culture, and fewer species were reported per sample; Klebsiella species remained the most prevalent pathogens. ConclusionFilmArray had a higher diagnostic yield than culture for ICU COVID-19 patients with suspected secondary pneumonias. The bacteria found mostly were Enterobacterales, S. aureus and P. aeruginosa, as in typical HAP/VAP, but with Klebsiella spp. more prominent. We found almost no viral co-infection. Turnaround from sample to results is around 1h 15 min compared with the usual 72h for culture, giving prescribers earlier data to inform antimicrobial decisions.

BackgroundCentral nervous system (CNS) infections are common causes of morbidity and mortality worldwide. Rapid, accurate identification of the likely cause is essential for clinical management and the early initiation of antimicrobial therapy, which potentially improves clinical outcome. MethodsWe applied liquid chromatography tandem mass-spectrometry on 45 cerebrospinal fluid (CSF) samples from a cohort of adults with/without CNS infections to discover potential diagnostic protein biomarkers. We then validated the diagnostic performance of a selected biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS infections admitted to a referral hospital in southern Vietnam. ResultsIn the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of bacterial meningitis. The analysis of the validation cohort showed that LCN2 could discriminate bacterial meningitis from other CNS infections, including tuberculous meningitis, cryptococcal meningitis and viral/antibody-mediated encephalitis (sensitivity: 0.88 (95% confident interval (CI): 0.77-0.94), specificity: 0.91 (95%CI: 0.88-0.94) and diagnostic odd ratio: 73.8 (95%CI: 31.8-171.4)). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) commonly used in routine care worldwide. The combination of LCN2 and these four routine CSF markers resulted in the highest diagnostic performance for bacterial meningitis (area under receiver-operating-characteristic-curve 0.96; 95%CI: 0.93-0.99). ConclusionsOur results suggest that LCN2 is a sensitive and specific biomarker for discriminating bacterial meningitis from a broad spectrum of CNS infections. A prospective study is needed to further assess the diagnostic utility of LCN2 in the diagnosis and management of CNS infections.

The appearance of the SARS-CoV-2 lineage B.1.1.7 in the UK in late 2020, associated with faster transmission, sparked the need to find effective ways to monitor its spread. The set of mutations that characterise this lineage include a deletion in position 69 and 70 of the spike protein, which is known to be associated with Spike Gene Target Failure (SGTF) in a commonly used three gene diagnostic qPCR assay. The lower cost and faster turnaround times compared to whole genome sequencing make the use of qPCR for monitoring of the variant spread an attractive proposition. However, there are several potential issues with this approach. Here we use 826 SARS-CoV-2 samples collected in a hospital setting as part of the Hospital Onset COVID Infection (HOCI) study where qPCR was used for viral detection, followed by whole genome sequencing (WGS), to identify the factors to consider when using SGTF to infer lineage B.1.1.7 prevalence in a hospital setting, with potential implications for locations where this variant has recently been introduced.

The availability of early serological assays for COVID-19 infection allows investigation of aspects of SARS-CoV-2 transmission which may not be evident on PCR testing. Here we describe two serological surveys in different settings in 2020 which assess the effectiveness of local infection prevention practices: i) a retrospective cohort of household contacts previously quarantined; and ii) health care workers in a tertiary hospital. Serological testing of household contacts did not diagnose any additional cases to that which had been notified by testing symptomatic contacts with PCR. The secondary household attack rate for these 53 contacts from 42 households was 36.2% (95% CI: 37.4, 74.5%). Sero-positivity in health care workers increased from 0.5% in May 2020 to 3.8-5.5% in August to October 2020. Multivariate analysis demonstrated that male HCW were less likely to be sero-positive (OR 0.19 95% CI 0.03-0.7, p=0.04), while there was an increased risk of sero-positivity associated with nursing staff (OR 8.1 95% CI 1.7-145.6, p=0.04), staff who experience anosmia (OR 22.7, 95% CI 5.4-112.4, p < 0.001); and those caring for COVID-19 patients (OR 4.1 95% CI 1.8-10.5, p=0.01). In this low prevalence setting with rapid access to PCR testing, serological testing provided a small additional benefit to PCR testing alone. Measures to detect COVID-19 cases in household contacts were found to be sufficient, while infection control measures during a period with a high burden of cases in a tertiary hospital were found to be inadequate to prevent COVID-19 infections in health care workers.

BackgroundWe have successfully used whole-genome sequencing to provide additional information for transmission pathways in infectious spread. We report and interpret genomic sequencing results in clinical context from a large outbreak of COVID-19 with 46 cases across staff and patients in a community hospital in the UK. MethodsFollowing multiple symptomatic cases within a two-week period, all staff and patients were screened by RT-PCR and staff subsequently had serology tests. ResultsThirty staff (25%) and 16 patients (62%) tested positive for COVID-19. Genomic sequencing data showed significant overlap of viral haplotypes in staff who had overlapping shift patterns. Patient haplotypes were more distinct from each other but had overlap with staff haplotypes. ConclusionsThis study includes clinical and genomic epidemiological detail that demonstrates the value of a combined approach. Viral genetic sequencing has identified that staff transmission of COVID-19 was important in this community hospital outbreak. Key pointsO_LIDetailed analysis of a large community hospital outbreak in older adults and staff with concurrent clinical and genomic data, including working patterns. C_LIO_LIStaff transmission was important in this community hospital outbreak. C_LIO_LIWe found plausible associations between staff and patient cases. C_LI

BackgroundEngland exited a four-week second national lockdown on 2nd December 2020 initiated in response to the COVID-19 pandemic. Prior results showed that prevalence dropped during the first half of lockdown, with greater reductions in higher-prevalence northern regions. MethodsREACT-1 is a series of community surveys of SARS-CoV-2 RT-PCR swab-positivity in England, designed to monitor the spread of the epidemic and thus increase situational awareness. Round 7 of REACT-1 commenced swab-collection on 13th November 2020. A prior interim report included data from 13th to 24th November 2020 for 105,122 participants. Here, we report data for the entire round with swab results obtained up to 3rd December 2020. ResultsBetween 13th November and 3rd December (round 7) there were 1,299 positive swabs out of 168,181 giving a weighted prevalence of 0.94% (95% CI 0.87%, 1.01%) or 94 per 10,000 people infected in the community in England. This compares with a prevalence of 1.30% (1.21%, 1.39%) from 16th October to 2nd November 2020 (round 6), a decline of 28%. Prevalence during the latter half of round 7 was 0.91% (95% CI, 0.81%, 1.03%) compared with 0.96% (0.87%, 1.05%) in the first half. The national R number in round 7 was estimated at 0.96 (0.88, 1.03) with a decline in prevalence observed during the first half of this period no longer apparent during the second half at the end of lockdown. During round 7 there was a marked fall in prevalence in West Midlands, a levelling off in some regions and a rise in London. R numbers at regional level ranged from 0.60 (0.41, 0.80) in West Midlands up to 1.27 (1.04, 1.54) in London, where prevalence was highest in the east and south-east of the city. Nationally, between 13th November and 3rd December, the highest prevalence was in school-aged children especially at ages 13-17 years at 2.04% (1.69%, 2.46%), or approximately 1 in 50. ConclusionBetween the previous round and round 7 (during lockdown), there was a fall in prevalence of SARS-CoV-2 swab-positivity nationally, but it did not fall uniformly over time or by geography. Continued vigilance is required to reduce rates of infection until effective immunity at the population level can be achieved through the vaccination programme.